Pharmacogenetic Results: Clinical Implications and Recommendations
These pharmacogenetic clinical implications and recommendations are based on the Clinical Pharmacogenetic Implementation Consortium (CPIC) Guidelines, FDA Table of Pharmacogenetic Associations, and FDA labeling. The pharmacogenetic results and accompanying clinical implications and therapeutic recommendations predict the function of drug metabolizing enzymes, drug transporters, and drug target proteins based on the genetic variants that encode these proteins.
Note: This information is based on genotype alone and does not consider possible phenoconversion. Phenoconversion occurs when a patient is taking a medication that induces or inhibits the drug metabolizing enzyme, which can change the predicted phenotype.
Pharmacogenetic test results, their predicted clinical implications, and recommendations should be used as a tool and one piece of information along with other patient-specific factors (e.g., renal function, hepatic function, sex, environment, comorbid diseases) to make prescribing decisions.
CYP2D6, CYP2C19 and Tertiary Amine Tricyclic Antidepressants (TCAs): Amitriptyline, Clomipramine, Doxepin, Imipramine, Trimipramine
These recommendations only apply when using higher doses for treatment of conditions such as depression. For neuropathic pain where lower doses are used, no dose modifications are recommended, however intermediate and poor metabolizers may have increased risk of side effects and ultra rapid metabolizers have an increased risk of failing therapy. Evidence for these recommendations is primarily based on amitriptyline evidence, but because of comparable pharmacokinetics, it is reasonable to apply to other tertiary amines as well.
Strong and moderate inhibitors of CYP2D6 (bupropion, fluoxetine, paroxetine, quinidine, terbinafine, cinacalcet, duloxetine, mirabegron, abiraterone, and lorcaserin) can lead to phenoconversion. If a patient is taking one or more of the above listed medications (and that medication will not be discontinued prior to starting the new medication of interest), use the CYP2D6 Phenoconversion Calculator to determine the clinical phenotype and use that phenotype in the table below.
If either CYP2D6 or CYP2C19 genotypes are unavailable, scroll down in this table to the “Instructions for Unavailable Genotypes”.
Important Instructions: Please use CYP2D6 Activity Score to select the appropriate column and then CYP2C19 phenotype to select the appropriate row in the table below.
CYP2D6 Ultra Rapid Metabolizer Increased CYP2D6 enzyme activity. Increased risk of treatment failure based on CYP2D6 alone. | CYP2D6 Normal – Ultra Rapid Metabolizer* Normal to increased CYP2D6 enzyme activity. Possible increased risk of treatment failure based on CYP2D6 alone. | CYP2D6 Normal Metabolizer* Normal CYP2D6 enzyme activity. | CYP2D6 Intermediate Metabolizer* Decreased CYP2D6 enzyme activity. | CYP2D6 Poor Metabolizer No CYP2D6 enzyme activity. | |
CYP2C19 Ultra Rapid Metabolizer Increased CYP2C19 enzyme activity. | Avoid use of tertiary amines or if warranted, utilize therapeutic drug monitoring to guide dose adjustments. | Avoid use of tertiary amines or if warranted, utilize therapeutic drug monitoring to guide dose adjustments. | Consider alternative not metabolized by CYP2C19 e.g., secondary amine TCA (i.e., nortriptyline, desipramine). | Consider alternative not metabolized by CYP2C19 e.g., secondary amine TCA (i.e., nortriptyline, desipramine). | Avoid use of tertiary amines or if warranted, utilize therapeutic drug monitoring to guide dose adjustments. |
CYP2C19 Rapid Metabolizer Increased CYP2C19 enzyme activity. | Avoid use of tertiary amines or if warranted, utilize therapeutic drug monitoring to guide dose adjustments. | Avoid use of tertiary amines or if warranted, utilize therapeutic drug monitoring to guide dose adjustments. | Consider alternative not metabolized by CYP2C19 e.g., secondary amine TCA (i.e., nortriptyline, desipramine). | Consider alternative not metabolized by CYP2C19 e.g., secondary amine TCA (i.e., nortriptyline, desipramine). | Avoid use of tertiary amines or if warranted, utilize therapeutic drug monitoring to guide dose adjustments. |
CYP2C19 Normal Metabolizer Normal CYP2C19 enzyme activity. | Avoid use of tertiary amines or if warranted, titrate to higher target dose. | Avoid use of tertiary amines or if warranted, titrate to higher target dose. | Use standard doses of tertiary amines. | Decrease dose by 25%. | Avoid use of tertiary amines or if warranted, decrease dose by 50%. |
CYP2C19 Intermediate Metabolizer Decreased CYP2C19 enzyme activity. Reduced conversion to secondary amines but normal response expected based on CYP2C19 alone. | Avoid use of tertiary amines or if warranted, utilize therapeutic drug monitoring to guide dose adjustments. | Avoid use of tertiary amines or if warranted, utilize therapeutic drug monitoring to guide dose adjustments. | Use standard doses of tertiary amines. | Decrease dose by 25%, utilize therapeutic drug monitoring to guide dose adjustments. | Avoid use of tertiary amines or if warranted, decrease dose by 50%, utilize therapeutic drug monitoring to guide dose adjustments. |
CYP2C19 Poor Metabolizer No CYP2C19 enzyme activity. Greatly reduced conversion to secondary amines, which may affect response or adverse effects (e.g., anticholinergic, CNS, and cardiac) based on CYP2C19 alone | Avoid use of tertiary amines or if warranted, utilize therapeutic drug monitoring to guide dose adjustments. | Avoid use of tertiary amines or if warranted, utilize therapeutic drug monitoring to guide dose adjustments. | Avoid use of tertiary amines or if warranted, decrease dose by 50%. | Avoid use of tertiary amines or if warranted, utilize therapeutic drug monitoring to guide dose adjustments. | Avoid use of tertiary amines or if warranted, utilize therapeutic drug monitoring to guide dose adjustments. |
Instructions for Unavailable Genotypes If for CYP2C19 either Assay Failure, Unable to Genotype, or Unknown Phenotype are resulted or CYP2C19 was not genotyped, but CYP2D6 is available, follow across the CYP2C19 Normal Metabolizer row to the appropriate CYP2D6 phenotype for the recommendation. These recommendations may be affected by the patient’s unavailable CYP2C19 genotype; consider testing or repeat testing of CYP2C19 as appropriate. | |||||
Unable to Genotype or Assay Failure | The analysis failed to yield an informative result and thus no genotype is reported. | ||||
Unknown Phenotype | This individual is carrying at least one allele with uncertain/unknown function and the predicted phenotype cannot be determined at this time. | ||||
Resources | |||||
Reference: Hicks JK et al. Clin Pharmacol Ther. 2017 Jul;102(1):37-44. PMID: 27997040. |
*Some laboratories have started calling activity scores of 1.0 as Intermediate Metabolizers, however they are still classified as Normal Metabolizers with UF Health Pathology.
CYP2D6 and Atomoxetine
Strong and moderate inhibitors of CYP2D6 (bupropion, fluoxetine, paroxetine, quinidine, terbinafine, cinacalcet, duloxetine, mirabegron, abiraterone, and lorcaserin) can lead to phenoconversion. If a patient is taking one or more of the above listed medications (and that medication will not be discontinued prior to starting the new medication of interest), use the CYP2D6 Phenoconversion Calculator to determine the clinical phenotype and use that phenotype in the table below.
CYP2D6 Predicted Phenotype | Clinical Implication | Therapeutic Recommendation | Resources |
Ultra Rapid Metabolizer | Increased CYP2D6 enzyme activity. | For children: Use standard dose and titrations of atomoxetine, if no response nor adverse effects after 2 weeks, consider obtaining a peak plasma concentration (1–2 hours after dose administered). If < 200 ng/mL, consider a proportional increase in dose to approach 400 ng/ml up to either 1.4 mg/kg/day or 100 mg/day, whichever is less. | |
Normal – Ultra Rapid Metabolizer with an enzyme | Normal to increased CYP2D6 enzyme activity. For children and adults: | For children: Use standard dose and titrations of atomoxetine, if no response nor adverse effects after 2 weeks, consider obtaining a peak plasma concentration (1–2 hours after dose administered). If < 200 ng/mL, consider a proportional increase in dose to approach 400 ng/ml up to either 1.4 mg/kg/day or 100 mg/day, whichever is less. For adults: Use standard dose and titrations of atomoxetine, if no response after 2 weeks, consider obtaining a peak plasma concentration (1–2 hours after dose administered). If < 200 ng/mL, consider a proportional increase in dose to approach 400 ng/ml. Dosages above the maximum 100 mg/day may be needed to achieve target concentrations, though >120 mg/day has not been evaluated. | |
Normal Metabolizer with an enzyme Activity Score of 1.5-2.0* | Normal CYP2D6 enzyme activity. For children and adults: Increased risk of treatment failure. | For children: Use standard dose and titrations of atomoxetine, if no response nor adverse effects after 2 weeks, consider obtaining a peak plasma concentration (1–2 hours after dose administered). If < 200 ng/mL, consider a proportional increase in dose to approach 400 ng/ml up to either 1.4 mg/kg/day or 100 mg/day, whichever is less. | |
Normal Metabolizer with an enzyme Activity Score of 1.0* | Normal CYP2D6 enzyme activity. For children and adults: | For children: Use standard dose and titrations of atomoxetine, if no response nor adverse effects after 2 weeks, consider obtaining a peak plasma concentration (1–2 hours after dose administered). If < 200 ng/mL, consider a proportional increase in dose to approach 400 ng/ml up to either 1.4 mg/kg/day or 100 mg/day, whichever is less. | |
Intermediate Metabolizer | Decreased CYP2D6 enzyme activity. For children and adults: | For children: Initiate with standard dose (0.5 mg/kg/day) and maintain dose instead of titrating after 3 days, if no response nor adverse effects after 2 weeks, consider obtaining a plasma concentration (2–4 hours after dose administered). If < 200 ng/mL, consider a proportional dose increase to achieve a concentration to approach 400 ng/ml. Reduce dose if experiencing unacceptable adverse effects. | |
Poor Metabolizer | No CYP2D6 enzyme activity. For children and adults: | PMs will likely require lower doses For children: Initiate with standard dose (0.5 mg/kg/day) and maintain dose instead of titrating after 3 days, if no response nor adverse effects after 2 weeks, consider obtaining a plasma concentration (2–4 hours after dose administered). If < 200 ng/mL, consider a proportional dose increase to achieve a concentration to approach 400 ng/ml. Reduce dose if experiencing unacceptable adverse effects. | |
Unable to Genotype or Assay Failure | The analysis failed to yield an informative result and thus no genotype is reported. | ||
Unknown Phenotype | This individual is carrying at least one allele with uncertain/unknown function and the predicted phenotype cannot be determined at this time. | ||
Reference: Brown JT et al. Clin Pharmacol Ther. 2019 Jul;106(1):94-102. PMID: 30801677. |
*Some laboratories have started calling activity scores of 1.0 as Intermediate Metabolizers, however they are still classified as Normal Metabolizers with UF Health Pathology.
