Ibrance

Small Molecule Antineoplastic Cyclin-Dependent Kinase (CDK) Inhibitors

Emetic Risk
Minimal/Low
Administer prn antiemetics as necessary.

neutropenia / Delayed / 54.0-67.0
leukopenia / Delayed / 19.0-46.0
lymphopenia / Delayed / 0-18.0
anemia / Delayed / 3.0-6.0
thromboembolism / Delayed / 5.0-5.0
pulmonary embolism / Delayed / 1.0-5.0
infection / Delayed / 0-4.0
diarrhea / Early / 0-4.0
fatigue / Early / 2.0-4.0
thrombocytopenia / Delayed / 2.0-3.0
nausea / Early / 0-2.0
asthenia / Delayed / 0-2.0
weakness / Early / 0-2.0
stomatitis / Delayed / 0-1.0
anorexia / Delayed / 1.0-1.0
vomiting / Early / 0-1.0
headache / Early / 0-1.0
rash / Early / 0-1.0

constipation / Delayed / 0-20.0
peripheral neuropathy / Delayed / 0-13.0
blurred vision / Early / 0-6.0
interstitial lung disease / Delayed / 0-1.0
pneumonitis / Delayed / 0-1.0
cystitis / Delayed / Incidence not known
conjunctivitis / Delayed / Incidence not known
glossitis / Early / Incidence not known
oral ulceration / Delayed / Incidence not known
palmar-plantar erythrodysesthesia (hand and foot syndrome) / Delayed / Incidence not known
erythema / Early / Incidence not known

alopecia / Delayed / 18.0-22.0
dysgeusia / Early / 0-7.0
xerosis / Delayed / 0-6.0
lacrimation / Early / 0-6.0
xerophthalmia / Early / 0-4.0
fever / Early / 0-1.0
pharyngitis / Delayed / Incidence not known
laryngitis / Delayed / Incidence not known
sinusitis / Delayed / Incidence not known
influenza / Delayed / Incidence not known
rhinitis / Early / Incidence not known
cheilitis / Delayed / Incidence not known
pruritus / Rapid / Incidence not known
acneiform rash / Delayed / Incidence not known
maculopapular rash / Early / Incidence not known

Ibrance

Rx

Cyclin-dependent kinase (CDK) 4 and 6 inhibitor
Used for the treatment of HR-positive, HER2-negative metastatic breast cancer in combination with an aromatase inhibitor in men and postmenopausal women who have not yet received an endocrine-based therapy, and in combination with fulvestrant in patients with disease progression following endocrine therapy
Monitor complete blood counts; an interruption of therapy, dose reduction, or discontinuation may be necessary for neutropenia

Baseline Hepatic Impairment:
Mild to moderate hepatic impairment (Child-Pugh A and B): No adjustment is needed.
Severe hepatic impairment (Child-Pugh C): Reduce the dose of palbociclib to 75 mg once daily with food for 21 days, followed by 7 days off, repeated every 28 days.
 
Treatment-Related Hepatotoxicity:
Grade 1 or 2 hepatotoxicity: No dosage adjustment needed.
Grade 3 or higher hepatotoxicity (AST or ALT greater than 5 times ULN or total bilirubin greater than 3 times ULN) that persists despite medical treatment: Hold palbociclib therapy. When toxicity resolves to Grade 2 or lower (AST or ALT less than or equal to 5 times ULN or total bilirubin less than or equal to 3 times ULN), resume treatment at the next lower dose level if not considered a safety risk for the patient (e.g., if original dose was 125 mg/day, resume treatment at 100 mg/day; if original dose was 100 mg/day, resume treatment at 75 mg/day). Discontinue palbociclib therapy if grade 3 or higher toxicity occurs at a dose of 75 mg/day.

Baseline Renal Impairment:
CrCl more than 15 mL/min: No dose adjustment is needed.
Hemodialysis: Palbociclib has not been studied in patients requiring hemodialysis.
 
Treatment-Related Nephrotoxicity:
Grade 1 or 2 nephrotoxicity: No dosage adjustment needed.
Grade 3 or higher nephrotoxicity (SCr greater than 3 times baseline or greater than 4 mg/dL, or requiring hospitalization or dialysis) that persists despite medical treatment: Hold palbociclib therapy. When toxicity resolves to less than or equal to grade 2 (SCr less than 3 times baseline or less than 4 mg/dL), resume treatment at the next lower dose level if not considered a safety risk for the patient (e.g., if original dose was 125 mg/day, resume treatment at 100 mg/day; if original dose was 100 mg/day, resume treatment at 75 mg/day). Discontinue palbociclib therapy if grade 3 or higher toxicity occurs at a dose of 75 mg/day.

Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with palbociclib may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of palbociclib could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If palbociclib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Palbociclib is a weak inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
Acetaminophen; Codeine: (Moderate) Monitor for an increase in codeine-related adverse reactions, including sedation and respiratory depression, if coadministration with palbociclib is necessary; consider reducing the dose of codeine if clinically appropriate. If palbociclib is discontinued, monitor for evidence of opioid withdrawal until stable drug effects are achieved and consider increasing the codeine dose if necessary. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Palbociclib is a CYP3A4 inhibitor. Concomitant use may result in an increase in codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and increased morphine concentrations.
Acetaminophen; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of palbociclib is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like palbociclib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If palbociclib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Acetaminophen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of palbociclib is necessary. If palbociclib is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a weak inhibitor like palbociclib can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If palbociclib is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Adagrasib: (Major) Avoid coadministration of palbociclib with adagrasib; significantly increased plasma exposure of palbociclib may occur. If concomitant use is unavoidable, reduce the dose of palbociclib to 75 mg PO once daily and monitor for increased adverse reactions. If adagrasib is discontinued, increase the palbociclib dose (after 3 to 5 half-lives of adagrasib) to the dose used before initiation of adagrasib. Palbociclib is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the exposure of palbociclib by 87%.
Albuterol; Budesonide: (Moderate) Monitor for an increase in budesonide-related adverse reactions if coadministration with palbociclib is necessary, including excessive HPA-axis suppression; this may also be clinically significant for inhaled forms of budesonide. Palbociclib is a weak time-dependent inhibitor of CYP3A while budesonide is a CYP3A4 substrate.
Alfentanil: (Moderate) Monitor patients for respiratory depression and sedation at frequent intervals if coadministration with palbociclib is necessary. The dose of alfentanil may need to be reduced. This interaction is most likely to occur if palbociclib is added after a stable dose of alfentanil is achieved. Palbociclib is a weak time-dependent inhibitor of CYP3A while alfentanil is a sensitive CYP3A4 substrate with narrow therapeutic range.
Alprazolam: (Major) Avoid coadministration of alprazolam and palbociclib due to the potential for elevated alprazolam concentrations, which may cause prolonged sedation and respiratory depression. If coadministration is necessary, consider reducing the dose of alprazolam as clinically appropriate and monitor for an increase in alprazolam-related adverse reactions. Lorazepam, oxazepam, or temazepam may be safer alternatives if a benzodiazepine must be administered in combination with palbociclib, as these benzodiazepines are not oxidatively metabolized. Alprazolam is a CYP3A4 substrate and palbociclib is a weak CYP3A4 inhibitor. Coadministration with another weak CYP3A4 inhibitor increased alprazolam maximum concentration by 82%, decreased clearance by 42%, and increased half-life by 16%.
Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid coadministration of clarithromycin with palbociclib; significantly increased palbociclib exposure may occur. If concomitant use cannot be avoided, reduce the dose of palbociclib to 75 mg PO once daily and monitor for increased adverse reactions. If clarithromycin is discontinued, increase the palbociclib dose (after 3 to 5 half-lives of atazanavir) to the dose used before initiation of clarithromycin. Palbociclib is primarily metabolized by CYP3A4 and clarithromycin is a strong CYP3A4 inhibitor. In a drug interaction trial, coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of palbociclib by 87% and 34%, respectively.
Apalutamide: (Major) Avoid coadministration of apalutamide with palbociclib due to decreased plasma concentrations of palbociclib, which may result in decreased efficacy. Palbociclib is primarily metabolized by CYP3A4 and apalutamide is a strong CYP3A4 inducer. In a drug interaction trial, coadministration with another strong CYP3A4 inducer decreased the AUC and Cmax of palbociclib by 85% and 70%, respectively.
Aripiprazole: (Moderate) Monitor for aripiprazole-related adverse reactions during concomitant use of palbociclib. Patients receiving both a CYP2D6 inhibitor plus palbociclib may require an aripiprazole dosage adjustment. Dosing recommendations vary based on aripiprazole dosage form, CYP2D6 inhibitor strength, and CYP2D6 metabolizer status. See prescribing information for details. Concomitant use may increase aripiprazole exposure and risk for side effects. Aripiprazole is a CYP3A and CYP2D6 substrate; palbociclib is a weak CYP3A inhibitor.
Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Monitor for an increase in codeine-related adverse reactions, including sedation and respiratory depression, if coadministration with palbociclib is necessary; consider reducing the dose of codeine if clinically appropriate. If palbociclib is discontinued, monitor for evidence of opioid withdrawal until stable drug effects are achieved and consider increasing the codeine dose if necessary. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Palbociclib is a CYP3A4 inhibitor. Concomitant use may result in an increase in codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and increased morphine concentrations.
Aspirin, ASA; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of palbociclib is necessary. If palbociclib is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a weak inhibitor like palbociclib can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If palbociclib is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Atazanavir: (Major) Avoid coadministration of atazanavir with palbociclib; significantly increased palbociclib exposure may occur. If concomitant use cannot be avoided, reduce the dose of palbociclib to 75 mg PO once daily and monitor for increased adverse reactions. If atazanavir is discontinued, increase the palbociclib dose (after 3 to 5 half-lives of atazanavir) to the dose used before initiation of atazanavir. Palbociclib is primarily metabolized by CYP3A4 and atazanavir is a strong CYP3A4 inhibitor. In a drug interaction trial, coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of palbociclib by 87% and 34%, respectively.
Atazanavir; Cobicistat: (Major) Avoid coadministration of atazanavir with palbociclib; significantly increased palbociclib exposure may occur. If concomitant use cannot be avoided, reduce the dose of palbociclib to 75 mg PO once daily and monitor for increased adverse reactions. If atazanavir is discontinued, increase the palbociclib dose (after 3 to 5 half-lives of atazanavir) to the dose used before initiation of atazanavir. Palbociclib is primarily metabolized by CYP3A4 and atazanavir is a strong CYP3A4 inhibitor. In a drug interaction trial, coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of palbociclib by 87% and 34%, respectively. (Major) Avoid coadministration of cobicistat with palbociclib; significantly increased plasma exposure of palbociclib may occur. If concomitant use cannot be avoided, reduce the dose of palbociclib to 75 mg PO once daily and monitor for increased adverse reactions. If cobicistat is discontinued, increase the palbociclib dose (after 3 to 5 half-lives of cobicistat) to the dose used before initiation of cobicistat. Palbociclib is primarily metabolized by CYP3A4 and cobicistat is a strong CYP3A4 inhibitor. In a drug interaction trial, coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of palbociclib by 87% and 34%, respectively.
Benzhydrocodone; Acetaminophen: (Moderate) Concurrent use of benzhydrocodone with palociclib may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Consider a dose reduction of benzhydrocodone until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. Discontinuation of palociclib in a patient taking benzhydrocodone may decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. If palociclib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Benzhydrocodone is a prodrug for hydrocodone. Hydrocodone is a substrate for CYP3A4. Palociclib is a weak inhibitor of CYP3A4.
Budesonide: (Moderate) Monitor for an increase in budesonide-related adverse reactions if coadministration with palbociclib is necessary, including excessive HPA-axis suppression; this may also be clinically significant for inhaled forms of budesonide. Palbociclib is a weak time-dependent inhibitor of CYP3A while budesonide is a CYP3A4 substrate.
Budesonide; Formoterol: (Moderate) Monitor for an increase in budesonide-related adverse reactions if coadministration with palbociclib is necessary, including excessive HPA-axis suppression; this may also be clinically significant for inhaled forms of budesonide. Palbociclib is a weak time-dependent inhibitor of CYP3A while budesonide is a CYP3A4 substrate.
Budesonide; Glycopyrrolate; Formoterol: (Moderate) Monitor for an increase in budesonide-related adverse reactions if coadministration with palbociclib is necessary, including excessive HPA-axis suppression; this may also be clinically significant for inhaled forms of budesonide. Palbociclib is a weak time-dependent inhibitor of CYP3A while budesonide is a CYP3A4 substrate.
Bupivacaine; Lidocaine: (Moderate) Concomitant use of systemic lidocaine and palbociclib may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; palbociclib inhibits CYP3A4.
Buprenorphine: (Moderate) Consider a reduced dose of buprenorphine with frequent monitoring for respiratory depression and sedation if concurrent use of palbociclib is necessary. If palbociclib is discontinued, consider increasing the buprenorphine dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Buprenorphine is a CYP3A4 substrate and palbociclib is a weak, time dependent CYP3A4 inhibitor. Coadministration can increase buprenorphine exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of buprenorphine If palbociclib is discontinued, buprenorphine plasma concentrations may decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to buprenorphine.
