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  • CLASSES

    Protein Kinase Inhibitors

    DEA CLASS

    Rx

    DESCRIPTION

    Oral, selective inhibitor of cyclin-dependent kinases (CDKs) 4 and 6 that prevents the deactivation of the retinoblastoma susceptibility gene protein, thereby interfering with tumor cell progression
    Used for the treatment of HR-positive, HER2-negative metastatic breast cancer in combination with an aromatase inhibitor in postmenopausal women who have not yet received an endocrine-based therapy, and in combination with fulvestrant in women with disease progression following endocrine therapy
    Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary

    COMMON BRAND NAMES

    Ibrance

    HOW SUPPLIED

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

    DOSAGE & INDICATIONS

    For the treatment of breast cancer.
    For the treatment of hormone receptor (HR)-positive, HER2-negative advanced breast cancer in postmenopausal women, in combination with an aromatase inhibitor as initial endocrine-based therapy.
    Oral dosage
    Adult females

    125 mg PO once daily with food for 21 days, followed by 7 days off, repeated every 28 days in combination with an aromatase inhibitor (at the recommended dose) until progressive disease or unacceptable toxicity occurs. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In an international, double-blind, parallel group clinical trial, postmenopausal women with ER-positive, HER2-negative advanced breast cancer who had not received previous systemic treatment for advanced disease were randomized to treatment with letrozole plus palbociclib (n = 444) or letrozole plus placebo (n = 222). Median progression-free survival (PFS) was significantly improved in the palbociclib arm compared with placebo (24.8 months vs. 14.5 months; HR 0.576; p < 0.0001); overall survival data were not yet mature. The objective response rate in patients with measurable disease was 55.3% in patients treated with letrozole plus palbociclib versus 44.4% in those receiving letrozole plus placebo.

    For the treatment of hormone receptor (HR)-positive, HER2-negative advanced or metastatic breast cancer, in combination with fulvestrant after disease progression following endocrine-based therapy.
    Oral dosage
    Adult females

    125 mg PO once daily with food for 21 days, followed by 7 days off, repeated every 28 days in combination with fulvestrant (500 mg IM as two 5 mL injections, one in each buttock, over 1 to 2 minutes on days 1, 15, 29, and once monthly thereafter) until progressive disease or unacceptable toxicity occurs. Premenopausal and perimenopausal women should also be treated with luteinizing hormone-releasing hormone (LHRH) agonists, according to current clinical practice standards. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Women (regardless of menopausal status) with endocrine therapy-resistant, HR-positive, HER2-negative advanced breast cancer were randomized to receive palbociclib plus fulvestrant (n = 347) or fulvestrant plus placebo (n = 174) in an international, randomized, double-blind, placebo-controlled clinical trial. Investigator assessed progression-free survival (PFS) was 9.5 months in the palbociclib group compared with 4.6 months in those who received placebo (HR 0.461; p < 0.0001), with a response duration of 9.3 months and 7.6 months, respectively; results were consistent across subgroups of disease site, sensitivity to prior hormonal therapy, and menopausal status. Investigator-assessed confirmed overall response rate was 24.6% in those treated with palbociclib and fulvestrant, compared with 10.9% in patients who received fulvestrant plus placebo. Overall survival data were not mature at the time of the PFS analysis.

    MAXIMUM DOSAGE

    Adults

    125 mg/day PO.

    Geriatric

    125 mg/day PO.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Not indicated.

    Neonates

    Not indicated.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Baseline Hepatic Impairment:
    Mild hepatic impairment (total bilirubin less than or equal to the upper limit of normal (ULN) and AST greater than ULN, or total bilirubin greater than 1 to 1.5 times ULN and any AST): No adjustment is needed to the starting dose of palbociclib
    Moderate to Severe hepatic impairment: Palbociclib has not been studied in these patients; however the drug is extensively metabolized in the liver. Closely monitor these patients and adjust the dose if not tolerated.
     
    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.

    Renal Impairment

    Baseline Renal Impairment:
    CrCL greater than or equal to 30 mL/min: No adjustment is needed to the starting dose of palbociclib in patients with mild or moderate renal impairment.
    CrCL less than 30 mL/min: Palbociclib has not been studied in patients with severe renal impairment.
     
    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.

    ADMINISTRATION

    Oral Administration
    Oral Solid Formulations

    Patients should swallow capsules whole; do not crush or open the capsules. Do not administer capsules which appear broken, cracked or otherwise not intact.
    Administer with food. Avoid grapefruit or grapefruit juice during palbociclib treatment; do not administer with grapefruit juice.
    Administer the dose at approximately the same time every day.
    If a patient vomits the dose or a dose is missed, the patient should not take an additional dose that day; the next dose should be taken at the usually scheduled time.

    STORAGE

    Ibrance:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Fungal infection, infection, neutropenia, viral infection

    Neutropenia, including febrile neutropenia, has been reported with palbociclib therapy. Monitor complete blood counts before starting each cycle of palbociclib, on day 14 of the first 2 cycles, and as clinically indicated. After the first 6 cycles, monitoring of complete blood counts may be decreased to every 3 months (prior to the start of a new cycle) and as clinically indicated for patients who have experienced a maximum of grade 1 or 2 neutropenia. Also monitor for signs and symptoms of infection, including bacterial infection, fungal infection, or viral infection, and treat as appropriate. Instruct patients to report any episodes of fever. An interruption of therapy, dose reduction, or delay in treatment may be necessary in patients who develop >= grade 3 neutropenia, including febrile neutropenia. The median time to first episode of neutropenia (any grade) was 15 days and the median duration of >= grade 3 neutropenia was 7 days.

    Pregnancy

    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.

    Contraception requirements, infertility, pregnancy testing, reproductive risk, testicular failure

    Discuss reproductive risk and contraception requirements with the patient prior to treatment with palbociclib. Females of reproductive potential should avoid becoming pregnant and should be instructed to use effective contraceptive methods during palbociclib therapy and for at least 3 weeks after the last dose. Males with female partners of reproductive potential should use effective contraception during treatment and for 3 months after the last dose. Females of reproductive potential should undergo pregnancy testing prior to initiation of therapy. Advise females to contact their healthcare provider if they become pregnant, or if they suspect they are pregnant, during treatment. Human fertility studies have not been conducted; however, fertility issues for females have not been noted in animal studies. Male infertility is possible during treatment with palbociclib. In repeat-dose studies in rats (>= 10 times the AUC in humans at the recommended dose) and dogs (0.1 times the AUC in humans at the recommended dose), palbociclib-related findings in the testis, epididymis, prostate, and seminal vesicle included testicular failure such as decreased organ weight or atrophy/degeneration, hypospermia, intratubular cellular debris, decreased sperm motility and density, and decreased secretion. The effects on fertility were partially reversible 4 and 12 weeks after the last dose of palbociclib in rats and dogs, respectively.

    Breast-feeding

    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.