SLCO1B1 and Atorvastatin
To compare statin-associated musculoskeletal symptoms (SAMS) by statin intensities with doses for SLCO1B1 decreased and poor function to guide alternative statin selection, click here. For recommendations for patients on existing statin therapy, see footnote below table*
SLCO1B1 Predicted Phenotype | Clinical Implication | Therapeutic Recommendation | Resources | |
SLCO1B1 Increased Function | Increased SLCO1B1 transporter function. | Initiate standard dosing. | ||
SLCO1B1 Normal Function | Normal SLCO1B1 transporter function. | Initiate standard dosing. | ||
SLCO1B1 Decreased Function | Decreased SLCO1B1 transporter function. Moderate risk of statin-induced myopathy with 40 mg. High risk of statin-induced myopathy with 80 mg. | Initiate ≤ 40 mg, if a dose > 40 mg is needed, consider combination therapy. | ||
SLCO1B1 Poor Function | No SLCO1B1 transporter function. | Initiate ≤ 20mg, if a dose > 20mg is needed, consider rosuvastatin (≤ 20mg) or combination therapy. | ||
Unable to Genotype or Assay Failure | The analysis failed to yield an informative result and thus no genotype is reported. | |||
Unknown Phenotype | This individual is carrying at least one allele with uncertain/unknown function and the predicted phenotype cannot be dtermined at this time. | |||
Reference: Cooper-DeHoff RM et al. Clin Pharmacol Ther. 2022 May;111(5):1007-1021. PMID: 35152405. |
*Recommendations for patients on existing statin therapy:
For patients who are currently taking a statin with moderate risk of statin-induced myopathy, if the statin has been continued at a stable dose for 4 weeks without symptoms suggestive of statin-induced myopathy it may be reasonable to continue the current statin therapy, while if dosing has continued for less than 4 weeks clinicians can consider changing the statin or dose to a regimen with lower risk that meets the appropriate guideline recommended intensity.
For patients who are currently taking a statin with high risk of statin-induced myopathy, if the statin has been continued at a stable dose for at least 1 year without symptoms suggestive of statin-induced myopathy it may be reasonable to continue the current statin therapy, while if dosing has continued for less than one year clinicians can consider changing the statin or dose to regimen with lower risk that meets the appropriate guideline recommended intensity.
To see statins with moderate and high risk of statin-induced myopathy, click here.
TPMT, NUDT15 and Azathioprine
If either TPMT or NUDT15 genotypes are unavailable, scroll down in this table to the “Instructions for Unavailable Genotypes”.
TPMT Normal Metabolizer Normal TPMT enzyme activity. | TPMT Intermediate Metabolizer Decreased TPMT enzyme activity. | TPMT Poor – Intermediate Metabolizer Decreased to no TPMT enzyme activity. | TPMT Poor Metabolizer No TPMT enzyme activity. | |
NUDT15 Normal Metabolizer Normal NUDT15 enzyme activity. | Start with normal starting dose per disease-specific guidelines. Allow 2 weeks to reach steady-state after each dose adjustment. | Reduce starting doses by 30–80%. Allow 2–4 weeks to reach steady-state after each dose adjustment. | For malignant conditions: For nonmalignant conditions: | For malignant conditions: For nonmalignant conditions: |
NUDT15 Intermediate Metabolizer Decreased NUDT15 enzyme activity. | Reduce starting doses by 30-80%. Allow 2–4 weeks to reach steady-state after each dose adjustment. | Reduce starting doses by 30-80%. Allow 2–4 weeks to reach steady-state after each dose adjustment. Due to the additive effect of both genes may require further dose reduction. | For malignant conditions: Start with drastically reduced doses (reduce daily dose by 10-fold and dose thrice weekly instead of daily). Allow 4–6 weeks to reach steady-state after each dose adjustment. For nonmalignant conditions: Consider alternative nonthiopurine immunosuppressant therapy. | For malignant conditions: Start with drastically reduced doses (reduce daily dose by 10-fold and dose thrice weekly instead of daily). Allow 4–6 weeks to reach steady-state after each dose adjustment. For nonmalignant conditions: Consider alternative nonthiopurine immunosuppressant therapy. |
NUDT15 Poor – Intermediate Metabolizer Decreased to no NUDT15 enzyme activity. | For malignant conditions: Start with drastically reduced doses (reduce daily dose by 10-fold). Allow 4–6 weeks to reach steady-state after each dose adjustment. For nonmalignant conditions: Consider alternative nonthiopurine immunosuppressant therapy. | For malignant conditions: Start with drastically reduced doses (reduce daily dose by 10-fold). Allow 4–6 weeks to reach steady-state after each dose adjustment. For nonmalignant conditions: | For malignant conditions: Start with drastically reduced doses (reduce daily dose by 10-fold and dose thrice weekly instead of daily). Allow 4–6 weeks to reach steady-state after each dose adjustment. For nonmalignant conditions: Consider alternative nonthiopurine immunosuppressant therapy. | For malignant conditions: Start with drastically reduced doses (reduce daily dose by 10-fold and dose thrice weekly instead of daily). Allow 4–6 weeks to reach steady-state after each dose adjustment. For nonmalignant conditions: Consider alternative nonthiopurine immunosuppressant therapy. |
NUDT15 Poor Metabolizer No NUDT15 enzyme activity. | For malignant conditions: Start with drastically reduced doses (reduce daily dose by 10-fold). Allow 4–6 weeks to reach steady-state after each dose adjustment. For nonmalignant conditions: | For malignant conditions: Start with drastically reduced doses (reduce daily dose by 10-fold). Allow 4–6 weeks to reach steady-state after each dose adjustment. For nonmalignant conditions: Consider alternative nonthiopurine immunosuppressant therapy. | For malignant conditions: Start with drastically reduced doses (reduce daily dose by 10-fold and dose thrice weekly instead of daily). Allow 4–6 weeks to reach steady-state after each dose adjustment. For nonmalignant conditions: | For malignant conditions: Start with drastically reduced doses (reduce daily dose by 10-fold and dose thrice weekly instead of daily). Allow 4–6 weeks to reach steady-state after each dose adjustment. For nonmalignant conditions: |
Instructions for Unavailable Genotypes If for NUDT15 either Assay Failure, Unable to Genotype, or Unknown Phenotype are resulted or NUDT15 was not genotyped, but TPMT is available, follow across the NUDT15 Normal Metabolizer row to the appropriate TPMT phenotype for the recommendation. These recommendations may be affected by the patient’s unavailable NUDT15 genotype; consider testing or repeat testing of NUDT15 as appropriate. | ||||
Unable to Genotype or Assay Failure | The analysis failed to yield an informative result and thus no genotype is reported. | |||
Unknown Phenotype | This individual is carrying at least one allele with uncertain/unknown function and the predicted phenotype cannot be determined at this time. | |||
Resources | ||||
Reference: Relling MV et al. Clin Pharmacol Ther. 2019 May;105(5):1095-1105. PMID: 30447069. |
DPYD and Capecitabine, Fluorouracil
DPYD Predicted Phenotype | Clinical Implication | Therapeutic Recommendation | Resources |
Normal Metabolizer | Normal DPD enzyme activity. | Use standard dose of fluoropyrimidines. | |
Intermediate Metabolizer with an enzyme | Decreased DPD enzyme activity. | Reduce starting dose by 50%, thereafter titrate dose based on toxicity tolerance or therapeutic drug monitoring. | |
Intermediate Metabolizer with an enzyme Activity Score 1.0 | Decreased DPD enzyme activity. | Reduce starting dose by 25 to 50%, thereafter titrate dose based on toxicity tolerance or therapeutic drug monitoring. | |
Poor Metabolizer with an enzyme | Little to no DPD enzyme activity. Very high risk for severe or even fatal drug toxicity (e.g. neutropenia, diarrhea, stomatitis, mucositis, hand-foot syndrome). | Avoid fluoropyrimidines and use alternative agent. If alternatives are not appropriate and phenotype testing is unavailable to estimate starting dose, may consider an initial dose reduction of 75% and utilize therapeutic drug monitoring. | |
Poor Metabolizer with an enzyme | Little to no DPD enzyme activity. | Avoid fluoropyrimidines and use alternative agent. | |
Unable to Genotype or Assay Failure | The analysis failed to yield an informative result and thus no genotype is reported. | ||
Reference: Amstutz U et al. Clin Pharmacol Ther. 2018 Feb;103(2):210-216. PMID: 29152729. |
CYP2C9 and Celecoxib, Flurbiprofen, Ibuprofen
CYP2C9 Predicted Phenotype Clinical Implication Therapeutic Recommendation Resources Normal Metabolizer (Normal Activity) Normal CYP2C9 enzyme activity. Initiate therapy with recommended starting dose. Intermediate Metabolizer (Decreased Activity) with an enzyme Activity Score of 1.5 Decreased CYP2C9 enzyme activity. Slightly increased risk of adverse events (e.g., GI bleed, cardiovascular). Initiate therapy with recommended starting dose. For ibuprofen, may consider initiating with a lower starting dose if CYP2C9 genotype includes *2. Intermediate Metabolizer (Decreased Activity) with an enzyme Activity Score 1.0 Decreased CYP2C9 enzyme activity. Initiate therapy with lowest starting dose and titrate dose upward to clinical effect or maximum recommended dose with caution. Additional caution should be implemented with ibuprofen if CYP2C9 genotype includes *2. Poor Metabolizer (Very Decreased Activity) Little to no CYP2C9 enzyme activity. Initiate therapy with a 25-50% initial dose reduction and titrate slowly, up to 50% of the maximum recommended dose. Allow at least one week between dose titrations. Alternatively, consider an alternate NSAID not metabolized by CYP2C9 (e.g., aspirin, ketorolac, naproxen, and sulindac). Unable to Genotype or Assay Failure The analysis failed to yield an informative result and thus no genotype is reported. Unknown Phenotype This individual is carrying at least one allele with uncertain/unknown function and the predicted phenotype cannot be determined at this time. Reference: Theken KN et al. Clin Pharmacol Ther. 2020 Aug;108(2):191-200. PMID: 32189324.
Normal response expected.
In accordance with the prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals.
In accordance with the prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals.
Increased risk of adverse events (e.g., GI bleed, cardiovascular).
In accordance with the prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals.
Increased risk of adverse events (e.g., GI bleed, cardiovascular).
In accordance with the prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals.
CYP2D6, CYP2C19 and SSRIs (Fluvoxamine, Paroxetine, Citalopram, Escitalopram, Sertraline), Vortioxetine, Venlafaxine
Strong and moderate inhibitors of CYP2D6 (bupropion, fluoxetine, paroxetine, quinidine, terbinafine, cinacalcet, duloxetine, mirabegron, abiraterone, and lorcaserin) can lead to phenoconversion. If a patient is taking one or more of the above listed medications (and that medication will not be discontinued prior to starting the new medication of interest), use the CYP2D6 Phenoconversion Calculator to determine the clinical phenotype and use that phenotype in the table below. However, please note that several CYP2D6 inhibitors are SSRIs and will not cause self-inhibition that would warrant a treatment change (e.g., CYP2D6 Normal Metabolizer phenotype can still be followed to guide dosing of paroxetine).