Buprenorphine; Naloxone: (Moderate) Consider a reduced dose of buprenorphine with frequent monitoring for respiratory depression and sedation if concurrent use of palbociclib is necessary. If palbociclib is discontinued, consider increasing the buprenorphine dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Buprenorphine is a CYP3A4 substrate and palbociclib is a weak, time dependent CYP3A4 inhibitor. Coadministration can increase buprenorphine exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of buprenorphine If palbociclib is discontinued, buprenorphine plasma concentrations may decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to buprenorphine.
Buspirone: (Moderate) Monitor for an increase in buspirone-related adverse reactions if coadministration with palbociclib is necessary. If palbociclib is added to a patient stabilized on buspirone, a buspirone dose adjustment may be necessary to avoid adverse events. Palbociclib is a weak time-dependent inhibitor of CYP3A while buspirone is a sensitive CYP3A4 substrate.
Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Monitor for an increase in codeine-related adverse reactions, including sedation and respiratory depression, if coadministration with palbociclib is necessary; consider reducing the dose of codeine if clinically appropriate. If palbociclib is discontinued, monitor for evidence of opioid withdrawal until stable drug effects are achieved and consider increasing the codeine dose if necessary. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Palbociclib is a CYP3A4 inhibitor. Concomitant use may result in an increase in codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and increased morphine concentrations.
Butalbital; Aspirin; Caffeine; Codeine: (Moderate) Monitor for an increase in codeine-related adverse reactions, including sedation and respiratory depression, if coadministration with palbociclib is necessary; consider reducing the dose of codeine if clinically appropriate. If palbociclib is discontinued, monitor for evidence of opioid withdrawal until stable drug effects are achieved and consider increasing the codeine dose if necessary. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Palbociclib is a CYP3A4 inhibitor. Concomitant use may result in an increase in codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and increased morphine concentrations.
Carbamazepine: (Major) Avoid coadministration of carbamazepine with palbociclib due to decreased palbociclib exposure which may compromise efficacy. Palbociclib is a CYP3A substrate and carbamazepine is a strong CYP3A4 inducer. Coadministration with another strong CYP3A inducer decreased palbociclib exposure by 85% after a single dose.
Celecoxib; Tramadol: (Moderate) If coadministration of palbociclib is necessary, monitor for increased tramadol-related adverse effects (e.g., seizures, serotonin syndrome and opioid toxicity including potentially fatal respiratory depression). Consider a tramadol dose reduction until stable drug effects are achieved. If palbociclib is discontinued, monitor for opioid withdrawal symptoms and consider increasing the tramadol dose. Coadministration of palbociclib, a weak time-dependent CYP3A4 inhibitor, may increase tramadol plasma concentrations and may result in increased metabolism of tramadol through 2D6 resulting in higher levels of the active metabolite, M1.
Ceritinib: (Major) Avoid coadministration of palbociclib with ceritinib if possible due to the risk of increased palbociclib exposure. If concomitant use is unavoidable, decrease the dose of palbociclib to 75 mg once daily; the original dose of palbociclib may be resumed after 3 to 5 half-lives of the discontinuation of ceritinib. Palbociclib is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased palbociclib exposure by 87%.
Chloramphenicol: (Major) Avoid coadministration of chloramphenicol with palbociclib; significantly increased palbociclib exposure may occur. If concomitant use cannot be avoided, reduce the dose of palbociclib to 75 mg PO once daily and monitor for increased adverse reactions. If chloramphenicol is discontinued, increase the palbociclib dose (after 3 to 5 half-lives of chloramphenicol) to the dose used before initiation of chloramphenicol. Palbociclib is primarily metabolized by CYP3A4 and chloramphenicol is a strong CYP3A4 inhibitor. In a drug interaction trial, coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of palbociclib by 87% and 34%, respectively.
Chlorpheniramine; Codeine: (Moderate) Monitor for an increase in codeine-related adverse reactions, including sedation and respiratory depression, if coadministration with palbociclib is necessary; consider reducing the dose of codeine if clinically appropriate. If palbociclib is discontinued, monitor for evidence of opioid withdrawal until stable drug effects are achieved and consider increasing the codeine dose if necessary. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Palbociclib is a CYP3A4 inhibitor. Concomitant use may result in an increase in codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and increased morphine concentrations.
Chlorpheniramine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of palbociclib is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like palbociclib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If palbociclib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Cisapride: (Moderate) Monitor for an increase in cisapride-related adverse reactions if coadministration with palbociclib is necessary. Palbociclib is a weak time-dependent inhibitor of CYP3A while cisapride is a CYP3A4 substrate with narrow therapeutic range.
Clarithromycin: (Major) Avoid coadministration of clarithromycin with palbociclib; significantly increased palbociclib exposure may occur. If concomitant use cannot be avoided, reduce the dose of palbociclib to 75 mg PO once daily and monitor for increased adverse reactions. If clarithromycin is discontinued, increase the palbociclib dose (after 3 to 5 half-lives of atazanavir) to the dose used before initiation of clarithromycin. Palbociclib is primarily metabolized by CYP3A4 and clarithromycin is a strong CYP3A4 inhibitor. In a drug interaction trial, coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of palbociclib by 87% and 34%, respectively.
Clozapine: (Moderate) Monitor for an increase in clozapine-related adverse reactions if coadministration with palbociclib is necessary, including seizures, orthostasis, sedation, and QT prolongation; clozapine-related neutropenia is not concentration-dependent. Consider a dosage reduction of clozapine. Palbociclib is a weak time-dependent inhibitor of CYP3A while clozapine is a CYP3A4 substrate.
Cobicistat: (Major) Avoid coadministration of cobicistat with palbociclib; significantly increased plasma exposure of palbociclib may occur. If concomitant use cannot be avoided, reduce the dose of palbociclib to 75 mg PO once daily and monitor for increased adverse reactions. If cobicistat is discontinued, increase the palbociclib dose (after 3 to 5 half-lives of cobicistat) to the dose used before initiation of cobicistat. Palbociclib is primarily metabolized by CYP3A4 and cobicistat is a strong CYP3A4 inhibitor. In a drug interaction trial, coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of palbociclib by 87% and 34%, respectively.
Codeine: (Moderate) Monitor for an increase in codeine-related adverse reactions, including sedation and respiratory depression, if coadministration with palbociclib is necessary; consider reducing the dose of codeine if clinically appropriate. If palbociclib is discontinued, monitor for evidence of opioid withdrawal until stable drug effects are achieved and consider increasing the codeine dose if necessary. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Palbociclib is a CYP3A4 inhibitor. Concomitant use may result in an increase in codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and increased morphine concentrations.
Codeine; Guaifenesin: (Moderate) Monitor for an increase in codeine-related adverse reactions, including sedation and respiratory depression, if coadministration with palbociclib is necessary; consider reducing the dose of codeine if clinically appropriate. If palbociclib is discontinued, monitor for evidence of opioid withdrawal until stable drug effects are achieved and consider increasing the codeine dose if necessary. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Palbociclib is a CYP3A4 inhibitor. Concomitant use may result in an increase in codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and increased morphine concentrations.
Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Monitor for an increase in codeine-related adverse reactions, including sedation and respiratory depression, if coadministration with palbociclib is necessary; consider reducing the dose of codeine if clinically appropriate. If palbociclib is discontinued, monitor for evidence of opioid withdrawal until stable drug effects are achieved and consider increasing the codeine dose if necessary. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Palbociclib is a CYP3A4 inhibitor. Concomitant use may result in an increase in codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and increased morphine concentrations.
Codeine; Phenylephrine; Promethazine: (Moderate) Monitor for an increase in codeine-related adverse reactions, including sedation and respiratory depression, if coadministration with palbociclib is necessary; consider reducing the dose of codeine if clinically appropriate. If palbociclib is discontinued, monitor for evidence of opioid withdrawal until stable drug effects are achieved and consider increasing the codeine dose if necessary. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Palbociclib is a CYP3A4 inhibitor. Concomitant use may result in an increase in codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and increased morphine concentrations.
Codeine; Promethazine: (Moderate) Monitor for an increase in codeine-related adverse reactions, including sedation and respiratory depression, if coadministration with palbociclib is necessary; consider reducing the dose of codeine if clinically appropriate. If palbociclib is discontinued, monitor for evidence of opioid withdrawal until stable drug effects are achieved and consider increasing the codeine dose if necessary. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Palbociclib is a CYP3A4 inhibitor. Concomitant use may result in an increase in codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and increased morphine concentrations.
Cyclosporine: (Moderate) Monitor cyclosporine levels and watch for cyclosporine-related adverse reactions if coadministration with palbociclib is necessary. Palbociclib is a weak time-dependent inhibitor of CYP3A while cyclosporine is a CYP3A4 substrate with narrow therapeutic index.