    ADVERSE REACTIONS

    Severe

    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
    weakness / Early / 0-2.0
    asthenia / Delayed / 0-2.0
    vomiting / Early / 0-1.0
    stomatitis / Delayed / 0-1.0
    anorexia / Delayed / 1.0-1.0
    headache / Early / 0-1.0
    rash (unspecified) / Early / 0-1.0

    Moderate

    constipation / Delayed / 0-20.0
    peripheral neuropathy / Delayed / 0-13.0
    blurred vision / Early / 0-6.0
    cystitis / Delayed / Incidence not known
    conjunctivitis / Delayed / Incidence not known
    oral ulceration / Delayed / Incidence not known
    glossitis / Early / Incidence not known
    erythema / Early / Incidence not known

    Mild

    alopecia / Delayed / 18.0-22.0
    epistaxis / Delayed / 7.0-11.0
    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
    rhinitis / Early / Incidence not known
    influenza / Delayed / Incidence not known
    pharyngitis / Delayed / Incidence not known
    sinusitis / Delayed / Incidence not known
    laryngitis / Delayed / 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

    DRUG INTERACTIONS

    Acetaminophen; Butalbital: (Major) Use caution and monitor patients for decreased palbociclib efficacy if butalbital is used concomitantly with palbociclib. Palbociclib is a primary substrate of CYP3A and butalbital, a barbiturate, is a CYP3A inducer. In a drug interaction study, coadministration of multiple daily doses of a moderate CYP3A inducer, modafinil, decreased the plasma exposure of a single dose of palbociclib in healthy patients by 32% and the Cmax by 11% (n = 14).
    Acetaminophen; Butalbital; Caffeine: (Major) Use caution and monitor patients for decreased palbociclib efficacy if butalbital is used concomitantly with palbociclib. Palbociclib is a primary substrate of CYP3A and butalbital, a barbiturate, is a CYP3A inducer. In a drug interaction study, coadministration of multiple daily doses of a moderate CYP3A inducer, modafinil, decreased the plasma exposure of a single dose of palbociclib in healthy patients by 32% and the Cmax by 11% (n = 14).
    Acetaminophen; Butalbital; Caffeine; Codeine: (Major) Use caution and monitor patients for decreased palbociclib efficacy if butalbital is used concomitantly with palbociclib. Palbociclib is a primary substrate of CYP3A and butalbital, a barbiturate, is a CYP3A inducer. In a drug interaction study, coadministration of multiple daily doses of a moderate CYP3A inducer, modafinil, decreased the plasma exposure of a single dose of palbociclib in healthy patients by 32% and the Cmax by 11% (n = 14). (Moderate) Use caution if coadministration of palbociclib with codeine is necessary, as the systemic exposure of codeine may be increased resulting in increase in treatment-related adverse reactions including sedation and respiratory depression; adjust the dose of codeine if necessary. Palbociclib is a weak time-dependent inhibitor of CYP3A. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norocodeine; norcodeine does not have analgesic properties. Concomitant use may result in an increase in codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and increased morphine concentrations.
    Acetaminophen; Codeine: (Moderate) Use caution if coadministration of palbociclib with codeine is necessary, as the systemic exposure of codeine may be increased resulting in increase in treatment-related adverse reactions including sedation and respiratory depression; adjust the dose of codeine if necessary. Palbociclib is a weak time-dependent inhibitor of CYP3A. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norocodeine; norcodeine does not have analgesic properties. Concomitant use may result in an increase in codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and increased morphine concentrations.
    Acetaminophen; Hydrocodone: (Moderate) Monitor frequently for an increase in hydrocodone-related adverse reactions (e.g., sedation, respiratory depression) if coadministered with palbociclib. Consider dosage reduction of hydrocodone until stable drug effects are achieved if concurrent use is necessary. If palbociclib is discontinued, consider an increased dose of hydrocodone and monitor for signs of opioid withdrawal. Palbociclib is a weak time-dependent inhibitor of CYP3A and hydrocodone is a CYP3A4 substrate.
    Acetaminophen; Oxycodone: (Moderate) Monitor frequently for an increase in oxycodone-related adverse reactions (e.g., sedation, respiratory depression) if coadministered with palbociclib. Consider dosage reduction of oxycodone until stable drug effects are achieved if concurrent use is necessary. If palbociclib is discontinued, consider an increased dose of oxycodone and monitor for signs of opioid withdrawal. Palbociclib is a weak time-dependent inhibitor of CYP3A and oxycodone is a CYP3A4 substrate.
    Acetaminophen; 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.
    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.
    Amobarbital: (Major) Use caution and monitor patients for decreased palbociclib efficacy if amobarbital is used concomitantly with palbociclib. Palbociclib is a primary substrate of CYP3A and amobarbital, a barbiturate, is a CYP3A inducer. In a drug interaction study, coadministration of multiple daily doses of a moderate CYP3A inducer, modafinil, decreased the plasma exposure of a single dose of palbociclib in healthy patients by 32% and the Cmax by 11% (n = 14).
    Amoxicillin; Clarithromycin; Lansoprazole: (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.
    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.
    Aspirin, ASA; Butalbital; Caffeine: (Major) Use caution and monitor patients for decreased palbociclib efficacy if butalbital is used concomitantly with palbociclib. Palbociclib is a primary substrate of CYP3A and butalbital, a barbiturate, is a CYP3A inducer. In a drug interaction study, coadministration of multiple daily doses of a moderate CYP3A inducer, modafinil, decreased the plasma exposure of a single dose of palbociclib in healthy patients by 32% and the Cmax by 11% (n = 14).
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) Use caution and monitor patients for decreased palbociclib efficacy if butalbital is used concomitantly with palbociclib. Palbociclib is a primary substrate of CYP3A and butalbital, a barbiturate, is a CYP3A inducer. In a drug interaction study, coadministration of multiple daily doses of a moderate CYP3A inducer, modafinil, decreased the plasma exposure of a single dose of palbociclib in healthy patients by 32% and the Cmax by 11% (n = 14). (Moderate) Use caution if coadministration of palbociclib with codeine is necessary, as the systemic exposure of codeine may be increased resulting in increase in treatment-related adverse reactions including sedation and respiratory depression; adjust the dose of codeine if necessary. Palbociclib is a weak time-dependent inhibitor of CYP3A. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norocodeine; norcodeine does not have analgesic properties. Concomitant use may result in an increase in codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and increased morphine concentrations.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Use caution if coadministration of palbociclib with codeine is necessary, as the systemic exposure of codeine may be increased resulting in increase in treatment-related adverse reactions including sedation and respiratory depression; adjust the dose of codeine if necessary. Palbociclib is a weak time-dependent inhibitor of CYP3A. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norocodeine; norcodeine does not have analgesic properties. 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) Monitor frequently for an increase in oxycodone-related adverse reactions (e.g., sedation, respiratory depression) if coadministered with palbociclib. Consider dosage reduction of oxycodone until stable drug effects are achieved if concurrent use is necessary. If palbociclib is discontinued, consider an increased dose of oxycodone and monitor for signs of opioid withdrawal. Palbociclib is a weak time-dependent inhibitor of CYP3A and oxycodone is a CYP3A4 substrate.