If either CYP2D6 or CYP2C19 genotypes are unavailable, scroll down in this table to the “Instructions for Unavailable Genotypes”.
CYP2D6 Ultra Rapid Metabolizer | CYP2D6 Normal – Ultra Rapid Metabolizer* | CYP2D6 Normal Metabolizer* Normal CYP2D6 enzyme activity. | CYP2D6 Intermediate Metabolizer* Decreased CYP2D6 enzyme activity. | CYP2D6 Poor Metabolizer No CYP2D6 enzyme activity. | |
CYP2C19 Ultra Rapid Metabolizer | Clinical Implications: Increased risk of treatment failure with paroxetine, escitalopram, citalopram, and sertraline. Therapeutic Recommendation: Avoid paroxetine, escitalopram, citalopram, and potentially sertraline;
| Clinical Implications: Increased risk of treatment failure with escitalopram, citalopram, sertraline and possibly paroxetine. Therapeutic Recommendation: Avoid paroxetine, escitalopram, citalopram, and potentially sertraline; | Clinical Implications: Normal response expected with paroxetine, fluvoxamine, vortioxetine, and venlafaxine. Increased risk of treatment failure with escitalopram, citalopram, and sertraline Therapeutic Recommendation: Avoid escitalopram, citalopram, and potentially sertraline;
Consider non-CYP2C19 SSRI (i.e., paroxetine, fluoxetine, or fluvoxamine) as alternative because of patient’s CYP2D6 metabolizer status; Consider non-SSRI antidepressant (e.g., duloxetine, bupropion, venlafaxine). | Clinical Implications: Slightly increased risk of adverse effects/events (e.g., insomnia, GI dysfunction, sexual dysfunction, arrythmias) with paroxetine and fluvoxamine. Increased risk of treatment failure with escitalopram, citalopram, and sertraline Therapeutic Recommendation: Avoid escitalopram, citalopram, and potentially sertraline; AND Consider non-CYP2C19 SSRI (i.e., paroxetine, fluoxetine, or fluvoxamine) as alternative because of patient’s CYP2D6 metabolizer status; Consider non-SSRI antidepressant (e.g., duloxetine, bupropion, venlafaxine). | Clinical Implications: Increased risk of adverse effects/events (e.g., insomnia, GI dysfunction, sexual dysfunction, arrythmias) with paroxetine, fluvoxamine, vortioxetine, and venlafaxine. Increased risk of treatment failure with escitalopram, citalopram, and sertraline Therapeutic Recommendation: Avoid paroxetine, fluvoxamine, and venlafaxine OR decrease dose by 50% if use is warranted; AND Avoid vortioxetine OR utilize with a maximum dose of 10 mg/day; AND Avoid escitalopram, citalopram, and potentially sertraline; |
CYP2C19 Rapid Metabolizer | Clinical Implications: Increased risk of treatment failure with paroxetine, escitalopram, citalopram, and sertraline. Therapeutic Recommendation: Avoid paroxetine, escitalopram, citalopram, and potentially sertraline; Consider fluoxetine or non-SSRI antidepressant (e.g., venlafaxine, duloxetine, bupropion, or others). | Clinical Implications: Increased risk of treatment failure with escitalopram, citalopram, sertraline, and possibly paroxetine. Therapeutic Recommendation: Avoid paroxetine, escitalopram, citalopram, and potentially sertraline; Consider fluoxetine or non-SSRI antidepressant (e.g., venlafaxine, duloxetine, bupropion, or others). | Clinical Implications: Normal response expected with paroxetine, fluvoxamine, vortioxetine, and venlafaxine. Increased risk of treatment failure with escitalopram, citalopram, and sertraline Therapeutic Recommendation: Avoid escitalopram, citalopram, and potentially sertraline; Consider non-CYP2C19 SSRI (i.e., paroxetine, fluoxetine, or fluvoxamine) as alternative because of patient’s CYP2D6 metabolizer status; | Clinical Implications: Slightly increased risk of adverse effects/events (e.g., insomnia, GI dysfunction, sexual dysfunction, arrythmias) with paroxetine and fluvoxamine. Increased risk of treatment failure with escitalopram, citalopram, and sertraline. Therapeutic Recommendation: Avoid escitalopram, citalopram, and potentially sertraline; AND Consider non-CYP2C19 SSRI (i.e., paroxetine, fluoxetine, or fluvoxamine) as alternative because of patient’s CYP2D6 metabolizer status; Consider non-SSRI antidepressant (e.g., duloxetine, bupropion, venlafaxine). | Clinical Implications: Increased risk of adverse effects/events (e.g., insomnia, GI dysfunction, sexual dysfunction, arrythmias) with paroxetine, fluvoxamine, vortioxetine, and venlafaxine. Increased risk of treatment failure with escitalopram, citalopram, and sertraline Therapeutic Recommendation: Avoid paroxetine, fluvoxamine, and venlafaxine OR decrease dose by 50% if use is warranted; AND Avoid vortioxetine OR utilize with a maximum dose of 10 mg/day; AND Avoid escitalopram, citalopram, and potentially sertraline; |
CYP2C19 Normal Metabolizer | Clinical Implications: Increased risk of treatment failure with paroxetine. Normal response expected with escitalopram, citalopram, and sertraline. Therapeutic Recommendation: Avoid paroxetine; Consider non-CYP2D6 SSRI (e.g., sertraline, escitalopram, or citalopram) as alternative because of patient’s CYP2C19 metabolizer status; Consider non-SSRI antidepressant (e.g., duloxetine, bupropion, venlafaxine). | Clinical Implications: Possible increased risk of treatment failure with paroxetine. Normal response expected with escitalopram, citalopram, and sertraline. Therapeutic Recommendation: Avoid paroxetine; Consider non-CYP2D6 SSRI (e.g., sertraline, escitalopram, or citalopram) as alternative because of patient’s CYP2C19 metabolizer status; Consider non-SSRI antidepressant (e.g., duloxetine, bupropion, venlafaxine). | Clinical Implications: Normal response expected with paroxetine, fluvoxamine, vortioxetine, venlafaxine, escitalopram, citalopram, and sertraline. Therapeutic Recommendation: | Clinical Implications: Slightly increased risk of adverse effects/events (e.g., insomnia, GI dysfunction, sexual dysfunction, arrythmias) with paroxetine and fluvoxamine. Normal response expected with escitalopram, citalopram, and sertraline. Therapeutic Recommendation: | Clinical Implications: Increased risk of adverse effects/events (e.g., insomnia, GI dysfunction, sexual dysfunction, arrythmias) with paroxetine and fluvoxamine. Normal response expected with escitalopram, citalopram, and sertraline. Therapeutic Recommendation: Avoid paroxetine, fluvoxamine, and venlafaxine OR decrease dose by 50% if use is warranted; AND Avoid vortioxetine OR utilize with a maximum dose of 10 mg/day; AND Consider non-CYP2D6 SSRI (e.g., sertraline, escitalopram, or citalopram) as alternative because of patient’s CYP2C19 metabolizer status; Consider non-SSRI antidepressant (e.g., desvenlafaxine, duloxetine, bupropion, or others). |
CYP2C19 Intermediate Metabolizer | Clinical Implications: Increased risk of treatment failure with paroxetine. Slightly increased risk of adverse effects/events (e.g., insomnia, GI dysfunction, sexual dysfunction, arrythmias) with escitalopram, citalopram, and sertraline. Therapeutic Recommendation: Avoid paroxetine; Consider non-CYP2D6 SSRI (e.g., sertraline, escitalopram, or citalopram) as alternative because of patient’s CYP2C19 metabolizer status; | Clinical Implications: Possible increased risk of treatment failure with paroxetine. Slightly increased risk of adverse effects/events (e.g., insomnia, GI dysfunction, sexual dysfunction, arrythmias) with escitalopram, citalopram, and sertraline. Therapeutic Recommendation: Avoid paroxetine; Consider non-CYP2D6 SSRI (e.g., sertraline, escitalopram, or citalopram) as alternative because of patient’s CYP2C19 metabolizer status; | Clinical Implications: Normal response expected with paroxetine, fluvoxamine, vortioxetine, and venlafaxine. Slightly increased risk of adverse effects/events (e.g., insomnia, GI dysfunction, sexual dysfunction, arrythmias) with escitalopram, citalopram, and sertraline. Therapeutic Recommendation: Use these SSRIs, vortioxetine, and venlafaxine at standard doses. | Clinical Implications: Slightly increased risk of adverse effects/events (e.g., insomnia, GI dysfunction, sexual dysfunction, arrythmias) with paroxetine, fluvoxamine, escitalopram, citalopram, and sertraline. Therapeutic Recommendation: Use these SSRIs, vortioxetine, and venlafaxine at standard doses. | Clinical Implications: Increased risk with paroxetine and fluvoxamine and slightly increased risk with escitalopram, citalopram, and sertraline of adverse effects/events (e.g., insomnia, GI dysfunction, sexual dysfunction, arrythmias). Therapeutic Recommendation: Avoid paroxetine, fluvoxamine, and venlafaxine OR decrease dose by 50% if use is warranted; AND Avoid vortioxetine OR utilize with a maximum dose of 10 mg/day; AND Consider non-CYP2D6 SSRI (e.g., sertraline, escitalopram, or citalopram) as alternative because of patient’s CYP2C19 metabolizer status; |
CYP2C19 Poor Metabolizer | Clinical Implications: Increased risk of treatment failure with paroxetine. Increased risk of adverse effects/events (e.g., insomnia, GI dysfunction, sexual dysfunction, arrythmias) with escitalopram, citalopram, and sertraline. Therapeutic Recommendation: Avoid sertraline, escitalopram, and citalopram OR decrease dose by 50% if use is warranted; AND Avoid paroxetine; Consider fluoxetine or non-SSRI antidepressant (e.g., venlafaxine, duloxetine, bupropion, or others). | Clinical Implications: Possible increased risk of treatment failure with paroxetine. Increased risk of adverse effects/events (e.g., insomnia, GI dysfunction, sexual dysfunction, arrythmias) with escitalopram, citalopram, and sertraline. Therapeutic Recommendation: Avoid sertraline, escitalopram, and citalopram OR decrease dose by 50% if use is warranted; AND Avoid paroxetine; AND Consider fluoxetine or non-SSRI antidepressant (e.g., venlafaxine, duloxetine, bupropion, or others). | Clinical Implications: Normal response expected with paroxetine, fluvoxamine, vortioxetine, and venlafaxine. Increased risk of adverse effects/events (e.g., insomnia, GI dysfunction, sexual dysfunction, arrythmias) with escitalopram, citalopram, and sertraline. Therapeutic Recommendation: Avoid sertraline, escitalopram, and citalopram OR decrease dose by 50% if use is warranted; AND Consider non-CYP2C19 SSRI (i.e., paroxetine, fluoxetine, or fluvoxamine) as alternative because of patient’s CYP2D6 metabolizer status; | Clinical Implications: Slightly increased risk with paroxetine and fluvoxamine and increased risk with escitalopram, citalopram, and sertraline of adverse effects/events (e.g., insomnia, GI dysfunction, sexual dysfunction, arrythmias). Therapeutic Recommendation: Avoid sertraline, escitalopram, and citalopram OR decrease dose by 50% if use is warranted; AND Consider non-CYP2C19 SSRI (i.e., paroxetine, fluoxetine, or fluvoxamine) as alternative because of patient’s CYP2D6 metabolizer status; | Clinical Implications: Increased risk of adverse effects/events (e.g., insomnia, GI dysfunction, sexual dysfunction, arrythmias) with paroxetine, fluvoxamine, vortioxetine, venlafaxine, escitalopram, citalopram, and sertraline. Therapeutic Recommendation: Avoid sertraline, escitalopram, citalopram, paroxetine, fluvoxamine, venlafaxine OR decrease dose by 50% if use is warranted; AND Avoid vortioxetine OR utilize with a maximum dose of 10 mg/day; AND |
Instructions for Unavailable Genotypes If for CYP2C19 either Assay Failure, Unable to Genotype, or Unknown Phenotype are resulted or CYP2C19 was not genotyped, but CYP2D6 is available, follow across the CYP2C19 Normal Metabolizer row to the appropriate CYP2D6 phenotype for the recommendation. These recommendations may be affected by the patient’s unavailable CYP2C19 genotype; consider testing or repeat testing of CYP2C19 as appropriate. | |||||
Unable to Genotype or Assay Failure | The analysis failed to yield an informative result and thus no genotype is reported. | ||||
Unknown Phenotype | This individual is carrying at least one allele with uncertain/unknown function and the predicted phenotype cannot be determined at this time. | ||||
Resources | |||||
*Some laboratories have started calling activity scores of 1.0 as Intermediate Metabolizers, however they are still classified as Normal Metabolizers with UF Health Pathology.