Darunavir: (Major) Avoid coadministration of darunavir with palbociclib; significantly increased palbociclib exposure may occur. Concentrations of darunavir may also increase. If concomitant use cannot be avoided, reduce the dose of palbociclib to 75 mg PO once daily and monitor for increased adverse reactions. If darunavir is discontinued, increase the palbociclib dose (after 3 to 5 half-lives of darunavir) to the dose used before initiation of darunavir. Palbociclib is primarily metabolized by CYP3A4 and darunavir is a strong CYP3A4 inhibitor. In a drug interaction trial, coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of palbociclib by 87% and 34%, respectively. Palbociclib is also a weak time-dependent inhibitor of CYP3A while darunavir is a sensitive CYP3A4 substrate.
Darunavir; Cobicistat: (Major) Avoid coadministration of cobicistat with palbociclib; significantly increased plasma exposure of palbociclib may occur. If concomitant use cannot be avoided, reduce the dose of palbociclib to 75 mg PO once daily and monitor for increased adverse reactions. If cobicistat is discontinued, increase the palbociclib dose (after 3 to 5 half-lives of cobicistat) to the dose used before initiation of cobicistat. Palbociclib is primarily metabolized by CYP3A4 and cobicistat is a strong CYP3A4 inhibitor. In a drug interaction trial, coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of palbociclib by 87% and 34%, respectively. (Major) Avoid coadministration of darunavir with palbociclib; significantly increased palbociclib exposure may occur. Concentrations of darunavir may also increase. If concomitant use cannot be avoided, reduce the dose of palbociclib to 75 mg PO once daily and monitor for increased adverse reactions. If darunavir is discontinued, increase the palbociclib dose (after 3 to 5 half-lives of darunavir) to the dose used before initiation of darunavir. Palbociclib is primarily metabolized by CYP3A4 and darunavir is a strong CYP3A4 inhibitor. In a drug interaction trial, coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of palbociclib by 87% and 34%, respectively. Palbociclib is also a weak time-dependent inhibitor of CYP3A while darunavir is a sensitive CYP3A4 substrate.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Avoid coadministration of cobicistat with palbociclib; significantly increased plasma exposure of palbociclib may occur. If concomitant use cannot be avoided, reduce the dose of palbociclib to 75 mg PO once daily and monitor for increased adverse reactions. If cobicistat is discontinued, increase the palbociclib dose (after 3 to 5 half-lives of cobicistat) to the dose used before initiation of cobicistat. Palbociclib is primarily metabolized by CYP3A4 and cobicistat is a strong CYP3A4 inhibitor. In a drug interaction trial, coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of palbociclib by 87% and 34%, respectively. (Major) Avoid coadministration of darunavir with palbociclib; significantly increased palbociclib exposure may occur. Concentrations of darunavir may also increase. If concomitant use cannot be avoided, reduce the dose of palbociclib to 75 mg PO once daily and monitor for increased adverse reactions. If darunavir is discontinued, increase the palbociclib dose (after 3 to 5 half-lives of darunavir) to the dose used before initiation of darunavir. Palbociclib is primarily metabolized by CYP3A4 and darunavir is a strong CYP3A4 inhibitor. In a drug interaction trial, coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of palbociclib by 87% and 34%, respectively. Palbociclib is also a weak time-dependent inhibitor of CYP3A while darunavir is a sensitive CYP3A4 substrate.
Delavirdine: (Major) Avoid coadministration of delavirdine with palbociclib; significantly increased palbociclib exposure may occur. If concomitant use cannot be avoided, reduce the dose of palbociclib to 75 mg PO once daily and monitor for increased adverse reactions. If delavirdine is discontinued, increase the palbociclib dose (after 3 to 5 half-lives of delavirdine) to the dose used before initiation of delavirdine. Palbociclib is primarily metabolized by CYP3A4 and delavirdine is a strong CYP3A4 inhibitor. In a drug interaction trial, coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of palbociclib by 87% and 34%, respectively.
Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine.
Diltiazem: (Moderate) Monitor blood pressure and heart rate if coadministration of diltiazem with palbociclib is necessary. Diltiazem is a CYP3A4 substrate and palbociclib is a weak time-dependent CYP3A4 inhibitor.
Disopyramide: (Moderate) Monitor for an increase in disopyramide-related adverse reactions if coadministration with palbociclib is necessary. Disopyramide is a CYP3A4 substrate and palbociclib is a weak time-dependent CYP3A4 inhibitor; concomitant use may increase plasma concentrations of disopyramide. Specific drug interaction studies have not been done for disopyramide; however, cases of life-threatening interactions have been reported when coadministered with moderate and strong CYP3A4 inhibitors. Coadministration of disopyramide with CYP3A4 inhibitors could result in a potentially fatal interaction.
Dofetilide: (Moderate) Monitor for an increase in dofetilide-related adverse reactions, including QT prolongation, if coadministration with palbociclib is necessary. Palbociclib is a weak time-dependent CYP3A4 inhibitor. Dofetilide is a minor CYP3A4 substrate; however, because there is a linear relationship between dofetilide plasma concentration and QTc, concomitant administration of CYP3A4 inhibitors may increase the risk of arrhythmia (torsade de pointes).
Doxorubicin Liposomal: (Major) Avoid coadministration of palbociclib with doxorubicin due to the risk of increased doxorubicin exposure. Palbociclib is a weak time-dependent inhibitor of CYP3A. Doxorubicin is a major substrate of CYP3A4; clinically significant interactions have been reported with other CYP3A4 inhibitors, resulting in increased concentration and clinical effect of doxorubicin.
Doxorubicin: (Major) Avoid coadministration of palbociclib with doxorubicin due to the risk of increased doxorubicin exposure. Palbociclib is a weak time-dependent inhibitor of CYP3A. Doxorubicin is a major substrate of CYP3A4; clinically significant interactions have been reported with other CYP3A4 inhibitors, resulting in increased concentration and clinical effect of doxorubicin.
Dronabinol: (Moderate) Monitor for an increase in dronabinol-related adverse reactions if coadministration with palbociclib is necessary. Dronabinol is a CYP3A4 substrate and palbociclib is a weak time-dependent CYP3A4 inhibitor.
Efavirenz: (Moderate) Monitor for an increase in efavirenz-related adverse reactions if coadministration with palbociclib is necessary. Palbociclib is a weak time-dependent inhibitor of CYP3A while efavirenz is a CYP3A4 substrate.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Monitor for an increase in efavirenz-related adverse reactions if coadministration with palbociclib is necessary. Palbociclib is a weak time-dependent inhibitor of CYP3A while efavirenz is a CYP3A4 substrate.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Monitor for an increase in efavirenz-related adverse reactions if coadministration with palbociclib is necessary. Palbociclib is a weak time-dependent inhibitor of CYP3A while efavirenz is a CYP3A4 substrate.
Eliglustat: (Major) Coadministration of palbociclib, a weak CYP3A4 inhibitor, and eliglustat, a CYP2D6 and CYP3A4 substrate, is not recommended in patients who are CYP2D6 poor metabolizers. In extensive CYP2D6 metabolizers (EM) with mild hepatic impairment, coadministration of these agents requires dosage reduction of eliglustat to 84 mg PO once daily. Monitor for an increase in eliglustat-related adverse reactions during concurrent use of palbociclib in CYP2D6 intermediate and extensive metabolizers. Increased exposure to eliglustat could result in prolongation of the PR, QTc, and/or QRS cardiac interval, which could result in cardiac arrhythmias.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid coadministration of cobicistat with palbociclib; significantly increased plasma exposure of palbociclib may occur. If concomitant use cannot be avoided, reduce the dose of palbociclib to 75 mg PO once daily and monitor for increased adverse reactions. If cobicistat is discontinued, increase the palbociclib dose (after 3 to 5 half-lives of cobicistat) to the dose used before initiation of cobicistat. Palbociclib is primarily metabolized by CYP3A4 and cobicistat is a strong CYP3A4 inhibitor. In a drug interaction trial, coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of palbociclib by 87% and 34%, respectively.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of cobicistat with palbociclib; significantly increased plasma exposure of palbociclib may occur. If concomitant use cannot be avoided, reduce the dose of palbociclib to 75 mg PO once daily and monitor for increased adverse reactions. If cobicistat is discontinued, increase the palbociclib dose (after 3 to 5 half-lives of cobicistat) to the dose used before initiation of cobicistat. Palbociclib is primarily metabolized by CYP3A4 and cobicistat is a strong CYP3A4 inhibitor. In a drug interaction trial, coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of palbociclib by 87% and 34%, respectively.
Encorafenib: (Major) Avoid coadministration of palbociclib with encorafenib due to the risk of decreased palbociclib exposure and reduced efficacy. Palbociclib is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration of another strong CYP3A inducer decreased the plasma exposure of palbociclib 85%.
Enzalutamide: (Major) Avoid coadministration of enzalutamide with palbociclib due to decreased plasma concentrations of palbociclib, which may result in decreased efficacy. Palbociclib is primarily metabolized by CYP3A4 and enzalutamide is a strong CYP3A4 inducer. In a drug interaction trial, coadministration with another strong CYP3A4 inducer decreased the AUC and Cmax of palbociclib by 85% and 70%, respectively.
Ethosuximide: (Moderate) Monitor for an increase in ethosuximide-related adverse reactions if coadministration with palbociclib is necessary. Ethosuximide is a CYP3A4 substrate with a narrow therapeutic index and palbociclib is a weak time-dependent CYP3A4 inhibitor.
Felodipine: (Moderate) Monitor blood pressure if coadministration of felodipine and palbociclib is necessary. Felodipine is a sensitive substrate of CYP3A4 and palbociclib is a weak, time-dependent CYP3A4 inhibitor. Concomitant use may increase felodipine exposure.
