Palbociclib

Class: Antineoplastic Agents
Chemical Name: 6-Acetyl-8-cyclopentyl-5-methyl-2-[[5-(1-piperazinyl)-2-pyridinyl]amino]-pyrido[2,3-d]pyrimidin-7(8H)-one
Molecular Formula: C₂₄H₂₉N₇O₂
CAS Number: 571190-30-2
Brands: Ibrance

Introduction

Antineoplastic agent; a reversible and selective inhibitor of cyclin-dependent kinase (CDK) 4 and 6.^{1 2 3 5 6 7 10}

Uses for Palbociclib

Breast Cancer

In combination with letrozole for initial treatment of hormone receptor-positive, human epidermal growth factor receptor type 2 (HER2)-negative advanced or metastatic breast cancer in postmenopausal women.^{1 2}

Accelerated approval for combination therapy with letrozole based on progression-free survival.¹ Continued approval may be contingent on verification and description of clinical benefit in confirmatory studies.¹

In combination with fulvestrant for treatment of hormone receptor-positive, HER2-negative advanced or metastatic breast cancer in women with disease progression following endocrine therapy.^{1 15}

Palbociclib Dosage and Administration

General

• Obtain CBC at baseline, prior to initiation of each cycle, on day 14 of cycles 1 and 2, and as clinically indicated.¹ More frequent monitoring may be required in patients who develop hematologic toxicity during therapy.¹ (See Dosage Modification for Toxicity under Dosage and Administration.)

• Consult respective manufacturers' labelings for information on dosage adjustments, adverse effects, and contraindications of other antineoplastic agents used in combination regimens.¹

Restricted Distribution

• Must obtain palbociclib through a specialty pharmacy.⁴

• Consult the Ibrance website (http://www.ibrance.com/getting-ibrance) for specific availability information.⁴

Administration

Oral Administration

Administer orally once daily with food at approximately the same time each day.¹ (See Absorption under Pharmacokinetics.)

Swallow palbociclib capsules whole; do not chew, crush, or open.¹

If a dose is missed or vomited, take the next dose at the regularly scheduled time.¹ Do not double the dose or take extra doses.¹

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 letrozole 2.5 mg orally once daily given continuously during 28-day cycle.¹ In principal efficacy study, therapy was continued until disease progression or unacceptable toxicity occurred.¹

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.¹ In principal efficacy study, therapy was continued until disease progression or unacceptable toxicity occurred.^{1 15}

Treat premenopausal or perimenopausal women receiving combination therapy with palbociclib and fulvestrant with a luteinizing hormone-releasing hormone (LHRH) agonist (e.g., goserelin) according to current standards of care.¹

Dosage Modification for Toxicity

Oral

Adverse effects may require temporary interruption, dosage reduction, and/or permanent discontinuance.¹ Adjust dosage based on individual safety and tolerability.¹

Up to 2 dosage reductions for toxicity may be made.¹ If dosage reduction from 125 mg once daily is necessary, initially reduce dosage to 100 mg once daily.¹

If further dosage reduction necessary, reduce dosage to 75 mg once daily.¹

Dosages <75 mg once daily not recommended.¹

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.¹ When ANC is ≥1000/mm³, resume therapy at reduced dosage.¹

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.¹ Delay next cycle until toxicity resolves to grade 2 or less; then continue palbociclib at the same dosage.¹

If grade 3 hematologic toxicity reported after CBC monitoring on day 14 of cycle 1 or 2, continue palbociclib at the same dosage; repeat CBC monitoring on day 21.¹

If prolonged grade 3 neutropenia (i.e., lasting >7 days) occurs or grade 3 neutropenia recurs in subsequent cycles, resume therapy at reduced dosage.¹

If grade 4 hematologic toxicity occurs, temporarily interrupt palbociclib therapy.¹ When toxicity resolves to grade 2 or less, resume therapy at reduced dosage.¹

Exception made for grade 3 or 4 lymphopenia without an associated clinical event (e.g., opportunistic infection); no dosage modification required in such patients.^{1 14}

Nonhematologic Toxicity

Oral

If persistent grade 3 or greater nonhematologic toxicity occurs despite appropriate medical management, temporarily interrupt palbociclib therapy.¹ 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.¹

Concomitant Use with Drugs Affecting Hepatic Microsomal Enzymes

Oral

If used concomitantly with a potent CYP3A inhibitor, reduce palbociclib dosage to 75 mg once daily.¹ (See Drugs Affecting Hepatic Microsomal Enzymes under Interactions.)