CYP2C19 and Clopidogrel
CYP2C19 Predicted Phenotype | Clinical Implication | Therapeutic Recommendation | Resources |
Ultra Rapid Metabolizer | Increased CYP2C19 enzyme activity. | Use standard dose of clopidogrel.* | |
Rapid Metabolizer | Increased CYP2C19 enzyme activity. | Use standard dose of clopidogrel.* | |
Normal Metabolizer | Normal CYP2C19 enzyme activity. | Use standard dose of clopidogrel. | |
Intermediate Metabolizer | Decreased CYP2C19 enzyme activity. | Avoid clopidogrel, if there are no contraindications use prasugrel (Effient) 10 mg daily OR use ticagrelor (Brilinta) 90 mg twice daily.* | |
Poor Metabolizer | No CYP2C19 enzyme activity. | Avoid clopidogrel, if there are no contraindications use prasugrel (Effient) 10 mg daily OR use ticagrelor (Brilinta) 90 mg twice daily. | |
Unable to Genotype or Assay Failure | The analysis failed to yield an informative result and thus no genotype is reported. | ||
Unknown Phenotype | This individual is carrying at least one allele with uncertain/unknown function and the predicted phenotype cannot be determined at this time. | ||
Reference: Lee CR et al. Clin Pharmacol Ther. 2022 Jan 16:10.1002/cpt.2526. PMID: 35034351. |
*The majority of evidence supporting recommendations is in the setting of ACS and PCI. For ultra rapid and rapid metabolizer predicted phenotypes there is limited evidence on clinical outcomes in neurovascular disease. For ultra rapid, rapid, and intermediate metabolizer predicted phenotypes there is limited evidence on clinical outcomes in non-ACS and non-PCI cardiovascular indications.
CYP2D6 and Codeine, Hydrocodone, Tramadol
Strong and moderate inhibitors of CYP2D6 (bupropion, fluoxetine, paroxetine, quinidine, terbinafine, cinacalcet, duloxetine, mirabegron, abiraterone, and lorcaserin) can lead to phenoconversion. If a patient is taking one or more of the above listed medications (and that medication will not be discontinued prior to starting the new medication of interest), use the CYP2D6 Phenoconversion Calculator to determine the clinical phenotype and use that phenotype in the table below.
CYP2D6 Predicted Phenotype | Clinical Implication | Therapeutic Recommendation | Resources |
Ultra Rapid Metabolizer | Increased CYP2D6 enzyme activity. | Use non-opioid if possible.** | |
Normal – Ultra Rapid Metabolizer* | Normal to increased CYP2D6 enzyme activity. | Use non-opioid if possible.** | |
Normal Metabolizer* | Normal CYP2D6 enzyme activity. | Use label recommended age-specific or weight-specific dosing. | |
Intermediate Metabolizer* | Decreased CYP2D6 enzyme activity. | Use non-opioid if possible.** | |
Poor Metabolizer | No CYP2D6 enzyme activity. | Use non-opioid if possible.** | |
Unable to Genotype or Assay Failure | The analysis failed to yield an informative result and thus no genotype is reported. | ||
Unknown Phenotype | This individual is carrying at least one allele with uncertain/unknown function and the predicted phenotype cannot be determined at this time. | ||
Reference: Crews KR et al., Clin Pharmacol Ther. 2021 Oct;110(4):888-896. PMID: 33387367. |
*Some laboratories have started calling activity scores of 1.0 as Intermediate Metabolizers, however they are still classified as Normal Metabolizers with UF Health Pathology.
**There is less evidence for this recommendation for hydrocodone.
CYP2D6 and Secondary Amine Tricyclic Antidepressants (TCAs): Nortriptyline, Desipramine
These recommendations only apply when using higher doses for treatment of conditions such as depression. For neuropathic pain where lower doses are used, no dose modifications are recommended, however intermediate and poor metabolizers may have increased risk of side effects and ultra rapid metabolizers have an increased risk of failing therapy. Evidence for these recommendations is primarily based on nortriptyline evidence, but because of comparable pharmacokinetics, it is reasonable to apply to other secondary amines as well.
Strong and moderate inhibitors of CYP2D6 (bupropion, fluoxetine, paroxetine, quinidine, terbinafine, cinacalcet, duloxetine, mirabegron, abiraterone, and lorcaserin) can lead to phenoconversion. If a patient is taking one or more of the above listed medications (and that medication will not be discontinued prior to starting the new medication of interest), use the CYP2D6 Phenoconversion Calculator to determine the clinical phenotype and use that phenotype in the table below.
CYP2D6 Predicted Phenotype | Clinical Implication | Therapeutic Recommendation | Resources |
Ultra Rapid Metabolizer | Increased CYP2D6 enzyme activity. | Avoid use of secondary amines or if warranted, titrate to higher target dose utilizing therapeutic drug monitoring. | |
Normal – Ultra Rapid Metabolizer* | Normal to increased CYP2D6 enzyme activity. Possible increased risk of treatment failure. | Avoid use of secondary amines or if warranted, titrate to higher target dose utilizing therapeutic drug monitoring. | |
Normal Metabolizer* | Normal CYP2D6 enzyme activity. | Use standard doses of secondary amines | |
Intermediate Metabolizer* | Decreased CYP2D6 enzyme activity. | Decrease dose by 25%, utilize therapeutic drug monitoring to guide dose adjustments. | |
Poor Metabolizer | No CYP2D6 enzyme activity. | Avoid use of secondary amines or if warranted, decrease dose by 50% and utilize therapeutic drug monitoring to guide dose adjustments. | |
Unable to Genotype or Assay Failure | The analysis failed to yield an informative result and thus no genotype is reported. | ||
Unknown Phenotype | This individual is carrying at least one allele with uncertain/unknown function and the predicted phenotype cannot be determined at this time. | ||
Reference: Hicks JK et al. Clin Pharmacol Ther. 2017 Jul;102(1):37-44. PMID: 27997040. |
*Some laboratories have started calling activity scores of 1.0 as Intermediate Metabolizers, however they are still classified as Normal Metabolizers with UF Health Pathology.
CYP2C19 and Omeprazole, Pantoprazole, Lansoprazole, Dexlansoprazole
CYP2C19 Predicted Phenotype | Clinical Implication | Therapeutic Recommendation | Resources |
Ultra Rapid Metabolizer | Increased CYP2C19 enzyme activity. | Increase PPI dose by 2 times the standard daily dose. | |
Rapid Metabolizer | Increased CYP2C19 enzyme activity. | For H. pylori infection or erosive esophagitis, increase PPI dose by 1.5-2 times the standard daily dose. | |
Normal Metabolizer | Normal CYP2C19 enzyme activity. | For H. pylori infection or erosive esophagitis, increase PPI dose by 1.5-2 times the standard daily dose. | |
Intermediate Metabolizer | Decreased CYP2C19 enzyme activity. | For chronic therapy, consider a 50% dose reduction once symptoms are controlled. | |
Poor Metabolizer | No CYP2C19 enzyme activity. | For chronic therapy, consider a 50% dose reduction once symptoms are controlled. | |
Unable to Genotype or Assay Failure | The analysis failed to yield an informative result and thus no genotype is reported. | ||
Unknown Phenotype | This individual is carrying at least one allele with uncertain/unknown function and the predicted phenotype cannot be determined at this time. | ||
Reference: Lima JJ et al. Clin Pharmacol Ther. 2021 Jun;109(6):1417-1423. PMID: 32770672. |
CYP2B6 and Efavirenz
CYP2B6 Predicted Phenotype | Clinical Implication | Therapeutic Recommendation | Resources |
Ultra Rapid Metabolizer | Increased CYP2B6 enzyme activity. | Initiate efavirenz with standard dosing (600 mg/day). | |
Rapid Metabolizer | Increased CYP2B6 enzyme activity. | Initiate efavirenz with standard dosing (600 mg/day). | |
Normal Metabolizer | Normal CYP2B6 enzyme activity. | Initiate efavirenz with standard dosing (600 mg/day). | |
Intermediate Metabolizer | Decreased CYP2B6 enzyme activity. | Initiate efavirenz with decreased dose of 400 mg/day and consider utilizing therapeutic drug monitoring, if available. | |
Poor Metabolizer | Little to no CYP2B6 enzyme activity. | Initiate efavirenz with decreased dose of 400 or 200 mg/day and consider utilizing therapeutic drug monitoring, if available. | |
Unable to Genotype or Assay Failure | The analysis failed to yield an informative result and thus no genotype is reported. | ||
Reference: Desta Z et al. Clin Pharmacol Ther. 2019 Oct;106(4):726-733. PMID: 31006110. |
SLCO1B1, CYP2C9 and Fluvastatin
To compare statin-associated musculoskeletal symptoms (SAMS) by statin intensities with doses for SLCO1B1 decreased and poor function to guide alternative statin selection, click here. For recommendations for patients on existing statin therapy, see footnote below table*
If either SLCO1B1 or CYP2C9 genotypes are unavailable, scroll down in this table to the “Instructions for Unavailable Genotypes”.
