Palbociclib (Monograph)

Brand name: Ibrance
Drug class: Antineoplastic Agents

Medically reviewed by Drugs.com on Aug 10, 2024. Written by ASHP.

[Web]

Introduction

Antineoplastic agent; a reversible and selective inhibitor of cyclin-dependent kinase (CDK) 4 and 6.

Uses for Palbociclib

Breast Cancer

In combination with an aromatase inhibitor for initial treatment of hormone receptor-positive, human epidermal growth factor receptor type 2 (HER2)-negative, advanced or metastatic breast cancer.

In combination with fulvestrant for treatment of hormone receptor-positive, HER2-negative, advanced or metastatic breast cancer in patients with disease progression following endocrine therapy.

The American Society of Clinical Oncology (ASCO) recommends CDK4/6 inhibitors (in combination with an aromatase inhibitor or fulvestrant) as first-line therapy for the treatment of hormone receptor-positive, HER2-negative, metastatic breast cancer.

Palbociclib Dosage and Administration

General

Pretreatment Screening

Obtain baseline CBC.
Verify pregnancy status in females of reproductive potential.
Because palbociclib may impair male fertility; consider sperm preservation prior to initiating therapy.

Patient Monitoring

Obtain CBC prior to initiation of each cycle, on day 15 of cycles 1 and 2, and as clinically indicated. More frequent monitoring may be required in patients who develop hematologic toxicity during therapy.
Monitor patients for manifestations of pneumonitis.

Other General Considerations

Consult respective manufacturers' labelings for information on dosage adjustments, adverse effects, and contraindications of other antineoplastic agents used in combination regimens.

Administration

Oral Administration

Administer orally (as capsules or tablets) once daily with food at approximately the same time each day.

Swallow capsules and tablets whole; do not chew, crush, or open/split.

If a dose is missed or vomited, take next dose at the regularly scheduled time. Do not double the dose or take extra doses.

Dosage

Adults

Breast Cancer

Initial Therapy for Advanced Breast Cancer

Oral

125 mg once daily on days 1–21 of each 28-day cycle in combination with an aromatase inhibitor. Continue until disease progression or unacceptable toxicity.

Treat premenopausal or perimenopausal women receiving combination therapy with palbociclib and an aromatase inhibitor with a luteinizing hormone-releasing hormone (LHRH) agonist according to current standards of care. Consider treating men receiving combination therapy with palbociclib and an aromatase inhibitor with a LHRH agonist according to current standards of care.

Previously Treated Advanced Breast Cancer

Oral

125 mg once daily on days 1–21 of each 28-day cycle in combination with fulvestrant 500 mg IM on days 1 and 15 of cycle 1, and then on day 1 of each 28-day cycle thereafter. Continue until disease progression or unacceptable toxicity.

Treat premenopausal or perimenopausal women receiving combination therapy with palbociclib and fulvestrant with an LHRH agonist according to current standards of care.

Dosage Modification for Toxicity

Oral

Adverse effects may require temporary interruption, dosage reduction, and/or permanent discontinuance. Adjust dosage based on individual safety and tolerability.

Up to 2 dosage reductions for toxicity may be made. If dosage reduction from 125 mg once daily is necessary, initially reduce dosage to 100 mg once daily.

If further dosage reduction necessary, reduce dosage to 75 mg once daily.

Dosages <75 mg once daily not recommended.

Hematologic Toxicity

Oral

If grade 3 febrile neutropenia (ANC 500 to <1000/mm³ with fever ≥38.5ºC and/or infection) occurs, temporarily interrupt palbociclib therapy. When ANC is ≥1000/mm³, resume therapy at reduced dosage.

If grade 1 or 2 hematologic toxicity occurs, continue palbociclib at the same dosage.

If grade 1 or 2 neutropenia occurs during cycles 1–6, repeat CBC monitoring every 3 months, prior to subsequent cycles, and as clinically indicated.

If grade 3 hematologic toxicity reported after CBC monitoring on day 1 of any cycle, temporarily interrupt palbociclib therapy; repeat CBC monitoring within 1 week. Delay next cycle until toxicity resolves to grade 2 or less; then continue palbociclib at the same dosage.