Fentanyl: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of palbociclib is necessary. If palbociclib is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like palbociclib can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If palbociclib is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Finerenone: (Moderate) Monitor serum potassium during initiation or dose adjustment of either finerenone or palbociclib; a finerenone dosage reduction may be necessary. Concomitant use may increase finerenone exposure and the risk of hyperkalemia. Finerenone is a CYP3A substrate and palbociclib is a weak CYP3A inhibitor. Coadministration with another weak CYP3A inhibitor increased overall exposure to finerenone by 21%.
Flibanserin: (Moderate) The concomitant use of flibanserin and multiple weak CYP3A4 inhibitors, including palbociclib, may increase flibanserin concentrations, which may increase the risk of flibanserin-induced adverse reactions. Therefore, patients should be monitored for hypotension, syncope, somnolence, or other adverse reactions, and the risks of combination therapy with multiple weak CYP3A4 inhibitors and flibanserin should be discussed with the patient.
Fosamprenavir: (Major) Avoid coadministration of fosamprenavir with palbociclib; significantly increased palbociclib exposure may occur. If concomitant use cannot be avoided, reduce the dose of palbociclib to 75 mg PO once daily and monitor for increased adverse reactions. If fosamprenavir is discontinued, increase the palbociclib dose (after 3 to 5 half-lives of fosamprenavir) to the dose used before initiation of fosamprenavir. Palbociclib is primarily metabolized by CYP3A4 and fosamprenavir is a strong CYP3A4 inhibitor. In a drug interaction trial, coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of palbociclib by 87% and 34%, respectively.
Fosphenytoin: (Major) Avoid coadministration of fosphenytoin with palbociclib due to decreased plasma concentrations of palbociclib, which may result in decreased efficacy. Palbociclib is primarily metabolized by CYP3A4 and fosphenytoin is a strong CYP3A4 inducer. In a drug interaction trial, coadministration with another strong CYP3A4 inducer decreased the AUC and Cmax of palbociclib by 85% and 70%, respectively.
Grapefruit juice: (Major) Avoid concomitant use of palbociclib, a CYP3A4 substrate and grapefruit juice, a strong CYP3A4 inhibitor, as palbociclib plasma exposure may increase.
Guaifenesin; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of palbociclib is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like palbociclib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If palbociclib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Haloperidol: (Moderate) Monitor for an increase in haloperidol-related adverse reactions if coadministration with palbociclib is necessary. Haloperidol is a CYP3A4 substrate and palbociclib is a weak, time-dependent CYP3A4 inhibitor. In clinical trials, mild to moderately increased haloperidol concentrations have been reported when haloperidol was given concomitantly with CYP3A4 inhibitors.
Homatropine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of palbociclib is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like palbociclib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If palbociclib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of palbociclib is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like palbociclib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If palbociclib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydrocodone; Ibuprofen: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of palbociclib is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like palbociclib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If palbociclib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of palbociclib is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like palbociclib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If palbociclib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Ibuprofen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of palbociclib is necessary. If palbociclib is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a weak inhibitor like palbociclib can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If palbociclib is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Idelalisib: (Major) Avoid coadministration of idelalisib with palbociclib; significantly increased palbociclib exposure may occur. If concomitant use cannot be avoided, reduce the dose of palbociclib to 75 mg PO once daily and monitor for increased adverse reactions. If idelalisib is discontinued, increase the palbociclib dose (3 to 5 half-lives of idelalisib) to the dose used before the initiation of idelalislib. Palbociclib is primarily metabolized by CYP3A4 and idelalisib is a strong CYP3A4 inhibitor. In a drug interaction trial, coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of palbociclib by 87% and 34%, respectively.
Indinavir: (Major) Avoid coadministration of indinavir with palbociclib; significantly increased palbociclib exposure may occur. Concentrations of indinavir may also increase. If concomitant use cannot be avoided, reduce the dose of palbociclib to 75 mg PO once daily and monitor for increased adverse reactions. If indinavir is discontinued, increase the palbociclib dose (after 3 to 5 half-lives of indinavir) to the dose used before initiation of indinavir. Palbociclib is primarily metabolized by CYP3A4 and indinavir is a strong CYP3A4 inhibitor. In a drug interaction trial, coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of palbociclib by 87% and 34%, respectively. Palbociclib is also a weak time-dependent inhibitor of CYP3A and indinavir is a sensitive CYP3A4 substrate.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid coadministration of rifampin with palbociclib due to decreased plasma concentrations of palbociclib, which may result in decreased efficacy. Palbociclib is primarily metabolized by CYP3A4 and rifampin is a strong CYP3A4 inducer. In a drug interaction trial, coadministration with rifampin decreased the AUC and Cmax of palbociclib by 85% and 70%, respectively.
Isoniazid, INH; Rifampin: (Major) Avoid coadministration of rifampin with palbociclib due to decreased plasma concentrations of palbociclib, which may result in decreased efficacy. Palbociclib is primarily metabolized by CYP3A4 and rifampin is a strong CYP3A4 inducer. In a drug interaction trial, coadministration with rifampin decreased the AUC and Cmax of palbociclib by 85% and 70%, respectively.
Isradipine: (Moderate) Monitor blood pressure if coadministration of isradipine with palbociclib is necessary. Isradipine is a CYP3A4 substrate and palbociclib is a weak, time-dependent CYP3A4 inhibitor. Coadministration with another weak CYP3A4 inhibitor increased isradipine exposure by 50%.
Itraconazole: (Major) Avoid coadministration of itraconazole with palbociclib; significantly increased plasma exposure of palbociclib may occur. If concomitant use cannot be avoided, reduce the dose of palbociclib to 75 mg PO once daily and monitor for increased adverse reactions. If itraconazole is discontinued, increase the palbociclib dose (after 3 to 5 half-lives of itraconazole) to the dose used before initiation of itraconazole. Palbociclib is primarily metabolized by CYP3A4 and itraconazole is a strong CYP3A4 inhibitor. In a drug interaction trial, coadministration with itraconazole increased the AUC and Cmax of palbociclib by 87% and 34%, respectively.
Ixabepilone: (Moderate) Monitor for ixabepilone toxicity and reduce the ixabepilone dose as needed if concurrent use of palbociclib is necessary. Concomitant use may increase ixabepilone exposure and the risk of adverse reactions. Ixabepilone is a CYP3A substrate and palbociclib is a weak CYP3A inhibitor.
Ketoconazole: (Major) Avoid coadministration of ketoconazole with palbociclib; significantly increased plasma exposure of palbociclib may occur. If concomitant use cannot be avoided, reduce the dose of palbociclib to 75 mg PO once daily and monitor for increased adverse reactions. If ketoconazole is discontinued, increase the palbociclib dose (after 3 to 5 half-lives of ketoconazole) to the dose used before initiation of ketoconazole. Palbociclib is primarily metabolized by CYP3A4 and ketoconazole is a strong CYP3A4 inhibitor. In a drug interaction trial, coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of palbociclib by 87% and 34%, respectively.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) Avoid coadministration of clarithromycin with palbociclib; significantly increased palbociclib exposure may occur. If concomitant use cannot be avoided, reduce the dose of palbociclib to 75 mg PO once daily and monitor for increased adverse reactions. If clarithromycin is discontinued, increase the palbociclib dose (after 3 to 5 half-lives of atazanavir) to the dose used before initiation of clarithromycin. Palbociclib is primarily metabolized by CYP3A4 and clarithromycin is a strong CYP3A4 inhibitor. In a drug interaction trial, coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of palbociclib by 87% and 34%, respectively.
Lemborexant: (Major) Limit the dose of lemborexant to a maximum of 5 mg PO once daily if coadministered with palbociclib as concurrent use may increase lemborexant exposure and the risk of adverse effects. Lemborexant is a CYP3A4 substrate; palbociclib is a weak CYP3A4 inhibitor. Coadministration of lemborexant with a weak CYP3A4 inhibitor is predicted to increase lemborexant exposure by less than 2-fold.
Letermovir: (Moderate) Caution is advised when administering palbociclib with letermovir, as taking these drugs together may increase palbociclib concentration and risk for adverse events. Avoid coadministration in patients also receiving cyclosporine because the magnitude of this interaction may be increased. If coadministration cannot be avoided, reduce the palbociclib dose to 75 mg/day. If letermovir or cyclosporine is discontinued, resume the prior palbociclib dose after 3 to 5 half-lives of the discontinued drug. Palbociclib is a substrate of CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Concurrent administration with a strong CYP3A inhibitor increased the exposure (AUC) and maximum plasma concentration (Cmax) of palbociclib by 87% and 34%, respectively.
Levoketoconazole: (Major) Avoid coadministration of ketoconazole with palbociclib; significantly increased plasma exposure of palbociclib may occur. If concomitant use cannot be avoided, reduce the dose of palbociclib to 75 mg PO once daily and monitor for increased adverse reactions. If ketoconazole is discontinued, increase the palbociclib dose (after 3 to 5 half-lives of ketoconazole) to the dose used before initiation of ketoconazole. Palbociclib is primarily metabolized by CYP3A4 and ketoconazole is a strong CYP3A4 inhibitor. In a drug interaction trial, coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of palbociclib by 87% and 34%, respectively.