Predicted Phenotype | CYP2C9 Normal Metabolizer (Normal activity) Normal CYP2C9 enzyme activity | CYP2C9 Intermediate Metabolizer (Decreased activity) Decreased CYP2C9 enzyme activity. | CYP2C9 Poor Metabolizer (Very Decreased Activity) Little to no CYP2C9 enzyme activity. |
SLCO1B1 Increased Function Increased SLCO1B1 transporter function. Normal myopathy risk expected based on SLCO1B1 alone. | Initiate standard dosing. | Initiate ≤ 40 mg, if a dose >40 mg is needed, consider alternative statin or combination therapy. | Initiate ≤ 20 mg, if a dose >20 mg is needed, consider alternative statin or combination therapy. |
SLCO1B1 Normal Function Normal SLCO1B1 transporter function. Normal myopathy risk expected based on SLCO1B1 alone. | Initiate standard dosing. | Initiate ≤ 40 mg, if a dose >40 mg is needed, consider alternative statin or combination therapy. | Initiate ≤ 20 mg, if a dose >20 mg is needed, consider alternative statin or combination therapy. |
SLCO1B1 Decreased Function Decreased SLCO1B1 transporter function. Moderate risk of statin-induced myopathy with 80 mg based on SLCO1B1 alone. | Initiate standard dosing. | Initiate ≤ 20 mg, if a dose >20 mg is needed, consider alternative statin or combination therapy. | Initiate an alternative statin with lower myopathy risk based on SLCO1B1 (refer to figure to choose based on desired potency). |
SLCO1B1 Poor Function No SLCO1B1 transporter function. Moderate risk of statin-induced myopathy with 80 mg based on SLCO1B1 alone. | Initiate ≤ 40 mg, if dose > 40 mg is needed, consider higher dose, alternative statin, or combination therapy. | Initiate an alternative statin with lower myopathy risk based on SLCO1B1 (refer to figure to choose based on desired potency). | Initiate an alternative statin with lower myopathy risk based on SLCO1B1 (refer to figure to choose based on desired potency). |
Instructions for Unavailable Genotypes If for SLCO1B1 either Assay Failure, Unable to Genotype, or Unknown Phenotype are resulted or SLCO1B1 was not genotyped, but CYP2C9 is available, follow across the SLCO1B1 Normal Metabolizer row to the appropriate CYP2C9 phenotype for the recommendation. These recommendations may be affected by the patient’s unavailable SLCO1B1 genotype; consider testing or repeat testing of SLCO1B1 as appropriate. | |||
Unable to Genotype or Assay Failure | The analysis failed to yield an informative result and thus no genotype is reported. | ||
Unknown Phenotype | This individual is carrying at least one allele with uncertain/unknown function and the predicted phenotype cannot be determined at this time. | ||
Resources | |||
Reference: Cooper-DeHoff RM et al. Clin Pharmacol Ther. 2022 May;111(5):1007-1021. PMID: 35152405. |
*Recommendations for patients on existing statin therapy:
For patients who are currently taking a statin with moderate risk of statin-induced myopathy, if the statin has been continued at a stable dose for 4 weeks without symptoms suggestive of statin-induced myopathy it may be reasonable to continue the current statin therapy, while if dosing has continued for less than 4 weeks clinicians can consider changing the statin or dose to a regimen with lower risk that meets the appropriate guideline recommended intensity.
For patients who are currently taking a statin with high risk of statin-induced myopathy, if the statin has been continued at a stable dose for at least 1 year without symptoms suggestive of statin-induced myopathy it may be reasonable to continue the current statin therapy, while if dosing has continued for less than one year clinicians can consider changing the statin or dose to regimen with lower risk that meets the appropriate guideline recommended intensity.
To see statins with moderate and high risk of statin-induced myopathy, click here.
CYP2C9 and Phenytoin, Fosphenytoin
CYP2C9 Predicted Phenotype | Clinical Implication | Therapeutic Recommendation | Resources |
Normal Metabolizer (Normal Activity) | Normal CYP2C9 enzyme activity. | Use standard dose and adjust based on clinical factors. | |
Intermediate Metabolizer (Decreased Activity) with an enzyme Activity Score of 1.5 | Decreased CYP2C9 enzyme activity. | Use standard dose and adjust based on clinical factors | |
Intermediate Metabolizer (Decreased Activity) with an enzyme Activity Score 1.0 | Decreased CYP2C9 enzyme activity. | Use standard initial or loading dose for first dose, then use a ~25% dose reduction for subsequent doses. Thereafter, adjust according to therapeutic drug monitoring, response, and adverse effects. | |
Poor Metabolizer (Very Decreased Activity) | Little to no CYP2C9 enzyme activity. | Use standard initial or loading dose for first dose, then use a ~50% dose reduction for subsequent doses. Thereafter, adjust according to therapeutic drug monitoring, response, and adverse effects. | |
Unable to Genotype or Assay Failure | The analysis failed to yield an informative result and thus no genotype is reported. | ||
Unknown Phenotype | This individual is carrying at least one allele with uncertain/unknown function and the predicted phenotype cannot be determined at this time. | ||
Reference: Karnes JH et al. Clin Pharmacol Ther. 2021 Feb;109(2):302-309. PMID: 32779747. |
SLCO1B1 and Lovastatin
To compare statin-associated musculoskeletal symptoms (SAMS) by statin intensities with doses for SLCO1B1 decreased and poor function to guide alternative statin selection, click here. For recommendations for patients on existing statin therapy, see footnote below table*
SLCO1B1 Predicted Phenotype | Clinical Implication | Therapeutic Recommendation | Resources |
SLCO1B1 Increased Function | Increased SLCO1B1 transporter function. Normal myopathy risk expected. | Initiate standard dosing. | |
SLCO1B1 Normal Function | Normal SLCO1B1 transporter function. Normal myopathy risk expected. | Initiate standard dosing. | |
SLCO1B1 Decreased Function | Decreased SLCO1B1 transporter function. Moderate risk of statin-induced myopathy with 20 mg. High risk of statin-induced myopathy with 40-80 mg. | Consider an alternative statin associated with lower risk, if lovastatin is warranted, limit dose to ≤ 20 mg/day. | |
SLCO1B1 Poor Function | No SLCO1B1 transporter function. | Consider an alternative statin associated with lower risk. | |
Unable to Genotype or Assay Failure | The analysis failed to yield an informative result and thus no genotype is reported. | ||
Unknown Phenotype | This individual is carrying at least one allele with uncertain/unknown function and the predicted phenotype cannot be determined at this time. | ||
Reference: Cooper-DeHoff RM et al. Clin Pharmacol Ther. 2022 May;111(5):1007-1021. PMID: 35152405. |
*Recommendations for patients on existing statin therapy:
For patients who are currently taking a statin with moderate risk of statin-induced myopathy, if the statin has been continued at a stable dose for 4 weeks without symptoms suggestive of statin-induced myopathy it may be reasonable to continue the current statin therapy, while if dosing has continued for less than 4 weeks clinicians can consider changing the statin or dose to a regimen with lower risk that meets the appropriate guideline recommended intensity.
For patients who are currently taking a statin with high risk of statin-induced myopathy, if the statin has been continued at a stable dose for at least 1 year without symptoms suggestive of statin-induced myopathy it may be reasonable to continue the current statin therapy, while if dosing has continued for less than one year clinicians can consider changing the statin or dose to regimen with lower risk that meets the appropriate guideline recommended intensity.
To see statins with moderate and high risk of statin-induced myopathy, click here.
CYP2C9 and Meloxicam
CYP2C9 Predicted Phenotype | Clinical Implication | Therapeutic Recommendation | Resources |
Normal Metabolizer (Normal Activity) | Normal CYP2C9 enzyme activity. Normal response expected. | Initiate therapy with recommended starting dose. | |
Intermediate Metabolizer (Decreased Activity) with an enzyme Activity Score of 1.5 | Decreased CYP2C9 enzyme activity. Slightly increased risk of adverse events (e.g., GI bleed, cardiovascular). | Initiate therapy with recommended starting dose. | |
Intermediate Metabolizer (Decreased Activity) with an enzyme Activity Score 1.0 | Decreased CYP2C9 enzyme activity. | Initiate therapy with a 50% initial dose reduction and titrate slowly, up to 50% of the maximum recommended dose. Allow at least one week between dose titrations. OR Choose an alternative non-NSAID pain medication not metabolized by CYP2C9 (e.g. acetaminophen). OR If an NSAID is indicated, ibuprofen, celecoxib, or flurbiprofen can be used at the lowest starting dose and titrated. Other NSAIDs not metabolized by CYP2C9 can be used at standard doses (e.g., aspirin, ketorolac, naproxen, and sulindac). In accordance with the prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals. | |
Poor Metabolizer (Very Decreased Activity) | Little to no CYP2C9 enzyme activity. | Choose an alternative non-NSAID pain medication not metabolized by CYP2C9 (e.g. acetaminophen) OR If an NSAID is indicated, ibuprofen, celecoxib, or flurbiprofen can be used with a 25-50% initial dose reduction and slow titration up to 50% of the maximum recommended dose. Other NSAIDs not metabolized by CYP2C9 can be used at standard doses (e.g., aspirin, ketorolac, naproxen, and sulindac). In accordance with the prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals. | |
Unable to Genotype or Assay Failure | The analysis failed to yield an informative result and thus no genotype is reported. | ||
Unknown Phenotype | This individual is carrying at least one allele with uncertain/unknown function and the predicted phenotype cannot be determined at this time. | ||
Reference: Theken KN et al. Clin Pharmacol Ther. 2020 Aug;108(2):191-200. PMID: 32189324. |
TPMT, NUDT15 and Mercaptopurine
If either TPMT or NUDT15 genotypes are unavailable, scroll down in this table to the “Instructions for Unavailable Genotypes”.