    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.
    Atropine; Hyoscyamine; Phenobarbital; 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.
    Axitinib: (Moderate) Use caution if coadministration of axitinib with palbociclib is necessary, due to the risk of increased axitinib-related adverse reactions. Axitinib is a CYP3A4 substrate and palbociclib is a weak CYP3A4 inhibitor. In a drug interaction trial in healthy subjects (n = 26), coadministration with palbociclib increased the AUC and Cmax of another CYP3A4 substrate, midazolam, by 61% and 37%, respectively. Coadministration with a strong CYP3A4/5 inhibitor, ketoconazole, significantly increased the plasma exposure of axitinib in healthy volunteers. The manufacturer of axitinib recommends a dose reduction in patients receiving strong CYP3A4 inhibitors, but recommendations are not available for moderate or weak CYP3A4 inhibitors.
    Belladonna Alkaloids; Ergotamine; 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. (Moderate) Monitor for an increase in ergotamine-related adverse reactions if coadministration with palbociclib is necessary. Palbociclib is a weak time-dependent inhibitor of CYP3A while ergotamine is a CYP3A4 substrate with a narrow therapeutic index.
    Bexarotene: (Major) Use caution and monitor patients for decreased palbociclib efficacy if bexarotene is used concomitantly with palbociclib. Palbociclib is a primary substrate of CYP3A and bexarotene is a moderate CYP3A inducer. In a drug interaction study, coadministration of multiple daily doses of a moderate CYP3A inducer, modafinil, decreased the plasma exposure of a single dose of palbociclib in healthy patients by 32% and the Cmax by 11% (n = 14).
    Boceprevir: (Major) Avoid coadministration of boceprevir with palbociclib if possible due to significantly increased plasma exposure of palbociclib. If concomitant use is necessary, reduce the dose of palbociclib to 75 mg once daily and monitor for increased adverse reactions including myelosuppression, diarrhea, asthenia, and fatigue. If boceprevir is discontinued, increase the palbociclib dose upward to the recommended dose after a washout period of 3 to 5 half-lives of boceprevir. Palbociclib is primarily metabolized by CYP3A4 and boceprevir is a strong CYP3A4 inhibitor. In a drug interaction trial in healthy subjects (n = 12), coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of palbociclib by 87% and 34%, respectively.
    Bosentan: (Major) Use caution and monitor patients for decreased palbociclib efficacy if bosentan is used concomitantly with palbociclib. Palbociclib is a primary substrate of CYP3A and bosentan is a moderate CYP3A inducer. In a drug interaction study, coadministration of multiple daily doses of a moderate CYP3A inducer, modafinil, decreased the plasma exposure of a single dose of palbociclib in healthy patients by 32% and the Cmax by 11% (n = 14).
    Brompheniramine; Guaifenesin; Hydrocodone: (Moderate) Monitor frequently for an increase in hydrocodone-related adverse reactions (e.g., sedation, respiratory depression) if coadministered with palbociclib. Consider dosage reduction of hydrocodone until stable drug effects are achieved if concurrent use is necessary. If palbociclib is discontinued, consider an increased dose of hydrocodone and monitor for signs of opioid withdrawal. Palbociclib is a weak time-dependent inhibitor of CYP3A and hydrocodone is a CYP3A4 substrate.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Monitor frequently for an increase in hydrocodone-related adverse reactions (e.g., sedation, respiratory depression) if coadministered with palbociclib. Consider dosage reduction of hydrocodone until stable drug effects are achieved if concurrent use is necessary. If palbociclib is discontinued, consider an increased dose of hydrocodone and monitor for signs of opioid withdrawal. Palbociclib is a weak time-dependent inhibitor of CYP3A and hydrocodone is a CYP3A4 substrate.
    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. Coadministration of a strong CYP3A inhibitor increased the AUC of budesonide by 8-fold.
    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. Coadministration of a strong CYP3A inhibitor increased the AUC of budesonide by 8-fold.
    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.
    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. When combined with a strong CYP3A4 inhibitor, the AUC of buspirone increased by 19%. Moderate CYP3A34 inhibitors have increased the buspirone AUC up to 6-fold. Weak CYP3A4 inhibitors may also increase buspirone exposure.
    Butabarbital: (Major) Use caution and monitor patients for decreased palbociclib efficacy if butabarbital is used concomitantly with palbociclib. Palbociclib is a primary substrate of CYP3A and butabarbital, a barbiturate, is a CYP3A inducer. In a drug interaction study, coadministration of multiple daily doses of a moderate CYP3A inducer, modafinil, decreased the plasma exposure of a single dose of palbociclib in healthy patients by 32% and the Cmax by 11% (n = 14).
    Caffeine; Ergotamine: (Moderate) Monitor for an increase in ergotamine-related adverse reactions if coadministration with palbociclib is necessary. Palbociclib is a weak time-dependent inhibitor of CYP3A while ergotamine is a CYP3A4 substrate with a narrow therapeutic index.
    Carbamazepine: (Major) Avoid coadministration of carbamazepine with palbociclib due to decreased plasma concentrations of palbociclib, which may result in decreased efficacy. Carbamazepine plasma concentrations may increase. Palbociclib is primarily metabolized by CYP3A4 and carbamazepine 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. Palbociclib is a weak time-dependent inhibitor of CYP3A4 and carbamazepine is a CYP3A4 substrate with narrow therapeutic index.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) Monitor frequently for an increase in hydrocodone-related adverse reactions (e.g., sedation, respiratory depression) if coadministered with palbociclib. Consider dosage reduction of hydrocodone until stable drug effects are achieved if concurrent use is necessary. If palbociclib is discontinued, consider an increased dose of hydrocodone and monitor for signs of opioid withdrawal. Palbociclib is a weak time-dependent inhibitor of CYP3A and hydrocodone is a CYP3A4 substrate.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) Monitor frequently for an increase in hydrocodone-related adverse reactions (e.g., sedation, respiratory depression) if coadministered with palbociclib. Consider dosage reduction of hydrocodone until stable drug effects are achieved if concurrent use is necessary. If palbociclib is discontinued, consider an increased dose of hydrocodone and monitor for signs of opioid withdrawal. Palbociclib is a weak time-dependent inhibitor of CYP3A and hydrocodone is a CYP3A4 substrate.
    Ceritinib: (Moderate) Monitor for an increase in palbociclib-related adverse reactions if coadministration with ceritinib is necessary. Ceritinib is a CYP3A4 inhibitor and palbociclib is metabolized by CYP3A4. Coadministration with a strong CYP3A4 inhibitor increased plasma exposure of palbociclib in healthy subjects by 87%. The manufacturer of palbociclib recommends a dose reduction if coadministration with a strong CYP3A4 inhibitor is unavoidable; the degree of CYP3A4 inhibition with ceritinib is unknown.