Lidocaine: (Moderate) Concomitant use of systemic lidocaine and palbociclib may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; palbociclib inhibits CYP3A4.
Lidocaine; Epinephrine: (Moderate) Concomitant use of systemic lidocaine and palbociclib may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; palbociclib inhibits CYP3A4.
Lidocaine; Prilocaine: (Moderate) Concomitant use of systemic lidocaine and palbociclib may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; palbociclib inhibits CYP3A4.
Lomitapide: (Major) Concomitant use of lomitapide and palbociclib may significantly increase the serum concentration of lomitapide. Therefore, the lomitapide dose should not exceed 30 mg/day PO during concurrent use. Palbociclib is a weak, time-dependent CYP3A4 inhibitor; the exposure to lomitapide is increased by approximately 2-fold in the presence of weak CYP3A4 inhibitors.
Lonafarnib: (Major) Avoid coadministration of lonafarnib and palbociclib; concurrent use may increase the exposure of both drugs and the risk of adverse effects. If coadministration is unavoidable, reduce the dose of palbociclib to 75 mg PO once daily and reduce to or continue lonafarnib at a dosage of 115 mg/m2; closely monitor patients for adverse reactions from both drugs. If lonafarnib is discontinued, increase the palbociclib dose (after 3 to 5 half-lives of lonafarnib) to the dose used before initiation of lonafarnib. Resume previous lonafarnib dosage 14 days after discontinuing palbociclib. Lonafarnib is a sensitive CYP3A4 substrate and strong CYP3A4 inhibitor; palbociclib is a CYP3A4 substrate and weak CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of palbociclib by 87%.
Lopinavir; Ritonavir: (Major) Avoid coadministration of ritonavir with palbociclib; significantly increased plasma exposure of palbociclib may occur. If concomitant use cannot be avoided, reduce the dose of palbociclib to 75 mg PO once daily and monitor for increased adverse reactions. If ritonavir is discontinued, increase the palbociclib dose (after 3 to 5 half-lives of ritonavir) to the dose used before initiation of ritonavir. Palbociclib is primarily metabolized by CYP3A4 and ritonavir is a strong CYP3A4 inhibitor. In a drug interaction trial, coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of palbociclib by 87% and 34%, respectively. (Moderate) Concentrations of lopinavir may increase when adminstered concurrently with palbociclib. Palbociclib is a weak, time-dependent inhibitor of CYP3A and lopinavir is a sensitive CYP3A4 substrate.
Lumacaftor; Ivacaftor: (Major) Avoid coadministration of lumacaftor; ivacaftor with palbociclib due to decreased plasma concentrations of palbociclib, which may result in decreased efficacy. Palbociclib is primarily metabolized by CYP3A4, lumacaftor is a strong CYP3A4 inducer. In a drug interaction trial, coadministration with another strong CYP3A4 inducer decreased the AUC and Cmax of palbociclib by 85% and 70%, respectively.
Lumacaftor; Ivacaftor: (Major) Avoid coadministration of lumacaftor; ivacaftor with palbociclib due to decreased plasma concentrations of palbociclib, which may result in decreased efficacy. Palbociclib is primarily metabolized by CYP3A4, lumacaftor is a strong CYP3A4 inducer. In a drug interaction trial, coadministration with another strong CYP3A4 inducer decreased the AUC and Cmax of palbociclib by 85% and 70%, respectively.
Methadone: (Moderate) Closely monitor for an increase in methadone-related adverse reactions (e.g., sedation, respiratory depression) if coadministration with palbociclib is necessary. Consider a methadone dose reduction until stable drug effects are achieved. The addition of palbociclib, a weak time-dependent inhibitor of CYP3A, and methadone, a sensitive CYP3A4 substrate, may increase methadone serum concentrations and prolong opioid adverse effects. Fatal respiratory depression may occur, especially if a CYP3A4 inhibitor is added to a stable dose of methadone. If palbociclib is discontinued, monitor for signs of opioid withdrawal.
Midazolam: (Moderate) Monitor for an increase in midazolam-related adverse reactions (e.g., sedation, respiratory depression) if coadministration with palbociclib is necessary. Palbociclib is a weak time-dependent inhibitor of CYP3A and midazolam is a sensitive CYP3A4 substrate. In a drug interaction trial in healthy subjects (n = 26), coadministration with palbociclib increased the AUC and Cmax of midazolam by 61% and 37%, respectively.
Mifepristone: (Major) Avoid coadministration of chronic mifepristone with palbociclib due to increased palbociclib exposure. If concomitant use is unavoidable, reduce the dose of palbociclib to 75 mg once daily. If mifepristone is discontinued, wait 3 to 5 half-lives of mifepristone and then increase palbociclib to its original dose. Palbociclib is a CYP3A substrate and mifepristone is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A inhibitor increased palbociclib exposure after a single dose by approximately 87%. The clinical significance of this interaction with the short-term use of mifepristone for termination of pregnancy is unknown.
Mitotane: (Major) Avoid coadministration of mitotane with palbociclib due to decreased plasma concentrations of palbociclib, which may result in decreased efficacy. Palbociclib is primarily metabolized by CYP3A4 and mitotane is a strong CYP3A4 inducer. In a drug interaction trial, coadministration with another strong CYP3A4 inducer decreased the AUC and Cmax of palbociclib by 85% and 70%, respectively.
Nanoparticle Albumin-Bound Sirolimus: (Major) Reduce the nab-sirolimus dose to 56 mg/m2 during concomitant use of palbociclib. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and palbociclib is a weak CYP3A inhibitor.
Nefazodone: (Major) Avoid coadministration of nefazodone with palbociclib; significantly increased palbociclib exposure may occur. If concomitant use cannot be avoided, reduce the dose of palbociclib to 75 mg PO once daily and monitor for increased adverse reactions. If nefazodone is discontinued, increase the palbociclib dose (after 3 to 5 half-lives of nefazodone) to the dose used before initiation of nefazodone. Palbociclib is primarily metabolized by CYP3A4 and nefazodone is a strong CYP3A4 inhibitor. In a drug interaction trial, coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of palbociclib by 87% and 34%, respectively.
Nelfinavir: (Major) Avoid coadministration of nelfinavir with palbociclib; significantly increased palbociclib exposure may occur. If concomitant use cannot be avoided, reduce the dose of palbociclib to 75 mg PO once daily and monitor for increased adverse reactions. If nelfinavir is discontinued, increase the palbociclib dose (after 3 to 5 half-lives of nelfinavir) to the dose used before initiation of nelfinavir. Palbociclib is primarily metabolized by CYP3A4 and nelfinavir is a strong CYP3A4 inhibitor. In a drug interaction trial, coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of palbociclib by 87% and 34%, respectively.
Nimodipine: (Moderate) Monitor blood pressure if coadministration of nimodipine with palbociclib is necessary; a reduction of the nimodipine dose may be necessary. Nimodipine is a CYP3A4 substrate and palbociclib is a weak, time-dependent CYP3A4 inhibitor. Coadministration with another weak CYP3A4 inhibitor increased mean peak nimodipine plasma concentrations by 50% and increased the mean AUC by 90%.
Nirmatrelvir; Ritonavir: (Major) Avoid coadministration of ritonavir with palbociclib; significantly increased plasma exposure of palbociclib may occur. If concomitant use cannot be avoided, reduce the dose of palbociclib to 75 mg PO once daily and m onitor for increased adverse reactions. If ritonavir is discontinued, increase the palbociclib dose (after 3 to 5 half-lives of ritonavir) to the dose used before initiation of ritonavir. Palbociclib is primarily metabolized by CYP3A4 and ritonavir is a strong CYP3A4 inhibitor. In a drug interaction trial, coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of palbociclib by 87% and 34%, respectively.
Nisoldipine: (Major) Avoid coadministration of nisoldipine with palbociclib due to increased plasma concentrations of nisoldipine. If coadministration is unavoidable, monitor blood pressure closely during concurrent use of these medications. Nisoldipine is a CYP3A4 substrate and palbociclib is a CYP3A4 inhibitor.
Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of palbociclib is necessary. If palbociclib is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a weak inhibitor like palbociclib can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If palbociclib is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Phenobarbital: (Major) Avoid coadministration of phenobarbital with palbociclib due to decreased plasma concentrations of palbociclib, which may result in decreased efficacy. Palbociclib is primarily metabolized by CYP3A4 and phenobarbital is a strong CYP3A4 inducer. In a drug interaction trial, coadministration with another strong CYP3A4 inducer decreased the AUC and Cmax of palbociclib by 85% and 70%, respectively.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Avoid coadministration of phenobarbital with palbociclib due to decreased plasma concentrations of palbociclib, which may result in decreased efficacy. Palbociclib is primarily metabolized by CYP3A4 and phenobarbital is a strong CYP3A4 inducer. In a drug interaction trial, coadministration with another strong CYP3A4 inducer decreased the AUC and Cmax of palbociclib by 85% and 70%, respectively.
Phenytoin: (Major) Avoid coadministration of phenytoin with palbociclib due to decreased plasma concentrations of palbociclib, which may result in decreased efficacy. Palbociclib is primarily metabolized by CYP3A4 and phenytoin is a strong CYP3A4 inducer. In a drug interaction trial, coadministration with another strong CYP3A4 inducer decreased the AUC and Cmax of palbociclib by 85% and 70%, respectively.
Pimozide: (Major) Monitor for an increase in pimozide-related adverse reactions if coadministration with palbociclib is necessary. The dose of pimozide may need to be reduced. Palbociclib is a weak time-dependent inhibitor of CYP3A while pimozide is a CYP3A4 substrate with a narrow therapeutic index.
Posaconazole: (Major) Avoid coadministration of posaconazole with palbociclib; significantly increased palbociclib exposure may occur. If concomitant use cannot be avoided, reduce the dose of palbociclib to 75 mg PO once daily and monitor for increased adverse reactions. If posaconazole is discontinued, increase the palbociclib dose (after 3 to 5 half-lives of posaconazole) to the dose used before initiation of posaconazole. Palbociclib is primarily metabolized by CYP3A4 and posaconazole is a strong CYP3A4 inhibitor. In a drug interaction trial, coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of palbociclib by 87% and 34%, respectively.