Prescribing Limits

Adults

Breast Cancer

Oral

Dosages <75 mg once daily not recommended.¹

Special Populations

Hepatic Impairment

No specific dosage recommendations at this time.¹ (See Hepatic Impairment under Cautions.)

Renal Impairment

No specific dosage recommendations at this time.¹ (See Renal Impairment under Cautions.)

Geriatric Patients

No specific dosage recommendations at this time.¹ (See Geriatric Use under Cautions.)

Cautions for Palbociclib

Contraindications

• Manufacturer states none known.¹

Warnings/Precautions

Neutropenia

Grade 3 or 4 neutropenia occurs frequently.^{1 2 15} Median time to onset: 15 days.¹ Median duration of grade 3 or greater neutropenia: 7 days.¹ Febrile neutropenia (temperature ≥38.5°C) and fatal neutropenic sepsis also reported.¹

Monitor CBC at baseline, prior to initiation of each cycle, on day 14 of cycles 1 and 2, and as clinically indicated.¹ If neutropenia occurs, more frequent CBC monitoring may be necessary.¹ If neutropenia occurs, temporary interruption, dosage reduction, or treatment delay may be necessary depending on severity.¹ (See Dosage Modification for Toxicity under Dosage and Administration.)

Pulmonary Embolism

Pulmonary embolism reported.^{1 2 15}

Monitor for signs and symptoms.¹ If pulmonary embolism occurs, initiate appropriate treatment.¹

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; embryofetal toxicity and teratogenicity demonstrated in animals.¹

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.¹

If used during pregnancy or patient becomes pregnant, apprise of potential fetal hazard.¹

Impairment of Male Fertility

May impair male fertility.¹ Decreased fertility and adverse effects on male reproductive organs and sperm observed in animal studies; male reproductive organ effects partially reversible following drug discontinuance.¹

Specific Populations

Pregnancy

May cause fetal harm.¹ (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether distributed into milk.¹ Discontinue nursing during treatment and for 3 weeks following drug discontinuance.¹

Effects of drug on nursing infants or milk production unknown.¹

Pediatric Use

Safety and efficacy not established in pediatric patients <18 years of age.¹

Geriatric Use

No overall differences in safety and efficacy relative to younger patients.¹

Hepatic Impairment

Mild hepatic impairment does not substantially alter systemic exposure.¹ (See Special Populations under Pharmacokinetics.)

Not studied in patients with moderate to severe hepatic impairment.¹

Renal Impairment

Mild to moderate renal impairment (Cl_cr 30 to <90 mL/minute) does not substantially alter systemic exposure.¹ (See Special Populations under Pharmacokinetics.)

Not studied in patients with severe renal impairment.¹

Common Adverse Effects

Combination therapy with letrozole: Neutropenia,^{1 2} leukopenia,^{1 2} fatigue,^{1 2} anemia,^{1 2} upper respiratory infection (e.g., influenza, laryngitis, nasopharyngitis, pharyngitis, rhinitis, sinusitis),^{1 2} nausea,^{1 2} stomatitis (e.g., oropharyngeal pain),^{1 2} alopecia,^{1 2} diarrhea,^{1 2} hot flush,² arthralgia,² thrombocytopenia,^{1 2} decreased appetite,^{1 2} vomiting,^{1 2} dyspnea,² back pain,² headache,² asthenia,^{1 2} peripheral neuropathy,^{1 2} bone pain,² constipation,² cough,² epistaxis,^{1 2} musculoskeletal pain,² dizziness,² extremity pain.²