    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) Use caution if coadministration of palbociclib with codeine is necessary, as the systemic exposure of codeine may be increased resulting in increase in treatment-related adverse reactions including sedation and respiratory depression; adjust the dose of codeine if necessary. Palbociclib is a weak time-dependent inhibitor of CYP3A. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norocodeine; norcodeine does not have analgesic properties. Concomitant use may result in an increase in codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and increased morphine concentrations.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Monitor frequently for an increase in hydrocodone-related adverse reactions (e.g., sedation, respiratory depression) if coadministered with palbociclib. Consider dosage reduction of hydrocodone until stable drug effects are achieved if concurrent use is necessary. If palbociclib is discontinued, consider an increased dose of hydrocodone and monitor for signs of opioid withdrawal. Palbociclib is a weak time-dependent inhibitor of CYP3A and hydrocodone is a CYP3A4 substrate.
    Chlorpheniramine; Hydrocodone: (Moderate) Monitor frequently for an increase in hydrocodone-related adverse reactions (e.g., sedation, respiratory depression) if coadministered with palbociclib. Consider dosage reduction of hydrocodone until stable drug effects are achieved if concurrent use is necessary. If palbociclib is discontinued, consider an increased dose of hydrocodone and monitor for signs of opioid withdrawal. Palbociclib is a weak time-dependent inhibitor of CYP3A and hydrocodone is a CYP3A4 substrate.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) Monitor frequently for an increase in hydrocodone-related adverse reactions (e.g., sedation, respiratory depression) if coadministered with palbociclib. Consider dosage reduction of hydrocodone until stable drug effects are achieved if concurrent use is necessary. If palbociclib is discontinued, consider an increased dose of hydrocodone and monitor for signs of opioid withdrawal. Palbociclib is a weak time-dependent inhibitor of CYP3A and hydrocodone is a CYP3A4 substrate.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Monitor frequently for an increase in hydrocodone-related adverse reactions (e.g., sedation, respiratory depression) if coadministered with palbociclib. Consider dosage reduction of hydrocodone until stable drug effects are achieved if concurrent use is necessary. If palbociclib is discontinued, consider an increased dose of hydrocodone and monitor for signs of opioid withdrawal. Palbociclib is a weak time-dependent inhibitor of CYP3A and hydrocodone is a CYP3A4 substrate.
    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, including neutropenia, if coadministration with palbociclib is necessary. 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.
    Cobicistat; Elvitegravir; 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.
    Cobicistat; Elvitegravir; 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.
    Codeine: (Moderate) Use caution if coadministration of palbociclib with codeine is necessary, as the systemic exposure of codeine may be increased resulting in increase in treatment-related adverse reactions including sedation and respiratory depression; adjust the dose of codeine if necessary. Palbociclib is a weak time-dependent inhibitor of CYP3A. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norocodeine; norcodeine does not have analgesic properties. Concomitant use may result in an increase in codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and increased morphine concentrations.
    Codeine; Guaifenesin: (Moderate) Use caution if coadministration of palbociclib with codeine is necessary, as the systemic exposure of codeine may be increased resulting in increase in treatment-related adverse reactions including sedation and respiratory depression; adjust the dose of codeine if necessary. Palbociclib is a weak time-dependent inhibitor of CYP3A. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norocodeine; norcodeine does not have analgesic properties. 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) Use caution if coadministration of palbociclib with codeine is necessary, as the systemic exposure of codeine may be increased resulting in increase in treatment-related adverse reactions including sedation and respiratory depression; adjust the dose of codeine if necessary. Palbociclib is a weak time-dependent inhibitor of CYP3A. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norocodeine; norcodeine does not have analgesic properties. Concomitant use may result in an increase in codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and increased morphine concentrations.
    Codeine; Promethazine: (Moderate) Use caution if coadministration of palbociclib with codeine is necessary, as the systemic exposure of codeine may be increased resulting in increase in treatment-related adverse reactions including sedation and respiratory depression; adjust the dose of codeine if necessary. Palbociclib is a weak time-dependent inhibitor of CYP3A. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norocodeine; norcodeine does not have analgesic properties. Concomitant use may result in an increase in codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and increased morphine concentrations.
    Colchicine: (Moderate) Monitor for an increase in colchicine-related adverse reactions including neuromuscular toxicity and other serious toxicities if coadministration with palbociclib is necessary, especially in patients with renal or hepatic impairment. Palbociclib is a weak time-dependent inhibitor of CYP3A while colchicine is a CYP3A4 substrate with a narrow therapeutic index.
    Conivaptan: (Major) Avoid coadministration of conivaptan with palbociclib; significantly increased palbociclib exposure may occur. Concentrations of conivaptan 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 conivaptan is discontinued, increase the palbociclib dose (after 3 to 5 half-lives of conivaptan) to the dose used before initiation of conivaptan. Palbociclib is primarily metabolized by CYP3A4 and conivaptan 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 conivaptan is a sensitive CYP3A4 substrate.
    Cyclosporine: (Major) Monitor for an increase in palbociclib-related adverse reactions if coadministration with cyclosporine is necessary. Concentrations of cyclosporine may also increase; monitor cyclosporine levels and adjust the dose as necessary. Palbociclib is primarily metabolized by CYP3A4 and cyclosporine is a moderate CYP3A4 inhibitor. In a drug interaction trial, coadministration with a strong CYP3A4 inhibitor increased the AUC and Cmax of palbociclib by 87% and 34%, respectively; moderate inhibitors may also increase palbociclib exposure. Palbociclib is also a weak time-dependent inhibitor of CYP3A while cyclosporine is a CYP3A4 substrate with a narrow therapeutic index. In a drug interaction trial in healthy subjects (n = 26), coadministration with palbociclib increased the AUC and Cmax of a sensitive CYP3A4 substrate by 61% and 37%, respectively.
    Dabrafenib: (Major) Use caution and monitor patients for decreased palbociclib efficacy if dabrafenib is used concomitantly with palbociclib. Palbociclib is a primary substrate of CYP3A and dabrafenib is a moderate CYP3A inducer. In a drug interaction study, coadministration of multiple daily doses of a moderate CYP3A inducer, modafinil, decreased the plasma exposure of a single dose of palbociclib in healthy patients by 32% and the Cmax by 11% (n = 14).
    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.
    Dasabuvir; Ombitasvir; Paritaprevir; 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.
    Deferasirox: (Major) Use caution and monitor patients for decreased palbociclib efficacy if deferasirox is used concomitantly with palbociclib. Palbociclib is a primary substrate of CYP3A and deferasirox is a moderate CYP3A inducer. Coadministration of multiple daily doses of a moderate CYP3A inducer, modafinil, decreased the plasma exposure of a single dose of palbociclib in healthy patients by 32% and the Cmax by 11% (n = 14).
    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.