If grade 3 hematologic toxicity reported after CBC monitoring on day 15 of cycle 1 or 2, continue palbociclib at the same dosage; repeat CBC monitoring on day 22. If grade 4 hematologic toxicity occurs after repeat CBC monitoring on day 22 of the cycle, temporarily interrupt palbociclib therapy until the toxicity resolves to grade 2 or less; then continue palbociclib at a reduced dosage.

If prolonged (i.e., lasting >7 days) recovery from grade 3 neutropenia occurs or grade 3 neutropenia recurs on day 1 of subsequent cycles, therapy may be resumed at a reduced dosage.

If grade 4 hematologic toxicity occurs, temporarily interrupt palbociclib therapy. When toxicity resolves to grade 2 or less, resume therapy at reduced dosage.

Exception made for grade 3 or 4 lymphopenia without an associated clinical event (e.g., opportunistic infection); no dosage modification required in such patients.

Interstitial Lung Disease (ILD)/Pneumonitis

Oral

If severe ILD/pneumonitis occurs, permanently discontinue palbociclib therapy.

Nonhematologic Toxicity

Oral

If persistent grade 3 or greater nonhematologic toxicity occurs despite appropriate medical management, temporarily interrupt palbociclib therapy. When toxicity resolves to grade 1 or less or to grade 2 or less (if toxicity not considered a safety risk for the patient), resume therapy at reduced dosage.

Concomitant Use with Drugs Affecting Hepatic Microsomal Enzymes

Oral

If used concomitantly with a strong CYP3A inhibitor, reduce palbociclib dosage to 75 mg once daily. If concomitant use of the strong CYP3A inhibitor is discontinued, return the palbociclib dosage (after 3-5 terminal half-lives of the CYP3A inhibitor) to the dosage used prior to initiation of the strong inhibitor.

Special Populations

Hepatic Impairment

Severe hepatic impairment (Child-Pugh class C): Reduce initial dosage to 75 mg once daily on days 1–21 of each 28-day cycle.

Mild or moderate hepatic impairment (Child-Pugh class A or B): No dosage adjustment required.

Renal Impairment

Cl_cr >15 mL/minute: No dosage adjustment required.

Geriatric Patients

No specific dosage recommendations at this time.

Cautions for Palbociclib

Contraindications

None.

Warnings/Precautions

Neutropenia

Grade 3 or 4 neutropenia occurs frequently. Median time to onset: 15 days. Median duration of grade 3 or greater neutropenia: 7 days. Febrile neutropenia (temperature ≥38.5°C) and fatal neutropenic sepsis also reported.

Monitor CBC at baseline, prior to initiation of each cycle, on day 15 of cycles 1 and 2, and as clinically indicated. If neutropenia occurs, more frequent CBC monitoring may be necessary. If neutropenia occurs, temporary interruption, dosage reduction, or treatment delay may be necessary depending on severity.

Interstitial Lung Disease (ILD)/Pneumonitis

Severe, life-threatening, or fatal ILD/pneumonitis reported with CDK4 and CDK6 inhibitors, including palbociclib.

Monitor patients for symptoms of pneumonitis.

If manifestations of ILD or pneumonitis occur, temporarily interrupt palbociclib therapy until other etiologies (e.g., infection, neoplasm) have been excluded. If severe ILD or pneumonitis occurs, permanently discontinue palbociclib therapy.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; embryofetal toxicity and teratogenicity demonstrated in animals.

Confirm pregnancy status prior to initiating palbociclib therapy. Advise women of childbearing potential and men who are partners of such women to use effective contraception during treatment and for at least 3 weeks in women and for 3 months in men following drug discontinuance.

If used during pregnancy or patient becomes pregnant, apprise of potential fetal hazard.

Specific Populations

Pregnancy

May cause fetal harm; avoid pregnancy during treatment with palbociclib. Confirm pregnancy status prior to initiating treatment.

Lactation

Not known whether distributed into human milk. Discontinue nursing during treatment and for 3 weeks following drug discontinuance.

Effects of drug on nursing infants or milk production unknown.

Females and Males of Reproductive Potential

May impair male fertility. Decreased fertility and adverse effects on male reproductive organs and sperm observed in animal studies; male reproductive organ effects partially reversible following drug discontinuance. Consider sperm preservation prior to initiating palbociclib therapy.

Confirm pregnancy status prior to initiating treatment. Advise women of childbearing potential and men who are partners of such women to use effective contraception during treatment and for ≥3 weeks in women and for ≥3 months in men following drug discontinuance. If used during pregnancy or patient becomes pregnant, apprise of potential fetal hazard.