TPMT Normal Metabolizer Normal TPMT enzyme activity. | TPMT Intermediate Metabolizer Decreased TPMT enzyme activity. | TPMT Poor – Intermediate Metabolizer Decreased to no TPMT enzyme activity. | TPMT Poor Metabolizer No TPMT enzyme activity. | |
NUDT15 Normal Metabolizer Normal NUDT15 enzyme activity. | Start with normal starting dose per disease-specific guidelines. Allow 2 weeks to reach steady-state after each dose adjustment. | Reduce starting doses by 30–80%. Allow 2–4 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing mercaptopurine over other agents. If normal starting dose is already < 75 mg/m2/day or < 1.5 mg/kg/day, dose reduction may not be recommended. | For malignant conditions: Start with drastically reduced doses (reduce daily dose by 10-fold and dose thrice weekly instead of daily). Allow 4–6 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing mercaptopurine over other agents. For nonmalignant conditions: Consider alternative nonthiopurine immunosuppressant therapy. | For malignant conditions: Start with drastically reduced doses (reduce daily dose by 10-fold and dose thrice weekly instead of daily). Allow 4–6 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing mercaptopurine over other agents. For nonmalignant conditions: |
NUDT15 Intermediate Metabolizer Decreased NUDT15 enzyme activity. | Reduce starting doses by 30–80%. Allow 2–4 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing mercaptopurine over other agents. | Reduce starting doses by 30–80%. Allow 2–4 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing mercaptopurine over other agents. If normal starting dose is already < 75 mg/m2/day or < 1.5 mg/kg/day, dose reduction may not be recommended. | For malignant conditions: Start with drastically reduced doses (reduce daily dose by 10-fold and dose thrice weekly instead of daily). Allow 4–6 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing mercaptopurine over other agents. For nonmalignant conditions: | For malignant conditions: Start with drastically reduced doses (reduce daily dose by 10-fold and dose thrice weekly instead of daily). Allow 4–6 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing mercaptopurine over other agents. For nonmalignant conditions: |
NUDT15 Poor – Intermediate Metabolizer Decreased to no NUDT15 enzyme activity. | For malignant conditions: Initiate dose at 10 mg/m2/day. Allow 4–6 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing mercaptopurine over other agents. For nonmalignant conditions: | For malignant conditions: Initiate dose at 10 mg/m2/day. Allow 4–6 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing mercaptopurine over other agents. For nonmalignant conditions: Consider alternative nonthiopurine immunosuppressant therapy. | For malignant conditions: Start with drastically reduced doses (reduce daily dose by 10-fold and dose thrice weekly instead of daily). Allow 4–6 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing mercaptopurine over other agents. For nonmalignant conditions: Consider alternative nonthiopurine immunosuppressant therapy. | For malignant conditions: Start with drastically reduced doses (reduce daily dose by 10-fold and dose thrice weekly instead of daily). Allow 4–6 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing mercaptopurine over other agents. For nonmalignant conditions: |
NUDT15 Poor Metabolizer No NUDT15 enzyme activity. | For malignant conditions: Initiate dose at 10 mg/m2/day. Allow 4–6 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing mercaptopurine over other agents. For nonmalignant conditions: Consider alternative nonthiopurine immunosuppressant therapy. | For malignant conditions: Initiate dose at 10 mg/m2/day. Allow 4–6 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing mercaptopurine over other agents. For nonmalignant conditions: | For malignant conditions: Start with drastically reduced doses (reduce daily dose by 10-fold and dose thrice weekly instead of daily). Allow 4–6 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing mercaptopurine over other agents. For nonmalignant conditions: | For malignant conditions: Start with drastically reduced doses (reduce daily dose by 10-fold and dose thrice weekly instead of daily). Allow 4–6 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing mercaptopurine over other agents. For nonmalignant conditions: |
Instructions for Unavailable Genotypes If for NUDT15 either Assay Failure, Unable to Genotype, or Unknown Phenotype are resulted or NUDT15 was not genotyped, but TPMT is available, follow across the NUDT15 Normal Metabolizer row to the appropriate TPMT phenotype for the recommendation. These recommendations may be affected by the patient’s unavailable NUDT15 genotype; consider testing or repeat testing of NUDT15 as appropriate. | ||||
Unable to Genotype or Assay Failure | The analysis failed to yield an informative result and thus no genotype is reported. | |||
Unknown Phenotype | This individual is carrying at least one allele with uncertain/unknown function and the predicted phenotype cannot be determined at this time. | |||
Resources | ||||
Reference: Relling MV et al. Clin Pharmacol Ther. 2019 May;105(5):1095-1105. PMID: 30447069. |
CYP2D6 and Ondansetron
Strong and moderate inhibitors of CYP2D6 (bupropion, fluoxetine, paroxetine, quinidine, terbinafine, cinacalcet, duloxetine, mirabegron, abiraterone, and lorcaserin) can lead to phenoconversion. If a patient is taking one or more of the above listed medications (and that medication will not be discontinued prior to starting the new medication of interest), use the CYP2D6 Phenoconversion Calculator to determine the clinical phenotype and use that phenotype in the table below.
CYP2D6 Predicted Phenotype | Clinical Implication | Therapeutic Recommendation | Resources |
Ultra Rapid Metabolizer | Increased CYP2D6 enzyme activity. | Select alternative 5-HT3 antagonist not metabolized by CYP2D6 (i.e., granisetron) or alternative anti-emetic as appropriate (e.g., promethazine). | |
Normal – Ultra Rapid Metabolizer | Normal to increased CYP2D6 enzyme activity. | Select alternative 5-HT3 antagonist not metabolized by CYP2D6 (i.e., granisetron) or alternative anti-emetic as appropriate (e.g., promethazine). | |
Normal Metabolizer | Normal CYP2D6 enzyme activity. | Use standard dose of ondansetron | |
Intermediate Metabolizer | Decreased CYP2D6 enzyme activity. | Use standard dose of ondansetron | |
Poor Metabolizer | No CYP2D6 enzyme activity. | Use standard dose of ondansetron. | |
Unable to Genotype or Assay Failure | The analysis failed to yield an informative result and thus no genotype is reported. | ||
Unknown Phenotype | This individual is carrying at least one allele with uncertain/unknown function and the predicted phenotype cannot be determined at this time. | ||
Reference: Bell GC et al. Clin Pharmacol Ther. 2017 Aug;102(2):213-218. PMID: 28002639. |
*Some laboratories have started calling activity scores of 1.0 as Intermediate Metabolizers, however they are still classified as Normal Metabolizers with UF Health Pathology.
CYP2C9 and Piroxicam
CYP2C9 Predicted Phenotype | Clinical Implication | Therapeutic Recommendation | Resources |
Normal Metabolizer (Normal Activity) | Normal CYP2C9 enzyme activity. | Initiate therapy with recommended starting dose. In accordance with the prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals | |
Intermediate Metabolizer (Decreased Activity) with an enzyme Activity Score of 1.5 | Decreased CYP2C9 enzyme activity. | Initiate therapy with recommended starting dose. | |
Intermediate Metabolizer (Decreased Activity) with an enzyme Activity Score 1.0 | Decreased CYP2C9 enzyme activity. | Choose an alternative non-NSAID pain medication not metabolized by CYP2C9 (e.g. acetaminophen) OR If an NSAID is indicated, ibuprofen, celecoxib, or flurbiprofen can be used at the lowest starting dose and titrated. Other NSAIDs not metabolized by CYP2C9 can be used at standard doses (e.g., aspirin, ketorolac, naproxen, and sulindac). In accordance with the prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals. | |
Poor Metabolizer (Very Decreased Activity) | Little to no CYP2C9 enzyme activity. | Choose an alternative non-NSAID pain medication not metabolized by CYP2C9 (e.g. acetaminophen) OR If an NSAID is indicated, ibuprofen, celecoxib, or flurbiprofen can be used with a 25-50% initial dose reduction and slow titration up to 50% of the maximum recommended dose. Other NSAIDs not metabolized by CYP2C9 can be used at standard doses (e.g., aspirin, ketorolac, naproxen, and sulindac). In accordance with the prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals. | |
Unable to Genotype or Assay Failure | The analysis failed to yield an informative result and thus no genotype is reported. | ||
Unknown Phenotype | This individual is carrying at least one allele with uncertain/unknown function and the predicted phenotype cannot be determined at this time. | ||
Reference: Theken KN et al. Clin Pharmacol Ther. 2020 Aug;108(2):191-200. PMID: 32189324. |
SLCO1B1 and Pitavastatin
To compare statin-associated musculoskeletal symptoms (SAMS) by statin intensities with doses for SLCO1B1 decreased and poor function to guide alternative statin selection, click here. For recommendations for patients on existing statin therapy, see footnote below table*
SLCO1B1 Predicted Phenotype | Clinical Implication | Therapeutic Recommendation | Resources |
SLCO1B1 Increased Function | Increased SLCO1B1 transporter function. Normal myopathy risk expected. | Initiate standard dosing. | |
SLCO1B1 Normal Function | Normal SLCO1B1 transporter function. Normal myopathy risk expected. | Initiate standard dosing. | |
SLCO1B1 Decreased Function | Decreased SLCO1B1 transporter function. Moderate risk of statin-induced myopathy with 20 mg. High risk of statin-induced myopathy with 40-80 mg. | Initiate ≤ 2 mg, if dose > 2 mg is needed, consider an alternative statin associated with lower risk or combination therapy. | |
SLCO1B1 Poor Function | No SLCO1B1 transporter function. High risk of statin-induced myopathy with 2-4 mg. | Initiate ≤ 1 mg, if dose > 1 mg is needed, consider an alternative statin associated with lower risk or combination therapy. | |
Unable to Genotype or Assay Failure | The analysis failed to yield an informative result and thus no genotype is reported. | ||
Unknown Phenotype | This individual is carrying at least one allele with uncertain/unknown function and the predicted phenotype cannot be determined at this time. | ||
Reference: Cooper-DeHoff RM et al. Clin Pharmacol Ther. 2022 May;111(5):1007-1021. PMID: 35152405. |
*Recommendations for patients on existing statin therapy:
For patients who are currently taking a statin with moderate risk of statin-induced myopathy, if the statin has been continued at a stable dose for 4 weeks without symptoms suggestive of statin-induced myopathy it may be reasonable to continue the current statin therapy, while if dosing has continued for less than 4 weeks clinicians can consider changing the statin or dose to a regimen with lower risk that meets the appropriate guideline recommended intensity.
For patients who are currently taking a statin with high risk of statin-induced myopathy, if the statin has been continued at a stable dose for at least 1 year without symptoms suggestive of statin-induced myopathy it may be reasonable to continue the current statin therapy, while if dosing has continued for less than one year clinicians can consider changing the statin or dose to regimen with lower risk that meets the appropriate guideline recommended intensity.
To see statins with moderate and high risk of statin-induced myopathy, click here.
SLCO1B1 and Pravastatin
To compare statin-associated musculoskeletal symptoms (SAMS) by statin intensities with doses for SLCO1B1 decreased and poor function to guide alternative statin selection, click here. For recommendations for patients on existing statin therapy, see footnote below table*
SLCO1B1 Predicted Phenotype | Clinical Implication | Therapeutic Recommendation | Resources |
SLCO1B1 Increased Function | Increased SLCO1B1 transporter function. Normal myopathy risk expected. | Initiate standard dosing. | |
SLCO1B1 Normal Function | Normal SLCO1B1 transporter function. Normal myopathy risk expected. | Initiate standard dosing. | |
SLCO1B1 Decreased Function | Decreased SLCO1B1 transporter function. Moderate risk of statin-induced myopathy with 80 mg. | Initiate standard dosing. | |
SLCO1B1 Poor Function | No SLCO1B1 transporter function. | Initiate ≤ 40 mg, if dose >40 mg is needed, consider an alternative statin associated with lower risk or combination therapy. | |
Unable to Genotype or Assay Failure | The analysis failed to yield an informative result and thus no genotype is reported. | ||
Unknown Phenotype | This individual is carrying at least one allele with uncertain/unknown function and the predicted phenotype cannot be determined at this time. | ||
Reference: Cooper-DeHoff RM et al. Clin Pharmacol Ther. 2022 May;111(5):1007-1021. PMID: 35152405. |
*Recommendations for patients on existing statin therapy:
For patients who are currently taking a statin with moderate risk of statin-induced myopathy, if the statin has been continued at a stable dose for 4 weeks without symptoms suggestive of statin-induced myopathy it may be reasonable to continue the current statin therapy, while if dosing has continued for less than 4 weeks clinicians can consider changing the statin or dose to a regimen with lower risk that meets the appropriate guideline recommended intensity.