    Dexamethasone: (Major) Use caution and monitor patients for decreased palbociclib efficacy if dexamethasone is used concomitantly with palbociclib. Palbociclib is a primary substrate of CYP3A and dexamethasone is a moderate CYP3A inducer. In a drug interaction study, coadministration of multiple daily doses of a moderate CYP3A inducer, modafinil, decreased the plasma exposure of a single dose of palbociclib in healthy patients by 32% and the Cmax by 11% (n = 14).
    Dextromethorphan; Quinidine: (Moderate) Monitor for an increase in quinidine-related adverse reactions if coadministration with palbociclib is necessary. A quinidine dose reduction may be necessary. Palbociclib is a weak time-dependent inhibitor of CYP3A and quinidine is a sensitive CYP3A4 substrate with a narrow therapeutic index.
    Dihydroergotamine: (Moderate) Monitor for an increase in dihydroergotamine-related adverse reactions if coadministration with palbociclib is necessary. The dose of dihydroergotamine may need to be reduced. Palbociclib is a weak time-dependent inhibitor of CYP3A while dihydroergotamine is a CYP3A4 substrate with a narrow therapeutic index.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) Monitor frequently for an increase in hydrocodone-related adverse reactions (e.g., sedation, respiratory depression) if coadministered with palbociclib. Consider dosage reduction of hydrocodone until stable drug effects are achieved if concurrent use is necessary. If palbociclib is discontinued, consider an increased dose of hydrocodone and monitor for signs of opioid withdrawal. Palbociclib is a weak time-dependent inhibitor of CYP3A and hydrocodone is a CYP3A4 substrate.
    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.
    Dronedarone: (Moderate) Monitor for an increase in dronedarone-related adverse reactions if coadministration with palbociclib is necessary. Palbociclib may increase dronedarone exposure which may increase the risk of dronedarone-induced QT prolongation. Palbociclib is a weak time-dependent inhibitor of CYP3A while dronedarone is a sensitive CYP3A4 substrate associated with a dose-related increase in the QTc interval.
    Efavirenz: (Major) Use caution and monitor patients for decreased palbociclib efficacy if efavirenz is used concomitantly with palbociclib. Palbociclib is a primary substrate of CYP3A and efavirenz is a moderate CYP3A inducer. In a drug interaction study, coadministration of multiple daily doses of a moderate CYP3A inducer, modafinil, decreased the plasma exposure of a single dose of palbociclib in healthy patients by 32% and the Cmax by 11% (n = 14).
    Efavirenz; Emtricitabine; Tenofovir: (Major) Use caution and monitor patients for decreased palbociclib efficacy if efavirenz is used concomitantly with palbociclib. Palbociclib is a primary substrate of CYP3A and efavirenz is a moderate CYP3A inducer. In a drug interaction study, coadministration of multiple daily doses of a moderate CYP3A inducer, modafinil, decreased the plasma exposure of a single dose of palbociclib in healthy patients by 32% and the Cmax by 11% (n = 14).
    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. 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.
    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.
    Ergotamine: (Moderate) Monitor for an increase in ergotamine-related adverse reactions if coadministration with palbociclib is necessary. Palbociclib is a weak time-dependent inhibitor of CYP3A while ergotamine is a CYP3A4 substrate with a narrow therapeutic index.
    Eslicarbazepine: (Major) Use caution and monitor patients for decreased palbociclib efficacy if eslicarbazepine is used concomitantly with palbociclib. Palbociclib is a primary substrate of CYP3A and eslicarbazepine is a moderate CYP3A inducer. In a drug interaction study, coadministration of multiple daily doses of a moderate CYP3A inducer, modafinil, decreased the plasma exposure of a single dose of palbociclib in healthy patients by 32% and the Cmax by 11% (n = 14).
    Ethanol: (Major) Use caution and monitor patients for decreased palbociclib efficacy if ethanol is used concomitantly with palbociclib. Palbociclib is a primary substrate of CYP3A and ethanol is a moderate CYP3A inducer. Coadministration of multiple daily doses of a moderate CYP3A inducer, modafinil, decreased the plasma exposure of a single dose of palbociclib in healthy patients by 32% and the Cmax by 11% (n = 14).
    Etravirine: (Major) Use caution and monitor patients for decreased palbociclib efficacy if etravirine is used concomitantly with palbociclib. Palbociclib is a primary substrate of CYP3A and etravirine is a moderate CYP3A inducer. In a drug interaction study, coadministration of multiple daily doses of a moderate CYP3A inducer, modafinil, decreased the plasma exposure of a single dose of palbociclib in healthy patients by 32% and the Cmax by 11% (n = 14).
    Ezetimibe; Simvastatin: (Moderate) Monitor for an increase in simvastatin-related adverse reactions (e.g., myopathy, rhabdomyolysis) if coadministration with palbociclib is necessary. Palbociclib is a weak time-dependent inhibitor of CYP3A and simvastatin is a sensitive CYP3A4 substrate.
    Fentanyl: (Moderate) Monitor for respiratory depression and sedation if coadministration of fentanyl and palbociclib is necessary; consider reducing the dose of fentanyl until stable drug effects are achieved. If palbociclib is discontinued, monitor for decreased fentanyl efficacy or signs of opioid withdrawal in patients who had developed dependence to fentanyl. Palbociclib is a weak time-dependent inhibitor of CYP3A and can increase fentanyl plasma concentrations resulting in increased or prolonged opioid effects. If palbociclib is discontinued, monitor for decreased fentanyl efficacy or signs of opioid withdrawal in patients who had developed dependence to fentanyl.
    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.
    Flutamide: (Major) Use caution and monitor patients for decreased palbociclib efficacy if flutamide is used concomitantly with palbociclib. Palbociclib is a primary substrate of CYP3A and in vitro, flutamide is a moderate CYP3A inducer. In a drug interaction study, coadministration of multiple daily doses of a moderate CYP3A inducer, modafinil, decreased the plasma exposure of a single dose of palbociclib in healthy patients by 32% and the Cmax by 11% (n = 14).
    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 grapefruit juice with palbociclib. If coadministration cannot be avoided, reduce the dose of palbociclib to 75 mg by mouth once daily and monitor for increased adverse reactions including myelosuppression, diarrhea, asthenia, and fatigue. If the patient stops taking grapefruit juice, increase the palbociclib dosage upward to the recommended dose after a washout period. Palbociclib is a primary substrate of CYP3A, and grapefruit juice is a strong CYP3A inhibitor. In a drug interaction trial, coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of palbociclib by 87% and 34%, respectively.
    Griseofulvin: (Major) Use caution and monitor patients for decreased palbociclib efficacy if griseofulvin is used concomitantly with palbociclib. Palbociclib is a primary substrate of CYP3A and in vitro, griseofulvin is a moderate CYP3A inducer. In a drug interaction study, coadministration of multiple daily doses of a moderate CYP3A inducer, modafinil, decreased the plasma exposure of a single dose of palbociclib in healthy patients by 32% and the Cmax by 11% (n = 14).