Pediatric Use

Safety and efficacy not established in pediatric patients <18 years of age.

Altered glucose metabolism associated with pancreatic islet cell vacuolation, cataracts, ocular lens degeneration, renal tubule vacuolation, chronic progressive nephropathy, and atrophy of adipose tissue observed in immature animals. Tooth abnormalities also observed in animals.

Geriatric Use

No overall differences in safety and efficacy relative to younger patients.

Hepatic Impairment

Increased exposure of unbound fraction of palbociclib in individuals with severe hepatic impairment; dosage reduction recommended.

Mild or moderate hepatic impairment does not substantially alter systemic exposure.

Mean unbound fraction of palbociclib increases incrementally with worsening hepatic function.

Renal Impairment

Mild, moderate, or severe renal impairment does not substantially alter systemic exposure.

Not studied in patients requiring dialysis.

Common Adverse Effects

Adverse effects (≥10%): Neutropenia, infection, leukopenia, fatigue, nausea, stomatitis, anemia, alopecia, diarrhea, thrombocytopenia, rash, vomiting, decreased appetite, asthenia, pyrexia.

Drug Interactions

Metabolized principally by CYP3A and sulfotransferase (SULT) 2A1.

In vitro, not an inhibitor of CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, and 2D6 or inducer of CYP1A2, 2B6, 2C8, and 3A4 at clinically relevant concentrations. In vivo, weak time-dependent inhibitor of CYP3A.

In vitro, low potential for inhibition of organic cation transporter (OCT) 2, organic anion transporter (OAT) 1, OAT 3, organic anion transport protein (OATP) 1B1 and OATP1B3 at clinically relevant concentrations. In vitro, potential for inhibition of P-gp and breast cancer resistance protein (BCRP).

Drugs Affecting Hepatic Microsomal Enzymes

Strong CYP3A inhibitors: Possible pharmacokinetic interaction (increased plasma concentrations and AUC of palbociclib). Avoid concomitant use; consider choosing alternative agent with no or minimal CYP3A inhibition potential. If concomitant use cannot be avoided, reduce palbociclib dosage to 75 mg once daily.

If strong CYP3A inhibitor is discontinued, resume palbociclib (after 3–5 terminal half-lives of the CYP3A inhibitor) at dosage used prior to initiation of the strong CYP3A inhibitor.

CYP3A inducers: Possible pharmacokinetic interaction (decreased plasma concentrations and AUC of palbociclib). Avoid concomitant use.

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP3A: Possible pharmacokinetic interaction (increased plasma concentrations of CYP3A substrate). If concomitant use of palbociclib and CYP3A substrates with a narrow therapeutic index cannot be avoided, consider dosage reduction of the CYP3A substrate.

Drugs Affecting Gastric Acidity

Potential pharmacokinetic interaction (decreased plasma concentrations and AUC of palbociclib) with drugs that increase gastric pH.

