Table 3.

CPIC dosing recommendations for different drugs based on CYP2D6 phenotype

Drug class	Medications	CYP2D6 phenotypes	Implications	Recommendations	Classification of recommendation	Reference
Tricyclic antidepressants	Amitriptyline and nortriptyline	UM	Increased metabolism to less active compounds increasing the probability to lack of efficacy.	Avoid use of amitriptyline and nortriptyline. Consider alternative drug not metabolized by CYP2D6.	Strong	Hicks et. al., 2017 [16]
		NM	Expected metabolism to less active compounds	Initiate therapy with recommended starting dose.	Strong
		IM	Reduced metabolism to less active compounds increasing risk of adverse effects	Consider a 25% reduction of recommended starting dose	Moderate
		PM	Greatly reduced metabolism to less active compounds increasing risk of adverse effects	Avoid use of amitriptyline and nortriptyline. Consider alternative drug not metabolized by CYP2D6.	Strong
	Clomipramine, desipramine, doxepin, imipramine, and trimipramine	UM	Increased metabolism to less active compounds increasing the probability for lack of efficacy.	Avoid use of the drugs. Consider alternative drug not metabolized by CYP2D6.	Optional
		NM	Expected metabolism to less active compounds	Initiate therapy with recommended starting dose.	Strong
		IM	Reduced metabolism to less active compounds increasing risk of adverse effects	Consider a 25% reduction of recommended starting dose.	Optional
		PM	Greatly reduced metabolism to less active compounds increasing risk of adverse effects	Avoid use of the drugs. Consider alternative drug not metabolized by CYP2D6.	Optional
Selective serotonin reuptake inhibitors	Paroxetine	UM	Increased metabolism to less active compounds increasing the probability for lack of efficacy.	Avoid paroxetine. Consider alternative drug not predominantly metabolized by CYP2D6	Strong	Hicks et. al., 2015 [21]
		NM	Expected metabolism to less active compounds	Initiate therapy with recommended starting dose.	Strong
		IM	Reduced metabolism to less active compounds increasing risk of adverse effects	Initiate therapy with recommended starting dose.	Moderate
		PM	Greatly reduced metabolism to less active compounds increasing risk of adverse effects	Avoid paroxetine. Consider alternative drug not predominantly metabolized by CYP2D6	Optional
	Fluvoxamine	UM	No data available for CYP2D6 ultrarapid metabolizers	No recommendation due to lack of evidence	Optional
		NM	Expected metabolism to less active compounds	Initiate therapy with recommended starting dose.	Strong
		IM	Reduced metabolism to less active compounds increasing risk of adverse effects	Initiate therapy with recommended starting dose.	Moderate
		PM	Greatly reduced metabolism to less active compounds increasing risk of adverse effects	Consider a 25–50% reduction of recommended starting dose and titrate to response. Or, Consider alternative drug not predominantly metabolized by CYP2D6	Optional
Antiemetic	Ondansetron and tropisetron	UM	Increased metabolism to less active compounds increasing the probability to lack of efficacy.	Avoid use of the drugs. Consider alternative drug not metabolized by CYP2D6.	Moderate	Bell et. al., 2017 [131]
		NM	Expected metabolism to less active compounds	Initiate therapy with recommended starting dose.	Strong
		IM	Very limited data available	Initiate therapy with recommended starting dose.	No recommendation
		PM	Very limited data available	Initiate therapy with recommended starting dose.	No recommendation
ADHD treatment	Atomoxetine	UM	Very limited data available	Initiate with a dose of 0.5mg/kg/day in children or 40 mg/day in adults and increase to 1.2mg/kg/day in children or 80 mg/ day in adults after 3 days. If no clinical response, consider titration to reach 400 ng/mL peak plasma concentration. Details here.	Moderate	Brown et. al., 2019 [14]
		NM	Expected metabolism to less active compounds	Initiate with a dose of 0.5mg/kg/day in children or 40 mg/day in adults and increase to 1.2mg/kg/day in children or 80 mg/ day in adults after 3 days. If no clinical response consider titration to reach 400 ng/mL peak plasma concentration. Details here. If unacceptable side effects are present at any time, consider a reduction in dose. Details here.	Moderate