Primidone: (Major) Avoid coadministration of primidone with palbociclib due to decreased plasma concentrations of palbociclib, which may result in decreased efficacy. Palbociclib is primarily metabolized by CYP3A4 and primidone is a strong CYP3A4 inducer. In a drug interaction trial, coadministration with another strong CYP3A4 inducer decreased the AUC and Cmax of palbociclib by 85% and 70%, respectively.
Ribociclib: (Major) Avoid coadministration of palbociclib with ribociclib if possible due to the risk of increased palbociclib exposure. If concomitant use is unavoidable, decrease the dose of palbociclib to 75 mg once daily; the original dose of palbociclib may be resumed after 3 to 5 half-lives of the discontinuation of ribociclib. Palbociclib is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased palbociclib exposure by 87%.
Ribociclib; Letrozole: (Major) Avoid coadministration of palbociclib with ribociclib if possible due to the risk of increased palbociclib exposure. If concomitant use is unavoidable, decrease the dose of palbociclib to 75 mg once daily; the original dose of palbociclib may be resumed after 3 to 5 half-lives of the discontinuation of ribociclib. Palbociclib is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased palbociclib exposure by 87%.
Rifampin: (Major) Avoid coadministration of rifampin with palbociclib due to decreased plasma concentrations of palbociclib, which may result in decreased efficacy. Palbociclib is primarily metabolized by CYP3A4 and rifampin is a strong CYP3A4 inducer. In a drug interaction trial, coadministration with rifampin decreased the AUC and Cmax of palbociclib by 85% and 70%, respectively.
Rifapentine: (Major) Avoid coadministration of palbociclib with rifapentine due to the risk of decreased palbociclib exposure and reduced efficacy. Palbociclib is a CYP3A4 substrate and rifapentine is a strong CYP3A4 inducer. Coadministration of another strong CYP3A4 inducer decreased the plasma exposure of palbociclib 85%.
Ritonavir: (Major) Avoid coadministration of ritonavir with palbociclib; significantly increased plasma exposure of palbociclib may occur. If concomitant use cannot be avoided, reduce the dose of palbociclib to 75 mg PO once daily and monitor for increased adverse reactions. If ritonavir is discontinued, increase the palbociclib dose (after 3 to 5 half-lives of ritonavir) to the dose used before initiation of ritonavir. Palbociclib is primarily metabolized by CYP3A4 and ritonavir is a strong CYP3A4 inhibitor. In a drug interaction trial, coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of palbociclib by 87% and 34%, respectively.
Saquinavir: (Major) Avoid coadministration of saquinavir with palbociclib; significantly increased plasma exposure of palbociclib may occur. Concentrations of saquinavir may also increase. If concomitant use cannot be avoided, reduce the dose of palbociclib to 75 mg PO once daily and monitor for increased adverse reactions. If saquinavir is discontinued, increase the palbociclib (after 3 to 5 half-lives of saquinavir) to the dose used before initiation of saquinavir. Palbociclib is primarily metabolized by CYP3A4 and saquinavir is a strong CYP3A4 inhibitor. In a drug interaction trial, coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of palbociclib by 87% and 34%, respectively. Palbociclib is also a weak time-dependent inhibitor of CYP3A while saquinavir is a sensitive CYP3A4 substrate that may increase the QT interval in a dose-dependent fashion.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Sirolimus: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of palbociclib. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and palbociclib is a weak CYP3A inhibitor.
St. John's Wort, Hypericum perforatum: (Major) Avoid coadministration of St. Johns Wort with palbociclib due to decreased plasma concentrations of palbociclib, which may result in decreased efficacy. Palbociclib is primarily metabolized by CYP3A4 and St. Johns Wort is a strong CYP3A4 inducer, although the amount of individual constituents in various products may alter the inducing effects, making drug interactions unpredictable. In a drug interaction trial, coadministration with another strong CYP3A4 inducer decreased the AUC and Cmax of palbociclib by 85% and 70%, respectively.
Sufentanil: (Moderate) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if palbociclib must be administered. Consider a reduced dose of sufentanil injection with frequent monitoring for respiratory depression and sedation if concurrent use of palbociclib is necessary. If palbociclib is discontinued, consider increasing the sufentanil injection dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Sufentanil is a CYP3A4 substrate, and coadministration with a weak CYP3A4 inhibitor like palbociclib can increase sufentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of sufentanil. If palbociclib is discontinued, sufentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to sufentanil.
Tacrolimus: (Moderate) Monitor tacrolimus concentrations and watch for an increase in tacrolimus-related adverse reactions if coadministration with palbociclib is necessary. The tacrolimus dose may need to be reduced. Palbociclib is a weak time-dependent inhibitor of CYP3A and tacrolimus is a sensitive CYP3A4 substrate with a narrow therapeutic index.
Tipranavir: (Major) Avoid coadministration of tipranavir with palbociclib; significantly increased palbociclib exposure may occur. Concentrations of tipranavir may also increase. If concomitant use cannot be avoided, reduce the dose of palbociclib to 75 mg PO once daily and monitor for increased adverse reactions. If tipranavir is discontinued, increase the palbociclib dose (after 3 to 5 half-lives of tipranavir) to the dose used before initiation of tipranavir. Palbociclib is primarily metabolized by CYP3A4 and tipranavir is a strong CYP3A4 inhibitor. In a drug interaction trial, coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of palbociclib by 87% and 34%, respectively. Palbociclib is also a weak time-dependent inhibitor of CYP3A and tipranavir is a sensitive CYP3A4 substrate.
Tramadol: (Moderate) If coadministration of palbociclib is necessary, monitor for increased tramadol-related adverse effects (e.g., seizures, serotonin syndrome and opioid toxicity including potentially fatal respiratory depression). Consider a tramadol dose reduction until stable drug effects are achieved. If palbociclib is discontinued, monitor for opioid withdrawal symptoms and consider increasing the tramadol dose. Coadministration of palbociclib, a weak time-dependent CYP3A4 inhibitor, may increase tramadol plasma concentrations and may result in increased metabolism of tramadol through 2D6 resulting in higher levels of the active metabolite, M1.
Tramadol; Acetaminophen: (Moderate) If coadministration of palbociclib is necessary, monitor for increased tramadol-related adverse effects (e.g., seizures, serotonin syndrome and opioid toxicity including potentially fatal respiratory depression). Consider a tramadol dose reduction until stable drug effects are achieved. If palbociclib is discontinued, monitor for opioid withdrawal symptoms and consider increasing the tramadol dose. Coadministration of palbociclib, a weak time-dependent CYP3A4 inhibitor, may increase tramadol plasma concentrations and may result in increased metabolism of tramadol through 2D6 resulting in higher levels of the active metabolite, M1.
Triazolam: (Moderate) Monitor for signs of triazolam toxicity during coadministration with palbociclib and consider appropriate dose reduction of triazolam if clinically indicated. Coadministration may increase triazolam exposure. Triazolam is a sensitive CYP3A substrate and palbociclib is a weak CYP3A inhibitor.
Tucatinib: (Major) Avoid coadministration of palbociclib with tucatinib; significantly increased plasma exposure of palbociclib may occur. If concomitant use cannot be avoided, reduce the dose of palbociclib to 75 mg PO once daily and monitor for increased adverse reactions. If tucatinib is discontinued, increase the palbociclib dose (after 3 to 5 half-lives of tucatinib) to the dose used before initiation of tucatinib. Palbociclib is primarily metabolized by CYP3A4 and tucatinib is a strong CYP3A4 inhibitor. In a drug interaction trial, coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of palbociclib by 87% and 34%, respectively.
Ubrogepant: (Major) Limit the initial and second dose of ubrogepant to 50 mg if coadministered with palbociclib. Concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a CYP3A4 substrate; palbociclib is a weak CYP3A4 inhibitor.
Vinorelbine: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with palbociclib is necessary. Vinorelbine is a CYP3A4 substrate and palbociclib is a weak CYP3A4 inhibitor.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) Avoid coadministration of clarithromycin with palbociclib; significantly increased palbociclib exposure may occur. If concomitant use cannot be avoided, reduce the dose of palbociclib to 75 mg PO once daily and monitor for increased adverse reactions. If clarithromycin is discontinued, increase the palbociclib dose (after 3 to 5 half-lives of atazanavir) to the dose used before initiation of clarithromycin. Palbociclib is primarily metabolized by CYP3A4 and clarithromycin is a strong CYP3A4 inhibitor. In a drug interaction trial, coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of palbociclib by 87% and 34%, respectively.
Voriconazole: (Major) Avoid coadministration of voriconazole with palbociclib; significantly increased plasma exposure of palbociclib may occur. If concomitant use cannot be avoided, reduce the dose of palbociclib to 75 mg PO once daily and monitor for increased adverse reactions. If voriconazole is discontinued, increase the palbociclib dose (after 3 to 5 half-lives of voriconazole) to the dose used before initiation of voriconazole. Palbociclib is primarily metabolized by CYP3A4 and voriconazole is a strong CYP3A4 inhibitor. In a drug interaction trial, coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of palbociclib by 87% and 34%, respectively.
Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with palbociclib is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Palbociclib is a weak CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Zolpidem: (Moderate) Monitor for an increase in sedation and other zolpidem-related adverse reactions if coadministration with palbociclib is necessary. Zolpidem is a CYP3A4 substrate and palbociclib is a weak, time-dependent CYP3A4 inhibitor.