Specific Drugs and Foods

Drug	Interaction	Comments
Anastrozole	No clinically important effect on pharmacokinetics of anastrozole or palbociclib expected
Antacids	No clinically important effects on palbociclib exposure when administered under fed conditions
Antifungals, azoles (e.g., itraconazole, ketoconazole, posaconazole, voriconazole)	Possible increased palbociclib exposure Itraconazole (200 mg daily) increased palbociclib (single 125-mg dose) AUC and peak concentrations by 87 and 34%, respectively	Avoid concomitant use Select alternative agent with no or minimal CYP3A inhibition potential; if concomitant use unavoidable, reduce palbociclib dosage to 75 mg once daily If strong CYP3A inhibitor is discontinued, resume palbociclib (after 3–5 terminal half-lives of the CYP3A inhibitor) at dosage used prior to initiation of strong CYP3A inhibitor
Antiretrovirals, HIV protease inhibitors (e.g., nelfinavir, ritonavir, ritonavir-boosted lopinavir, saquinavir)	Possible increased palbociclib exposure	Avoid concomitant use Select alternative agent with no or minimal CYP3A inhibition potential; if concomitant use unavoidable, reduce palbociclib dosage to 75 mg once daily If strong CYP3A inhibitor is discontinued, resume palbociclib (after 3–5 terminal half-lives of the CYP3A inhibitor) at dosage used prior to initiation of strong CYP3A inhibitor
Carbamazepine	Possible decreased palbociclib exposure	Avoid concomitant use
Ergot derivatives (e.g., dihydroergotamine, ergotamine)	Possible increased concentrations of ergot derivative	Concomitant use not recommended; if concomitant use unavoidable, consider dosage reduction of ergot derivative
Exemestane	No clinically important effect on pharmacokinetics of exemestane or palbociclib expected
Fulvestrant	No effect on pharmacokinetics of fulvestrant or palbociclib
Goserelin	No effect on pharmacokinetics of goserelin or palbociclib
Grapefruit or grapefruit juice	Possible increased palbociclib exposure	Avoid concomitant use
Histamine H₂-receptor antagonists	No clinically important effects on palbociclib exposure when administered under fed conditions
Immunosuppressive agents (e.g., cyclosporine, everolimus, sirolimus, tacrolimus)	Possible increased concentrations of immunosuppressive agents metabolized by CYP3A	Concomitant use not recommended; if concomitant use unavoidable, consider dosage reduction of CYP3A substrate drug
Letrozole	No effect on pharmacokinetics of letrozole or palbociclib
Macrolides (e.g., clarithromycin)	Possible increased palbociclib exposure	Avoid concomitant use Select alternative agent with no or minimal CYP3A inhibition potential; if concomitant use unavoidable, reduce palbociclib dosage to 75 mg once daily If strong CYP3A inhibitor is discontinued, resume palbociclib (after 3–5 terminal half-lives of the CYP3A inhibitor) at dosage used prior to initiation of strong CYP3A inhibitor
Midazolam	Palbociclib (multiple 125-mg doses) increased midazolam AUC and peak concentrations by 61 and 37%, respectively	Concomitant use not recommended; if concomitant use unavoidable, consider dosage reduction of midazolam
Modafinil	Modafinil (400 mg daily) decreased palbociclib (single 125-mg dose) AUC and peak concentrations by 32 and 11%, respectively	Avoid concomitant use
Nefazodone	Possible increased palbociclib exposure	Avoid concomitant use Select alternative agent with no or minimal CYP3A inhibition potential; if concomitant use unavoidable, reduce palbociclib dosage to 75 mg once daily If nefazodone is discontinued, resume palbociclib (after 3–5 terminal half-lives of nefazodone) at dosage used prior to initiation of nefazodone
Opiate agonists (e.g., alfentanil, fentanyl)	Possible increased concentrations of opiate agonists metabolized by CYP3A	Concomitant use not recommended; if concomitant use unavoidable, consider dosage reduction of CYP3A substrate drug
Phenytoin	Possible decreased palbociclib exposure	Avoid concomitant use
Pimozide	Possible increased concentrations of pimozide	Concomitant use not recommended; if concomitant use unavoidable, consider dosage reduction of pimozide
Proton-pump inhibitors (e.g., rabeprazole)	Possible decreased palbociclib exposure Rabeprazole decreased palbociclib (single 125-mg dose) AUC and peak concentrations by 13 and 41%, respectively, when administered under fed conditions, and by 62 and 80%, respectively, under fasting conditions No clinically important effects on palbociclib exposure when administered under fed conditions
Quinidine	Possible increased concentrations of quinidine	Concomitant use not recommended; if concomitant use unavoidable, consider dosage reduction of quinidine
Rifampin	Rifampin (600 mg daily) decreased AUC and peak concentrations of palbociclib (single 125-mg dose) by 85 and 70%, respectively	Avoid concomitant use
St. John’s wort (Hypericum perforatum)	Possible decreased palbociclib exposure	Avoid concomitant use

Palbociclib Pharmacokinetics

Absorption

Bioavailability

Mean absolute bioavailability is 46%.

Following oral administration of capsule, peak plasma concentrations attained in 6–12 hours.

Following oral administration of tablet, peak plasma concentrations attained in 4–12 hours.

Exposure is dose proportional over dosage range of 25–225 mg; median accumulation ratio is 2.4.

Steady-state concentrations achieved in 8 days.

Food

Administration of capsules in a fasting state decreased absorption and systemic exposure in approximately 13% of patients. Systemic exposure increased when drug was administered with food in these individuals; no effect on systemic exposure in other individuals. Administration of capsules with food reduces interindividual variability in systemic exposure.