    Guaifenesin; Hydrocodone: (Moderate) Monitor frequently for an increase in hydrocodone-related adverse reactions (e.g., sedation, respiratory depression) if coadministered with palbociclib. Consider dosage reduction of hydrocodone until stable drug effects are achieved if concurrent use is necessary. If palbociclib is discontinued, consider an increased dose of hydrocodone and monitor for signs of opioid withdrawal. Palbociclib is a weak time-dependent inhibitor of CYP3A and hydrocodone is a CYP3A4 substrate.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Monitor frequently for an increase in hydrocodone-related adverse reactions (e.g., sedation, respiratory depression) if coadministered with palbociclib. Consider dosage reduction of hydrocodone until stable drug effects are achieved if concurrent use is necessary. If palbociclib is discontinued, consider an increased dose of hydrocodone and monitor for signs of opioid withdrawal. Palbociclib is a weak time-dependent inhibitor of CYP3A and hydrocodone is a CYP3A4 substrate.
    Homatropine; Hydrocodone: (Moderate) Monitor frequently for an increase in hydrocodone-related adverse reactions (e.g., sedation, respiratory depression) if coadministered with palbociclib. Consider dosage reduction of hydrocodone until stable drug effects are achieved if concurrent use is necessary. If palbociclib is discontinued, consider an increased dose of hydrocodone and monitor for signs of opioid withdrawal. Palbociclib is a weak time-dependent inhibitor of CYP3A and hydrocodone is a CYP3A4 substrate.
    Hydrocodone: (Moderate) Monitor frequently for an increase in hydrocodone-related adverse reactions (e.g., sedation, respiratory depression) if coadministered with palbociclib. Consider dosage reduction of hydrocodone until stable drug effects are achieved if concurrent use is necessary. If palbociclib is discontinued, consider an increased dose of hydrocodone and monitor for signs of opioid withdrawal. Palbociclib is a weak time-dependent inhibitor of CYP3A and hydrocodone is a CYP3A4 substrate.
    Hydrocodone; Ibuprofen: (Moderate) Monitor frequently for an increase in hydrocodone-related adverse reactions (e.g., sedation, respiratory depression) if coadministered with palbociclib. Consider dosage reduction of hydrocodone until stable drug effects are achieved if concurrent use is necessary. If palbociclib is discontinued, consider an increased dose of hydrocodone and monitor for signs of opioid withdrawal. Palbociclib is a weak time-dependent inhibitor of CYP3A and hydrocodone is a CYP3A4 substrate.
    Hydrocodone; Phenylephrine: (Moderate) Monitor frequently for an increase in hydrocodone-related adverse reactions (e.g., sedation, respiratory depression) if coadministered with palbociclib. Consider dosage reduction of hydrocodone until stable drug effects are achieved if concurrent use is necessary. If palbociclib is discontinued, consider an increased dose of hydrocodone and monitor for signs of opioid withdrawal. Palbociclib is a weak time-dependent inhibitor of CYP3A and hydrocodone is a CYP3A4 substrate.
    Hydrocodone; Potassium Guaiacolsulfonate: (Moderate) Monitor frequently for an increase in hydrocodone-related adverse reactions (e.g., sedation, respiratory depression) if coadministered with palbociclib. Consider dosage reduction of hydrocodone until stable drug effects are achieved if concurrent use is necessary. If palbociclib is discontinued, consider an increased dose of hydrocodone and monitor for signs of opioid withdrawal. Palbociclib is a weak time-dependent inhibitor of CYP3A and hydrocodone is a CYP3A4 substrate.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Moderate) Monitor frequently for an increase in hydrocodone-related adverse reactions (e.g., sedation, respiratory depression) if coadministered with palbociclib. Consider dosage reduction of hydrocodone until stable drug effects are achieved if concurrent use is necessary. If palbociclib is discontinued, consider an increased dose of hydrocodone and monitor for signs of opioid withdrawal. Palbociclib is a weak time-dependent inhibitor of CYP3A and hydrocodone is a CYP3A4 substrate.
    Hydrocodone; Pseudoephedrine: (Moderate) Monitor frequently for an increase in hydrocodone-related adverse reactions (e.g., sedation, respiratory depression) if coadministered with palbociclib. Consider dosage reduction of hydrocodone until stable drug effects are achieved if concurrent use is necessary. If palbociclib is discontinued, consider an increased dose of hydrocodone and monitor for signs of opioid withdrawal. Palbociclib is a weak time-dependent inhibitor of CYP3A and hydrocodone is a CYP3A4 substrate.
    Ibrutinib: (Moderate) Monitor for an increase in ibrutinib-related adverse reactions (e.g., hematologic toxicity, bleeding, infection) if coadministration with palbociclib is necessary. Palbociclib is a weak time-dependent inhibitor of CYP3A and ibrutinib is a sensitive CYP3A4 substrate. In the presence of a strong CYP3A4 inhibitor, the AUC of ibrutinib was increased by 24-fold. Moderate CYP3A4 inhibitors may increase the ibrutinib AUC by 5 to 8-fold. It is possible that weak 3A4 inhibitors may also increase ibrutinib exposure.
    Ibuprofen; Oxycodone: (Moderate) Monitor frequently for an increase in oxycodone-related adverse reactions (e.g., sedation, respiratory depression) if coadministered with palbociclib. Consider dosage reduction of oxycodone until stable drug effects are achieved if concurrent use is necessary. If palbociclib is discontinued, consider an increased dose of oxycodone and monitor for signs of opioid withdrawal. Palbociclib is a weak time-dependent inhibitor of CYP3A and oxycodone is a CYP3A4 substrate.
    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.
    Ifosfamide: (Moderate) Monitor for a possible decrease in the efficacy of ifosfamide if coadministration with palbociclib is necessary. Palbociclib is a weak time-dependent inhibitor of CYP3A. Ifosfamide is a prodrug that is converted to its active alkylating metabolites via CYP3A4. Coadministration of ifosfamide with CYP3A4 inhibitors may reduce the metabolism of ifosfamide to its active metabolites and therefore decrease efficacy.
    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.
    Irinotecan Liposomal: (Moderate) Use caution if irinotecan liposomal is coadministered with palbociclib, a weak CYP3A4 inhibitor, due to a possible increased risk of irinotecan-related toxicity. The metabolism of liposomal irinotecan has not been evaluated; however, coadministration of ketoconazole, a strong CYP3A4 and UGT1A1 inhibitor, with non-liposomal irinotecan HCl resulted in increased exposure to both irinotecan and its active metabolite, SN-38.
    Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with palbociclib may result in increased serum concentrations of both drugs. Palbociclib is a substrate and inhibitor of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a sensitive substrate and moderate inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are used together.
    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.
    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.
    Ivabradine: (Moderate) Use caution during coadministration of ivabradine and palbociclib as increased concentrations of ivabradine are possible. Ivabradine is primarily metabolized by CYP3A4; palbociclib is a weak time-dependent inhibitor of CYP3A. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
    Ixabepilone: (Moderate) Frequently monitor peripheral blood counts between ixabepilone cycles and watch for an increase in ixabepilone-related adverse reactions if coadministration with palbociclib is necessary; consider substituting an agent that does not inhibit CYP3A4 for palbociclib if appropriate. Palbociclib is a weak time-dependent inhibitor of CYP3A and ixabepilone is a CYP3A4 substrate. Coadministration with a strong CYP3A4 inhibitor increased the AUC of ixabepilone by 79%; the effect of mild or moderate inhibitors on exposure to ixabepilone has not been studied; however, the ixabepilone manufacturer recommends caution with concurrent use.
    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.
    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.