Ibrance Oral Cap: 75mg, 100mg, 125mg
Ibrance Oral Tab: 75mg, 100mg, 125mg

125 mg/day PO.

125 mg/day PO.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Not indicated.

Not indicated.

Palbociclib is a cyclin-dependent kinase (CDK) 4 and 6 inhibitor. Cyclin D1 and CDK 4/6 are downstream of signaling pathways that lead to cellular proliferation. In vitro, palbociclib inhibited progression of the cell cycle from G1 into S phase, resulting in decreased proliferation of ER-positive breast cancer cell lines. When combined with antiestrogen therapy (e.g., letrozole), palbociclib decreases retinoblastoma protein (Rb) phosphorylation, reducing E2F expression and signaling, and increasing growth arrest compared to palbociclib or antiestrogen monotherapy. In vitro, combination therapy with antiestrogens also increased cell senescence compared with either drug alone, which was sustained for up to 6 days after palbociclib removal and was greater if the antiestrogen treatment was continued. Human bone marrow mononuclear cells treated with palbociclib in the presence or absence of an antiestrogen in vitro did not become senescent and resumed proliferation following palbociclib withdrawal.

Palbociclib is administered orally. Palbociclib is approximately 85% protein bound in vitro, which is not concentration-dependent. The geometric mean apparent volume of distribution (Vz/F) was 2,583 L (26% CV). The primary metabolic pathway in humans are oxidation via CYP3A and sulfonation via SULT2A1; acylation and glucuronidation are minor pathways of metabolism. The geometric mean apparent clearance (CL/F) was 63.1 L/hour (29% CV) in patients with advanced breast cancer. Unchanged drug accounts for 2.3% and 6.9% of radioactivity in the feces and urine, respectively. In healthy patients, 74.1% of a radioactive dose was recovered in the feces as metabolites, with 91.6% of the dose recovered in 15 days. The mean plasma elimination half-life was 29 +/- 5 hours in patients with advanced breast cancer.
 
Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: CYP3A
Palbociclib is primarily metabolized in the liver by CYP3A; concomitant administration of strong CYP3A inhibitors may increase palbociclib concentrations significantly; avoid use when possible. Potent CYP3A inducers may significantly reduce palbociclib exposure; consider alternative therapeutic agents with less potential for CYP3A induction. In vivo, palbociclib is also a weak time-dependent inhibitor of CYP3A.

Fetal harm may occur if palbociclib is administered during pregnancy, based on animal studies. The use of effective contraception is recommended to avoid pregnancy during treatment and for at least 3 weeks following the last dose. No human data are available regarding teratogenic risk. Women who become pregnant while receiving palbociclib should be apprised of the potential hazard to the fetus. During the period of organogenesis, exposures of greater than or equal to 4 times the human exposure at the recommended dose resulted in reduced fetal body weights and an increased incidence of skeletal variations in rats; an increased incidence of skeletal variations was noted in rabbits at exposures of 9 times the human exposure that the recommended dose.

According to the manufacturer, breast-feeding should be discontinued during treatment with palbociclib and for at least 3 weeks after the last dose because of the potential for serious adverse reactions in a nursing infant from drug exposure. It is not known if palbociclib is excreted into human milk.