		IM	Reduced metabolism to less active compounds increasing risk of discontinuation	Initiate with a dose of 0.5mg/kg/day in children or 40 mg/day in adults. If no clinical response, consider titration to reach 400 ng/mL peak plasma concentration. Details here. If unacceptable side effects are present at any time, consider a reduction in dose. Details here.	Moderate
		PM	Greatly reduced metabolism to less active compounds increasing risk of adverse effects but may result in greater improvement of ADHD.	Initiate with a dose of 0.5mg/kg/day in children or 40 mg/day in adults. If no clinical response, consider titration to reach 400 ng/mL peak plasma concentration. Details here. If unacceptable side effects are present at any time, consider a reduction in dose. Details here.	Moderate
Opioids	Codeine	UM	Increase formation of morphine leading to higher risk of toxicity	Avoid use of codeine. Consider use of non-tramadol opioid or other analgesics	Strong	Crews et. al., 2021 [7]
		NM	Expected metabolism to morphine	Initiate therapy with recommended starting dose.	Strong
		IM	Reduced formation of morphine	Initiate therapy with recommended starting dose. If no response consider use of non-tramadol opioid or other analgesics	Moderate
		PM	Greatly reduced formation of morphine leading to diminished analgesia	Avoid use of codeine. Consider use of non-tramadol opioid or other analgesics	Strong
	Tramadol	UM	Increase formation of o-desmethyltramadol leading to higher risk of toxicity	Avoid use of tramadol. Consider use of non-codeine opioid or other analgesics	Strong
		NM	Expected metabolism to o-desmethyltramadol	Initiate therapy with recommended starting dose.	Strong
		IM	Reduced formation of o-desmethyltramadol	Initiate therapy with recommended starting dose. If no response consider use of non-codeine opioid or other analgesics	Optional
		PM	Greatly reduced formation of o-desmethyltramadol leading to diminished analgesia	Avoid use of tramadol. Consider use of non-codeine opioid or other analgesics	Strong
	Hydrocodone	UM	Very limited data available	No recommendation due to lack of evidence	No recommendation
		NM	Expected metabolism to hydromorphone	Initiate therapy with recommended starting dose.	Strong
		IM	Very limited data available	Initiate therapy with recommended starting dose. If no response consider use of non-codeine or non-tramadol opioid or other analgesics	Optional
		PM	Reduced formation of hydromorphone, but there is insufficient evidence to determine if these effects on pharmacokinetics translate into decreased analgesia or side effects	Initiate therapy with recommended starting dose. If no response consider use of non-codeine or non-tramadol opioid or other analgesics	Optional
Antiestrogens	Tamoxifen	UM	Expected metabolism to endoxifen	Avoid moderate and strong inhibitors. Initiate therapy with recommended starting dose.	Strong	Goetz et. al., 2018 [15]
		NM	Expected metabolism to endoxifen	Avoid moderate and strong inhibitors. Initiate therapy with recommended starting dose.	Strong
		IM	Reduced formation of endoxifen. May increase the risk of breast cancer recurrence, event-free and recurrence-free survival	Avoid moderate and strong inhibitors. Consider hormonal therapy such as an aromatase inhibitor with/without ovarian function suppression. If aromatase inhibitor use is contraindicated, consideration should be given to use a higher but FDA approved tamoxifen dose (40 mg/day). Details here.	Moderate
		PM	Reduced formation of endoxifen. May increase the risk of breast cancer recurrence, event-free and recurrence-free survival	Recommend alternative hormonal therapy such as an aromatase inhibitor with/without ovarian function suppression. If aromatase inhibitor use is contraindicated, consideration should be given to use a higher but FDA approved tamoxifen dose (40 mg/day). Details here.	Strong