    Lopinavir; Ritonavir: (Major) Avoid coadministration of lopinavir with palbociclib; significantly increased palbociclib exposure may occur. Concentrations of lopinavir 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 lopinavir is discontinued, increase the palbociclib dose (after 3 to 5 half-lives) to the dose used before initiation of lopinavir. Palbociclib is primarily metabolized by CYP3A4 and lopinavir 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 lopinavir is a sensitive CYP3A4 substrate. (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.
    Lovastatin: (Moderate) Monitor for an increase in lovastatin-related adverse reactions if coadministration with palbociclib is necessary. Palbociclib is a weak time-dependent inhibitor of CYP3A and lovastatin is a sensitive CYP3A4 substrate.
    Lovastatin; Niacin: (Moderate) Monitor for an increase in lovastatin-related adverse reactions if coadministration with palbociclib is necessary. Palbociclib is a weak time-dependent inhibitor of CYP3A and lovastatin 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.
    Mephobarbital: (Major) Avoid coadministration of mephobarbital with palbociclib due to decreased plasma concentrations of palbociclib, which may result in decreased efficacy. Palbociclib is primarily metabolized by CYP3A4; mephobarbital is metabolized to phenobarbital, 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.
    Methohexital: (Major) Use caution and monitor patients for decreased palbociclib efficacy if methohexital is used concomitantly with palbociclib. Palbociclib is a primary substrate of CYP3A and methohexital, a barbiturate, is a CYP3A inducer. In a drug interaction study, coadministration of multiple daily doses of a moderate CYP3A inducer, modafinil, decreased the plasma exposure of a single dose of palbociclib in healthy patients by 32% and the Cmax by 11% (n = 14).
    Metyrapone: (Major) Use caution and monitor patients for decreased palbociclib efficacy if metyrapone is used concomitantly with palbociclib. Palbociclib is a primary substrate of CYP3A and in vitro, metyrapone is a moderate CYP3A inducer. In a drug interaction study, coadministration of multiple daily doses of a moderate CYP3A inducer, modafinil, decreased the plasma exposure of a single dose of palbociclib in healthy patients by 32% and the Cmax by 11% (n = 14).
    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.
    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.
    Modafinil: (Major) Use caution and monitor patients for decreased palbociclib efficacy if modafinil is used concomitantly with palbociclib. Palbociclib is a primary substrate of CYP3A and modafinil is a moderate CYP3A inducer. In a drug interaction study, coadministration of multiple daily doses modafinil decreased the plasma exposure of a single dose of palbociclib in healthy patients by 32% and the Cmax by 11% (n = 14).
    Nafcillin: (Major) Use caution and monitor patients for decreased palbociclib efficacy if nafcillin is used concomitantly with palbociclib. Palbociclib is a primary substrate of CYP3A and nafcillin is a moderate CYP3A inducer. In a drug interaction study, coadministration of multiple daily doses of a moderate CYP3A inducer, modafinil, decreased the plasma exposure of a single dose of palbociclib in healthy patients by 32% and the Cmax by 11% (n = 14).
    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.
    Nevirapine: (Major) Avoid concomitant use of nevirapine with palbociclib. If coadministration cannot be avoided, monitor patients for decreased palbociclib efficacy. Palbociclib is a primary substrate of CYP3A and in vitro, nevirapine is a moderate CYP3A inducer. Coadministration of multiple daily doses of a strong CYP3A inducer, rifampin, decreased the plasma exposure of a single dose of palbociclib in healthy patients by 85% and the Cmax by 70% (n = 14). Moderate CYP3A inducers may also decrease the plasma exposure of palbociclib.
    Niacin; Simvastatin: (Moderate) Monitor for an increase in simvastatin-related adverse reactions (e.g., myopathy, rhabdomyolysis) if coadministration with palbociclib is necessary. Palbociclib is a weak time-dependent inhibitor of CYP3A and simvastatin is a sensitive CYP3A4 substrate.
    Nisoldipine: (Moderate) Avoid coadministration of nisoldipine with palbociclib if possible, due to a possible increase in the exposure of nisoldipine. If concomitant use is necessary, monitor for an increase in nisoldipine-related adverse reaction. Palbociclib is a weak time-dependent inhibitor of CYP3A and nisoldipine is a sensitive CYP3A4 substrate. Coadministration of nisoldipine with a strong CYP3A4 inhibitor increased the AUC and Cmax by 24-fold and 11-fold, respectively. Weak inhibitors of CYP3A4, like palbociclib may also increase nisoldipine exposure.
    Ombitasvir; Paritaprevir; 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.
    Oxcarbazepine: (Major) Use caution and monitor patients for decreased palbociclib efficacy if oxcarbazepine is used concomitantly with palbociclib. Palbociclib is a primary substrate of CYP3A and oxcarbazepine is a moderate CYP3A inducer. In a drug interaction study, coadministration of multiple daily doses of a moderate CYP3A inducer, modafinil, decreased the plasma exposure of a single dose of palbociclib in healthy patients by 32% and the Cmax by 11% (n = 14).
    Oxycodone: (Moderate) Monitor frequently for an increase in oxycodone-related adverse reactions (e.g., sedation, respiratory depression) if coadministered with palbociclib. Consider dosage reduction of oxycodone until stable drug effects are achieved if concurrent use is necessary. If palbociclib is discontinued, consider an increased dose of oxycodone and monitor for signs of opioid withdrawal. Palbociclib is a weak time-dependent inhibitor of CYP3A and oxycodone is a CYP3A4 substrate.
    Pentobarbital: (Major) Use caution and monitor patients for decreased palbociclib efficacy if pentobarbital is used concomitantly with palbociclib. Palbociclib is a primary substrate of CYP3A and pentobarbital, a barbiturate, is a CYP3A inducer. In a drug interaction study, coadministration of multiple daily doses of a moderate CYP3A inducer, modafinil, decreased the plasma exposure of a single dose of palbociclib in healthy patients by 32% and the Cmax by 11% (n = 14).
    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.
    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.
    Quinidine: (Moderate) Monitor for an increase in quinidine-related adverse reactions if coadministration with palbociclib is necessary. A quinidine dose reduction may be necessary. Palbociclib is a weak time-dependent inhibitor of CYP3A and quinidine is a sensitive CYP3A4 substrate with a narrow therapeutic index.
    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) Use caution and monitor patients for decreased palbociclib efficacy if rifapentine is used concomitantly with palbociclib. Palbociclib is a primary substrate of CYP3A and rifapentine is a moderate CYP3A inducer. Coadministration of multiple daily doses of a moderate CYP3A inducer, modafinil, decreased the plasma exposure of a single dose of palbociclib in healthy patients by 32% and the Cmax by 11% (n = 14).
    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.
    Secobarbital: (Major) Use caution and monitor patients for decreased palbociclib efficacy if secobarbital is used concomitantly with palbociclib. Palbociclib is a primary substrate of CYP3A and secobarbital, a barbiturate, is a CYP3A inducer. In a drug interaction study, coadministration of multiple daily doses of a moderate CYP3A inducer, modafinil, decreased the plasma exposure of a single dose of palbociclib in healthy patients by 32% and the Cmax by 11% (n = 14).
    Simeprevir: (Moderate) Monitor for an increase in simeprevir-related adverse reactions if coadministration with palbociclib is necessary. Palbociclib is a weak time-dependent inhibitor of CYP3A while simeprevir is a CYP3A4 substrate. Coadministration of simeprevir with a moderate CYP3A4 inhibitor increased the simeprevir AUC by more than 7-fold. Although the simeprevir manufacturer does not provide recommendations for use with weak CYP3A4 inhibitors, coadministration may also increase simeprevir exposure.