Systemic exposure of palbociclib increased when the tablets were administered with food.

Special Populations

Mild hepatic impairment (total bilirubin concentrations not exceeding ULN with AST concentrations exceeding ULN, or total bilirubin concentrations >1 to 1.5 times ULN with any AST concentrations) does not substantially affect systemic exposure.

Mild, moderate, or severe hepatic impairment (Child-Pugh class A, B, or C, respectively) increased AUC of palbociclib unbound fraction by 17, 34, or 77%, respectively, and peak concentrations of unbound fraction by 7, 38, or 72%, respectively.

Mild (Cl_cr 60 to <90 mL/minute), moderate (Cl_cr 30 to <60 mL/minute), or severe (Cl_cr <30 mL/minute) renal impairment does not substantially affect systemic exposure. Pharmacokinetics not studied in patients requiring dialysis.

Mild, moderate, or severe renal impairment increased AUC of palbociclib by 39, 42, or 31%, respectively, and peak concentrations by 17, 12, or 15%, respectively. Renal impairment does not appear to affect mean unbound fraction.

Age, sex, race (Asian versus non-Asian), and body weight do not have clinically important effects on palbociclib exposure.

Distribution

Extent

Not known whether distributed into human milk.

Plasma Protein Binding

Approximately 85%.

Elimination

Metabolism

Principally metabolized by CYP3A and SULT2A1.

Elimination Route

Eliminated in feces (74.1%) and urine (17.5%), mainly as metabolites.

Half-life

29 hours.

Stability

Storage

Oral

Capsules

20–25°C (excursions permitted between 15–30°C).

Tablets

20–25°C (excursions permitted between 15–30°C). Store in original blister pack.

Actions

Reversible and selective inhibitor of cyclin-dependent kinase (CDK) 4 and 6.
CDK4 and 6 involved in regulation of progression from the G1 into S phase of the cell cycle through regulation of phosphorylation of the tumor suppressor protein retinoblastoma.
Inhibits the G1 into S phase of the cell cycle and reduces cellular proliferation of estrogen receptor-positive breast cancer cells.
Increased cell growth arrest in breast cancer cells treated with palbociclib and antiestrogens compared with either drug alone.
Increased cell senescence for up to 6 days following discontinuance of therapy in estrogen receptor-positive breast cancer cells treated with palbociclib and antiestrogens.
Increased inhibition of retinoblastoma phosphorylation, downstream signaling, and tumor growth when treated with palbociclib and letrozole compared with either drug alone in patient-derived estrogen receptor-positive breast tumor xenografts.
No effect on human bone marrow mononuclear cell senescence when treated with palbociclib with or without an antiestrogen; cell proliferation resumes following discontinuance of therapy.

Advice to Patients

Stress importance of taking palbociclib with food. Avoid grapefruit and grapefruit juice while taking the drug.
For premenopausal or perimenopausal women, stress importance of receiving concomitant LHRH agonist therapy.
Advise patients to swallow capsules or tablets whole and not to chew, crush, or open/split.
If a dose of palbociclib is missed or vomited, take the next dose at the regularly scheduled time; do not double the dose or take extra doses.
Risk of myelosuppression or infection. Stress importance of contacting clinician promptly if signs or symptoms of myelosuppression or infection (e.g., fever, chills, dizziness, shortness of breath, weakness, increased tendency to bleed and/or bruise) occur.
Risk of severe, life-threatening, or fatal ILD/pneumonitis. Stress importance of informing clinician immediately if new or worsening cough (with or without mucus), chest pain, or shortness of breath occurs.
Risk of fetal harm. Advise women of childbearing potential and men who are partners of such women to use effective contraception during treatment and for at least 3 weeks in women and for 3 months in men after discontinuance of therapy. Stress importance of women informing clinicians if they are or plan to become pregnant. If pregnancy occurs, advise patients of potential fetal risk.
Risk of serious adverse reactions in nursing infants. Advise women to discontinue nursing during treatment and for 3 weeks following drug discontinuance.
Risk of male infertility. Advise men to consider sperm preservation prior to initiating palbociclib therapy.
Stress importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements (e.g., St. John’s wort), as well as any concomitant illnesses.
Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Palbociclib is obtained from specialty pharmacy providers. Contact manufacturer for additional information.