For patients who are currently taking a statin with high risk of statin-induced myopathy, if the statin has been continued at a stable dose for at least 1 year without symptoms suggestive of statin-induced myopathy it may be reasonable to continue the current statin therapy, while if dosing has continued for less than one year clinicians can consider changing the statin or dose to regimen with lower risk that meets the appropriate guideline recommended intensity.
To see statins with moderate and high risk of statin-induced myopathy, click here.
SLCO1B1, ABCG2 and Rosuvastatin
To compare statin-associated musculoskeletal symptoms (SAMS) by statin intensities with doses for SLCO1B1 decreased and poor function to guide alternative statin selection, click here. For recommendations for patients on existing statin therapy, see footnote below table*
If either SLCO1B1 or ABCG2 genotypes are unavailable, scroll down in this table to the “Instructions for Unavailable Genotypes”.
Predicted Phenotype | ABCG2 Normal Function Normal ABCG2 transporter function. | ABCG2 Decreased Function Decreased ABCG2 transporter function. | ABCG2 Poor Function Little ABCG2 transporter function. |
SLCO1B1 Increased Function Increased SLCO1B1 transporter function. | Initiate standard dosing. | Initiate standard dosing. | Initiate ≤ 20 mg, if dose > 20 mg is needed, consider alternative statin or combination therapy. |
SLCO1B1 Normal Function Normal SLCO1B1 transporter function. | Initiate standard dosing. | Initiate standard dosing. | Initiate ≤ 20 mg, if dose > 20 mg is needed, consider alternative statin or combination therapy. |
SLCO1B1 Decreased Function Decreased SLCO1B1 transporter function. | Initiate standard dosing. | Initiate standard dosing. | Initiate ≤ 10 mg, if dose > 10 mg is needed, consider alternative statin or combination therapy. |
SLCO1B1 Poor Function No SLCO1B1 transporter function. | Initiate ≤ 20 mg, if dose > 20 mg is needed, consider combination therapy. | Initiate ≤ 20 mg, if dose > 20 mg is needed, consider combination therapy. | Initiate ≤ 10 mg, if dose > 10 mg is needed, consider combination therapy. |
Instructions for Unavailable Genotypes If for SLCO1B1 either Assay Failure, Unable to Genotype, or Unknown Phenotype are resulted or SLCO1B1 was not genotyped, but ABCG2 is available, follow across the SLCO1B1 Normal Metabolizer row to the appropriate ABCG2 phenotype for the recommendation. These recommendations may be affected by the patient’s unavailable SLCO1B1 genotype; consider testing or repeat testing of SLCO1B1 as appropriate. | |||
Unable to Genotype or Assay Failure | The analysis failed to yield an informative result and thus no genotype is reported. | ||
Unknown Phenotype | This individual is carrying at least one allele with uncertain/unknown function and the predicted phenotype cannot be determined at this time. | ||
Resources | |||
Reference: Cooper-DeHoff RM et al. Clin Pharmacol Ther. 2022 May;111(5):1007-1021. PMID: 35152405. |
*Recommendations for patients on existing statin therapy:
For patients who are currently taking a statin with moderate risk of statin-induced myopathy, if the statin has been continued at a stable dose for 4 weeks without symptoms suggestive of statin-induced myopathy it may be reasonable to continue the current statin therapy, while if dosing has continued for less than 4 weeks clinicians can consider changing the statin or dose to a regimen with lower risk that meets the appropriate guideline recommended intensity.
For patients who are currently taking a statin with high risk of statin-induced myopathy, if the statin has been continued at a stable dose for at least 1 year without symptoms suggestive of statin-induced myopathy it may be reasonable to continue the current statin therapy, while if dosing has continued for less than one year clinicians can consider changing the statin or dose to regimen with lower risk that meets the appropriate guideline recommended intensity.
To see statins with moderate and high risk of statin-induced myopathy, click here.
SLCO1B1 and Simvastatin
To compare statin-associated musculoskeletal symptoms (SAMS) by statin intensities with doses for SLCO1B1 decreased and poor function to guide alternative statin selection, click here. For recommendations for patients on existing statin therapy, see footnote below table*
SLCO1B1 Predicted Phenotype | Clinical Implication | Therapeutic Recommendation | Resources |
SLCO1B1 Increased Function | Increased SLCO1B1 transporter function. Normal myopathy risk expected. | Initiate standard dosing. | |
SLCO1B1 Normal Function | Normal SLCO1B1 transporter function. Normal myopathy risk expected. | Initiate standard dosing. | |
SLCO1B1 Decreased Function | Decreased SLCO1B1 transporter function. Moderate risk of statin-induced myopathy with 10 mg. | Consider an alternative statin associated with lower risk, if simvastatin is warranted, limit dose to < 20 mg/day. | |
SLCO1B1 Poor Function | No SLCO1B1 transporter function. | Consider an alternative statin associated with lower risk. | |
Unable to Genotype or Assay Failure | The analysis failed to yield an informative result and thus no genotype is reported. | ||
Unknown Phenotype | This individual is carrying at least one allele with uncertain/unknown function and the predicted phenotype cannot be determined at this time. | ||
Reference: Cooper-DeHoff RM et al. Clin Pharmacol Ther. 2022 May;111(5):1007-1021. PMID: 35152405. |
*Recommendations for patients on existing statin therapy:
For patients who are currently taking a statin with moderate risk of statin-induced myopathy, if the statin has been continued at a stable dose for 4 weeks without symptoms suggestive of statin-induced myopathy it may be reasonable to continue the current statin therapy, while if dosing has continued for less than 4 weeks clinicians can consider changing the statin or dose to a regimen with lower risk that meets the appropriate guideline recommended intensity.
For patients who are currently taking a statin with high risk of statin-induced myopathy, if the statin has been continued at a stable dose for at least 1 year without symptoms suggestive of statin-induced myopathy it may be reasonable to continue the current statin therapy, while if dosing has continued for less than one year clinicians can consider changing the statin or dose to regimen with lower risk that meets the appropriate guideline recommended intensity.
To see statins with moderate and high risk of statin-induced myopathy, click here.
CYP3A5 and Tacrolimus
These recommendations include the use of tacrolimus in kidney, heart, lung, and hematopoietic stem cell transplant patients, and liver transplant patients in which the donor and recipient genotypes are identical.
CYP3A5 Predicted Phenotype | Clinical Implication | Therapeutic Recommendation | Resources |
Normal Metabolizer (CYP3A5 Expresser) | Functional CYP3A5 enzyme activity present (“Abnormal result”; inconsistent with the majority of the population). | Increase starting dose by 1.5–2 times the recommended starting dose without exceeding | |
Intermediate Metabolizer | Functional CYP3A5 enzyme activity present (“Abnormal result”; inconsistent with the majority of the population). | Increase starting dose by 1.5–2 times the recommended starting dose without exceeding 0.3 mg/kg/day. Adjust as clinically appropriate per therapeutic drug monitoring | |
Poor Metabolizer (CYP3A5 Non-Expresser) | No CYP3A5 enzyme activity (“Normal result”; consistent with the majority of the population). | Initiate standard dosing and adjust as clinically appropriate per therapeutic drug monitoring. | |
Unable to Genotype or Assay Failure | The analysis failed to yield an informative result and thus no genotype is reported. | ||
Reference: Birdwell KA et al. Clin Pharmacol Ther. 2015 Jul;98(1):19-24. PMID: 25801146. |
CYP2D6 and Tamoxifen
Strong and moderate inhibitors of CYP2D6 (bupropion, fluoxetine, paroxetine, quinidine, terbinafine, cinacalcet, duloxetine, mirabegron, abiraterone, and lorcaserin) can lead to phenoconversion. If a patient is taking one or more of the above listed medications (and that medication will not be discontinued prior to starting the new medication of interest), use the CYP2D6 Phenoconversion Calculator to determine the clinical phenotype and use that phenotype in the table below.
CYP2D6 Predicted Phenotype | Clinical Implication | Therapeutic Recommendation | Resources |
Ultra Rapid Metabolizer | Increased CYP2D6 enzyme activity. | Use standard dose of tamoxifen. | |
Normal – Ultra Rapid Metabolizer with an enzyme Activity Score of 1.5+ or 2+* | Normal to increased CYP2D6 enzyme activity. | Use standard dose of tamoxifen. | |
Normal – Ultra Rapid Metabolizer with an enzyme Activity Score of 1+* | Normal to increased CYP2D6 enzyme activity. Possibly reduced activation of tamoxifen and increased risk of treatment failure (e.g., high risk of breast cancer reoccurrence) or normal activation with normal response. | Consider alternative: aromatase inhibitor for postmenopausal women or aromatase inhibitor along with ovarian function suppression if premenopausal. If aromatase inhibitor is contraindicated, consider a higher dose (i.e., tamoxifen 40 mg/day). | |
Normal Metabolizer | Normal CYP2D6 enzyme activity. | Use standard dose of tamoxifen. | |
Normal Metabolizer | Normal CYP2D6 enzyme activity. Reduced activtion of tamoxifen and increased risk of treatment failure (e.g., high risk of breast cancer reocurrance). | Consider alternative: aromatase inhibitor for postmenopausal women or aromatase inhibitor along with ovarian function suppression if premenopausal. If aromatase inhibitor is contraindicated, consider a higher dose (i.e., tamoxifen 40 mg/day). | |
Intermediate Metabolizer | Decreased CYP2D6 enzyme activity. | Consider alternative: aromatase inhibitor for postmenopausal women or aromatase inhibitor along with ovarian function suppression if premenopausal. If aromatase inhibitor is contraindicated, consider a higher dose (i.e., tamoxifen 40 mg/day). | |
Poor Metabolizer | No CYP2D6 enzyme activity. Significantly reduced activation of tamoxifen and increased risk of treatment failure (e.g., high risk | Use alternative: aromatase inhibitor for postmenopausal women or aromatase inhibitor along with ovarian function suppression if premenopausal. May consider higher dose of tamoxifen (40 mg/day) if contraindications to aromatase inhibitor exist, noting that activation of tamoxifen will increase but not normalize. | |
Unable to Genotype or Assay Failure | The analysis failed to yield an informative result and thus no genotype is reported. | ||
Unknown Phenotype | This individual is carrying at least one allele with uncertain/unknown function and the predicted phenotype cannot be determined at this time. | ||
Reference: Goetz MP et al. Clin Pharmacol Ther. 2018 May;103(5):770-777. PMID: 29385237. |
*Some laboratories have started calling activity scores of 1.0 as Intermediate Metabolizers, however they are still classified as Normal Metabolizers with UF Health Pathology.
TPMT, NUDT15 and Thioguanine
If either TPMT or NUDT15 genotypes are unavailable, scroll down in this table to the “Instructions for Unavailable Genotypes”.
