Table 15.

Opioid analgesics categorized according to their risk for DDIs and QTc prolongation when used concomitantly with ribociclib or palbociclib.

Opioid analgesics	CYP3A4 Substrate	CYP3A4 Inhibitor	CYP3A4Inducer	Membrane transporter substrate	TdP risk	Comments
Morphine Hydromorphone TapentadolCodeine	– – –Minor	– – – –	– – – –	P-gp* – – –	Not known Not known Not knownNot known	Low risk of interaction with palbociclib and ribociclib SAFE OPTIONS
Tramadol Buprenorphine Oxycodone	Major Major Major	– – –	– – –	– – –	Possible Possible Not known	Caution: risk of increased toxicity of the substrate
Methadone Fentanyl‡	Major Major NTI	– –	– –	– –	Known risk$ Not known	High risk of DDIs. Should be avoided the combination with ribociclib or palbociclib

Green: Low risk of interaction with palbociclib and ribociclib, SAFE OPTIONS. Orange: Caution should be exercised. Red: High risk: Plasmatic concentrations of the substrate could be increased when used concomitantly with a CYP3A4 inhibitor, such as palbociclib (weak) or ribociclib (moderate-potent). Risk of increased toxicity. NTI: narrow therapeutic index.

^*In vitro data suggest that palbociclib and ribociclib may inhibit P-glycoprotein (P-gp) and that inhibition may increase exposition to substrates, but there is no in vivo evidence of this interaction.

^$QTc interval prolongation risk of the CYP3A4 substrate can be increased as a consequence of the metabolic inhibition (substrate accumulation).

^‡If fentanyl cannot be changed when starting treatment with palbociclib or ribociclib, consider reducing the dose and closely monitoring for side effects.