    Simvastatin: (Moderate) Monitor for an increase in simvastatin-related adverse reactions (e.g., myopathy, rhabdomyolysis) if coadministration with palbociclib is necessary. Palbociclib is a weak time-dependent inhibitor of CYP3A and simvastatin is a sensitive CYP3A4 substrate.
    Simvastatin; Sitagliptin: (Moderate) Monitor for an increase in simvastatin-related adverse reactions (e.g., myopathy, rhabdomyolysis) if coadministration with palbociclib is necessary. Palbociclib is a weak time-dependent inhibitor of CYP3A and simvastatin is a sensitive CYP3A4 substrate.
    Sirolimus: (Moderate) Monitor sirolimus concentrations and watch for an increase in sirolimus-related adverse reactions if coadministration with palbociclib is necessary. The dose of sirolimus may need to be reduced. Palbociclib is a weak time-dependent inhibitor of CYP3A and sirolimus is a sensitive CYP3A4 substrate with a narrow therapeutic index.
    Sofosbuvir; Velpatasvir: (Moderate) Use caution when administering velpatasvir with palbociclib. Taking these drugs together may increase velpatasvir plasma concentrations, potentially resulting in adverse events. Palbociclib is a weak CYP3A4 inhibitor; velpatasvir is a substrate of CYP3A4.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Moderate) Use caution when administering velpatasvir with palbociclib. Taking these drugs together may increase velpatasvir plasma concentrations, potentially resulting in adverse events. Palbociclib is a weak CYP3A4 inhibitor; velpatasvir is a substrate of CYP3A4.
    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.
    Streptogramins: (Major) Avoid coadministration of Streptogramins such as dalfopristin; quinupristin 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 dalfopristin; quinupristin is discontinued, increase the palbociclib dose (after 3 to 5 half-lives of quinupristin) to the dose used before initiation of dalfopristin; quinupristin. Palbociclib is primarily metabolized by CYP3A4 and quinupristin 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.
    Sufentanil: (Moderate) Monitor frequently for an increase in sufentanil-related adverse reactions (e.g., sedation, respiratory depression) if coadministered with palbociclib. Consider dosage reduction of sufentanil until stable drug effects are achieved if concurrent use is necessary. If palbociclib is discontinued, consider an increased dose of sufentanil and monitor for signs of opioid withdrawal. Palbociclib is a weak time-dependent inhibitor of CYP3A and sufentanil is a CYP3A4 substrate.
    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.
    Telaprevir: (Major) Avoid coadministration of telaprevir with palbociclib if possible due to significantly increased plasma exposure of palbociclib. If concomitant use is necessary, reduce the dose of palbociclib to 75 mg once daily and monitor for increased adverse reactions including myelosuppression, diarrhea, asthenia, and fatigue. If telaprevir is discontinued, increase the palbociclib dose upward to the recommended dose after a washout period of 3 to 5 half-lives of telaprevir. Palbociclib is primarily metabolized by CYP3A4 and telaprevir 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.
    Telithromycin: (Major) Avoid coadministration of telithromycin 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 telithromycin is discontinued, increase the palbociclib dose (after 3 to 5 half-lives of telithromycin) to the dose used before initiation of telithromycin. Palbociclib is primarily metabolized by CYP3A4 and telithromycin 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.
    Telotristat Ethyl: (Moderate) Use caution if coadministration of telotristat ethyl and palbociclib is necessary, as the systemic exposure of palbociclib may be decreased resulting in reduced efficacy. If these drugs are used together, monitor patients for suboptimal efficacy of palbociclib. Palbociclib is a CYP3A4 substrate. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when co-administered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate. In a drug interaction study, coadministration of multiple daily doses of a moderate CYP3A inducer, modafinil, decreased the plasma exposure of a single dose of palbociclib in healthy patients by 32% and the Cmax by 11% (n = 14).
    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.
    Trabectedin: (Moderate) Use caution if coadministration of trabectedin and palbociclib is necessary, due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and palbociclib is a weak CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), a strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone. The manufacturer of trabectedin recommends avoidance of strong CYP3A inhibitors within 1 day before and 1 week after trabectedin administration; there are no recommendations for concomitant use of moderate or weak CYP3A inhibitors.
    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.
    Triazolam: (Moderate) Monitor for an increase in triazolam-related adverse reactions (e.g., sedation, respiratory depression) if coadministration with palbociclib is necessary. Consider a reduced dose of triazolam. Palbociclib is a weak time-dependent inhibitor of CYP3A and triazolam is a sensitive CYP3A4 substrate.
    Vardenafil: (Moderate) Monitor for an increase in vardenafil-related adverse reactions if coadministration with palbociclib is necessary. Palbociclib is a weak time-dependent inhibitor of CYP3A and vardenafil is a sensitive CYP3A4 substrate. Coadministration with a moderate CYP3A4 inhibitor increased the AUC of vardenafil by 4-fold and the Cmax by 3-fold. It is possible that a weak CYP3A4 inhibitor like palbociclib may also increase vardenafil exposure.
    Vemurafenib: (Major) Use caution and monitor patients for decreased palbociclib efficacy if vemurafenib is used concomitantly with palbociclib. Palbociclib is a primary substrate of CYP3A and vemurafenib is a moderate CYP3A inducer. In a drug interaction study, coadministration of multiple daily doses of a moderate CYP3A inducer, modafinil, decreased the plasma exposure of a single dose of palbociclib in healthy patients by 32% and the Cmax by 11% (n = 14).
    Vinorelbine: (Moderate) Use caution with concurrent use of palbociclib, a weak CYP3A4 inhibitor, and vinorelbine, a CYP3A4 substrate, as the metabolism of vinorelbine may be decreased. Monitor patients for an earlier onset and/or an increased severity of adverse effects including neurotoxicity and myelosuppression.
    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.

    PREGNANCY AND LACTATION

    Pregnancy

    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.

    MECHANISM OF ACTION

    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.

    PHARMACOKINETICS

    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.
    In vitro, palbociclib is not an inhibitor of CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, and 2D6, and is not an inducer of CYP1A2, 2B6, 2C8, and 3A4 at clinically relevant concentrations.

    Oral Route

    Peak serum concentrations of palbociclib are observed 6 to 12 hours after oral administration (Tmax). The mean absolute bioavailability after a 125 mg dose is 46%. Palbociclib absorption and AUC were very low in approximately 13% of patients under fasting conditions. In this population, food intake increased palbociclib exposure; it did not significantly alter palbociclib exposure in the rest of the population. Because food intake decreases the intersubject variability of AUC, palbociclib should be taken with food. AUC and Cmax increase proportionally with dose over the range of 25 mg to 225 mg. Steady state was achieved within 8 days of repeated once daily dosing, with a median accumulation ratio of 2.4 (range, 1.5 to 4.2).