TPMT Normal Metabolizer Normal TPMT enzyme activity. | TPMT Intermediate Metabolizer Decreased TPMT enzyme activity. | TPMT Poor – Intermediate Metabolizer Decreased to no TPMT enzyme activity. | TPMT Poor Metabolizer No TPMT enzyme activity. | |
NUDT15 Normal Metabolizer Normal NUDT15 enzyme activity. | Start with normal starting dose per disease-specific guidelines. Allow 2 weeks to reach steady-state after each dose adjustment. | Reduce starting doses by 50–80%. Allow 2–4 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing thioguanine over other agents. | For malignant conditions: Start with drastically reduced doses (reduce daily dose by 10-fold and dose thrice weekly instead of daily). Allow 4–6 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing thioguanine over other agents. For nonmalignant conditions: | For malignant conditions: Start with drastically reduced doses (reduce daily dose by 10-fold and dose thrice weekly instead of daily). Allow 4–6 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing thioguanine over other agents. For nonmalignant conditions: |
NUDT15 Intermediate Metabolizer Decreased NUDT15 enzyme activity. | Reduce starting doses by 50–80%. Allow 2–4 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing thioguanine over other agents. | Reduce starting doses by 50–80%. Allow 2–4 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing thioguanine over other agents. | For malignant conditions: Start with drastically reduced doses (reduce daily dose by 10-fold and dose thrice weekly instead of daily). Allow 4–6 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing thioguanine over other agents. For nonmalignant conditions: Consider alternative nonthiopurine immunosuppressant therapy. | For malignant conditions: Start with drastically reduced doses (reduce daily dose by 10-fold and dose thrice weekly instead of daily). Allow 4–6 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing thioguanine over other agents. For nonmalignant conditions: |
NUDT15 Poor – Intermediate Metabolizer Decreased to no NUDT15 enzyme activity. | For malignant conditions: Reduce starting dose by 75%. Allow 4–6 weeks to reach steady-state after each dose adjustment. In setting of myelosuppression, emphasis should be on reducing thioguanine over other agents. For nonmalignant conditions: Consider alternative nonthiopurine immunosuppressant therapy. | For malignant conditions: Reduce starting dose by 75%. Allow 4–6 weeks to reach steady-state after each dose adjustment. In setting of myelosuppression, emphasis should be on reducing thioguanine over other agents. For nonmalignant conditions: Consider alternative nonthiopurine immunosuppressant therapy. | For malignant conditions: Start with drastically reduced doses (reduce daily dose by 10-fold and dose thrice weekly instead of daily). Allow 4–6 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing thioguanine over other agents. For nonmalignant conditions: | For malignant conditions: Start with drastically reduced doses (reduce daily dose by 10-fold and dose thrice weekly instead of daily). Allow 4–6 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing thioguanine over other agents. For nonmalignant conditions: |
NUDT15 Poor Metabolizer No NUDT15 enzyme activity. | For malignant conditions: Reduce starting dose by 75%. Allow 4–6 weeks to reach steady-state after each dose adjustment. In setting of myelosuppression, emphasis should be on reducing thioguanine over other agents. For nonmalignant conditions: | For malignant conditions: Reduce starting dose by 75%. Allow 4–6 weeks to reach steady-state after each dose adjustment. In setting of myelosuppression, emphasis should be on reducing thioguanine over other agents. For nonmalignant conditions: | For malignant conditions: Start with drastically reduced doses (reduce daily dose by 10-fold and dose thrice weekly instead of daily). Allow 4–6 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing thioguanine over other agents. For nonmalignant conditions: | For malignant conditions: Start with drastically reduced doses (reduce daily dose by 10-fold and dose thrice weekly instead of daily). Allow 4–6 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing thioguanine over other agents. For nonmalignant conditions: |
Instructions for Unavailable Genotypes If for NUDT15 either Assay Failure, Unable to Genotype, or Unknown Phenotype are resulted or NUDT15 was not genotyped, but TPMT is available, follow across the NUDT15 Normal Metabolizer row to the appropriate TPMT phenotype for the recommendation. These recommendations may be affected by the patient’s unavailable NUDT15 genotype; consider testing or repeat testing of NUDT15 as appropriate. | ||||
Unable to Genotype or Assay Failure | The analysis failed to yield an informative result and thus no genotype is reported. | |||
Unknown Phenotype | This individual is carrying at least one allele with uncertain/unknown function and the predicted phenotype cannot be determined at this time. | |||
Resources | ||||
Reference: Relling MV et al. Clin Pharmacol Ther. 2019 May;105(5):1095-1105. PMID: 30447069. |
CYP2D6 and Vortioxetine
Strong and moderate inhibitors of CYP2D6 (bupropion, fluoxetine, paroxetine, quinidine, terbinafine, cinacalcet, duloxetine, mirabegron, abiraterone, and lorcaserin) can lead to phenoconversion. If a patient is taking one or more of the above listed medications (and that medication will not be discontinued prior to starting the new medication of interest), use the CYP2D6 Phenoconversion Calculator to determine the clinical phenotype and use that phenotype in the table below.
CYP2D6 Predicted Phenotype | Clinical Implication | Therapeutic Recommendation | Resources |
Ultra Rapid Metabolizer | Increased CYP2D6 enzyme activity. | Given limited data available, consider initiating therapy with recommended starting dose with careful monitoring. | |
Normal – Ultra Rapid Metabolizer* | Normal to increased CYP2D6 enzyme activity. | Given limited data available, consider initiating therapy with recommended starting dose with careful monitoring. | |
Normal Metabolizer* | Normal CYP2D6 enzyme activity. | Initiate therapy with recommended starting dose. | |
Intermediate Metabolizer* | Decreased CYP2D6 enzyme activity. | Initiate therapy with recommended starting dose. | |
Poor Metabolizer | No CYP2D6 enzyme activity. | Initiate vortioxetine at 5 mg once daily or consider an alternative drug (click here for table of alternatives). The maximum recommend dose of vortioxetine is 10 mg/day. | |
Unable to Genotype or Assay Failure | The analysis failed to yield an informative result and thus no genotype is reported. | ||
Unknown Phenotype | This individual is carrying at least one allele with uncertain/unknown function and the predicted phenotype cannot be determined at this time. | ||
*Some laboratories have started calling activity scores of 1.0 as Intermediate Metabolizers, however they are still classified as Normal Metabolizers with UF Health Pathology.
CYP2C9, VKORC1, rs12777823 (CYP2C Cluster) and Warfarin
Genotype information can be utilized along with clinical information to guide initial warfarin dosing and predict a patient’s stable daily warfarin dose. Utilize the flowchart below to determine which warfarin algorithm should be used and additional modifications warranted.*
Adults
Pediatric
*Note: This flow chart has been adapted from CPIC guidelines to reflect a pharmacogenetics panel that includes CYP2C9 *2,*3,*5,*6,*8,*11, VKORC1 1639G>A, and rs12777823(CYP2C Cluster). If you have results that include different variants, please follow the link to the CPIC guideline below to utilize the full flowchart.
Reference: Johnson JA et al. Clin Pharmacol Ther. 2017 Sep;102(3):397-404. PMID: 28198005.
Resources:
Warfarin Dosing CPIC Guideline
More Information on Warfarin Dosing from PharmGKB
CYP2C19 and Voriconazole
For the TREATMENT of invasive fungal infections:
CYP2C19 Predicted Phenotype | Clinical Implication | Therapeutic Recommendation | Resources |
Ultra Rapid Metabolizer | Increased CYP2C19 enzyme activity. | Choose an alternative agent that is | |
Rapid Metabolizer | Increased CYP2C19 enzyme activity. | Choose an alternative agent that is not dependent on CYP2C19 metabolism (e.g., isavuconazole, liposomal amphotericin B, and posaconazole). | |
Normal Metabolizer | Normal CYP2C19 enzyme activity. | Use standard dose of voriconazole. | |
Intermediate Metabolizer | Decreased CYP2C19 enzyme activity. | Use standard dose of voriconazole. | |
Poor Metabolizer | No CYP2C19 enzyme activity. | Choose alternative agent that is not dependent on CYP2C19 metabolism (e.g., isavuconazole, liposomal amphotericin B, and posaconazole). | |
Unable to Genotype or Assay Failure | The analysis failed to yield an informative result and thus no genotype is reported. | ||
Unknown Phenotype | This individual is carrying at least one allele with uncertain/unknown function and the predicted phenotype cannot be determined at this time. | ||
Reference: Moriyama B et al. Clin Pharmacol Ther. 2017 Jul;102(1):45-51. PMID: 27981572. |
CYP2D6 and Venlafaxine
Strong and moderate inhibitors of CYP2D6 (bupropion, fluoxetine, paroxetine, quinidine, terbinafine, cinacalcet, duloxetine, mirabegron, abiraterone, and lorcaserin) can lead to phenoconversion. If a patient is taking one or more of the above listed medications (and that medication will not be discontinued prior to starting the new medication of interest), use the CYP2D6 Phenoconversion Calculator to determine the clinical phenotype and use that phenotype in the table below.
CYP2D6 Predicted Phenotype | Clinical Implication | Therapeutic Recommendation | Resources |
Ultra Rapid Metabolizer | Increased CYP2D6 enzyme activity. | Initiate therapy with recommended starting dose. | |
Normal – Ultra Rapid Metabolizer* | Normal to increased CYP2D6 enzyme activity. | Initiate therapy with recommended starting dose. | |
Normal Metabolizer* | Normal CYP2D6 enzyme activity. | Initiate therapy with recommended starting dose. | |
Intermediate Metabolizer* | Decreased CYP2D6 enzyme activity. | Initiate therapy with recommended starting dose. | |
Poor Metabolizer | No CYP2D6 enzyme activity. | Avoid venlafaxine and consider an alternative drug (click here for table of alternatives). | |
Unable to Genotype or Assay Failure | The analysis failed to yield an informative result and thus no genotype is reported. | ||
Unknown Phenotype | This individual is carrying at least one allele with uncertain/unknown function and the predicted phenotype cannot be determined at this time. | ||
*Some laboratories have started calling activity scores of 1.0 as Intermediate Metabolizers, however they are still classified as Normal Metabolizers with UF Health Pathology.
SLCO1B1 and Statin Selection Recommendations
The figure below provides statin specific statin-associated musculoskeletal symptoms (SAMS) risk, also known as statin-induced myopathy risk, based on SLCO1B1 predicted phenotype and statin intensity.
Recommendations for new start or dose changes in statin therapy:
This figure is for starting, changing dose, or selecting alternative statin therapy, for more specific recommendations see each individual statin table below, especially for fluvastatin and rosuvastatin, which utilize additional pharmacogenetic information.
Recommendations for patients on existing statin therapy:
For patients on existing moderate SAMS risk statin therapy, if the statin has been continued at a stable dose for 4 weeks without symptoms suggestive of SAMS it may be reasonable to continue the moderate SAMS risk statin therapy, while if dosing has continued for less than 4 weeks clinicians can consider changing the statin or dose to a low SAMS risk regimen that meets the appropriate guideline recommended intensity.
For patients on existing high SAMS risk statin therapy, if the statin has been continued at a stable dose for at least 1 year without symptoms suggestive of SAMS it may be reasonable to continue the high SAMS risk statin therapy, while if dosing has continued for less than one year clinicians can consider changing the statin or dose to a low SAMS risk regimen that meets the appropriate guideline recommended intensity.

Reference: Cooper-DeHoff RM et al. Clin Pharmacol Ther. 2022 May;111(5):1007-1021. PMID: 35152405.