Combination therapy with fulvestrant: Neutropenia,^{1 15} leukopenia,^{1 15} infections,^{1 15} fatigue,^{1 15} nausea,^{1 15} anemia,^{1 15} stomatitis,^{1 15} headache,^{1 15} diarrhea,^{1 15} thrombocytopenia,^{1 15} constipation,^{1 15} vomiting,^{1 15} alopecia,^{1 15} rash,¹ decreased appetite,^{1 15} hot flush, ¹⁵ arthralgia,¹⁵ cough,¹⁵ pyrexia,^{1 15} back pain,¹⁵ dizziness,¹⁵ dyspnea.¹⁵

Interactions for Palbociclib

Metabolized principally by CYP3A and sulfotransferase (SULT) 2A1.¹

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.¹ In vivo, weak time-dependent inhibitor of CYP3A.¹

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

Drugs Affecting Hepatic Microsomal Enzymes

Potent CYP3A inhibitors: Possible pharmacokinetic interaction (increased plasma concentrations and AUC of palbociclib).¹ Avoid concomitant use; consider choosing alternative agent with no or minimal CYP3A inhibition potential.¹ If concomitant use cannot be avoided, reduce palbociclib dosage to 75 mg once daily.¹

If potent CYP3A inhibitor is discontinued, resume palbociclib (after 3–5 terminal half-lives of the CYP3A inhibitor) at dosage used prior to initiation of the potent CYP3A inhibitor.¹ (See Specific Drugs and Foods under Interactions.)

Moderate and potent CYP3A inducers: Possible pharmacokinetic interaction (decreased plasma concentrations and AUC of palbociclib).¹ Avoid concomitant use.¹ (See Specific Drugs and Foods under Interactions.)

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP3A: Possible pharmacokinetic interaction (increased plasma concentrations of CYP3A substrate).¹ If concomitant use of palbociclib and CYP3A substrates with a narrow therapeutic index cannot be avoided, consider dosage reduction of the CYP3A substrate.¹ (See Specific Drugs and Foods under Interactions.)

Drugs Affecting Gastric Acidity

Potential pharmacokinetic interaction (decreased plasma concentrations and AUC of palbociclib) with drugs that increase gastric pH.¹ (See Specific Drugs and Foods under Interactions.)

Specific Drugs and Foods

Palbociclib Pharmacokinetics

Absorption

Bioavailability

Mean absolute bioavailability is 46%.¹

Following oral administration, peak plasma concentrations attained in 6–12 hours.¹

Exposure is dose proportional over dosage range of 25–225 mg; median accumulation ratio is 2.4.¹

Steady-state concentrations achieved in 8 days.¹

Food

Administration in a fasting state decreased absorption and systemic exposure in approximately 13% of patients.¹ Systemic exposure increased when drug was administered with food in these individuals; no effect on systemic exposure in other individuals.¹ Administration with food reduces interindividual variability in systemic exposure.¹

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.¹ Pharmacokinetics not studied in moderate or severe (total bilirubin concentrations >1.5 times ULN with any AST concentrations) hepatic impairment.¹

Mild (Cl_cr 60 to <90 mL/minute) or moderate (Cl_cr 30 to <60 mL/minute) renal impairment does not substantially affect systemic exposure.¹ Pharmacokinetics not studied in severe renal impairment.¹

Age, gender, and body weight do not have clinically important effects on palbociclib exposure.¹

Distribution

Extent

Not known whether distributed into human milk.¹

Plasma Protein Binding

Approximately 85%.¹

Elimination

Metabolism

Principally metabolized by CYP3A and SULT2A1.¹

Elimination Route

Eliminated in feces (74.1%) and urine (17.5%), mainly as metabolites.¹

Half-life

29 hours.¹

Stability

Storage

Oral

Capsules

20–25°C (may be exposed to 15–30°C).¹

Actions

• Reversible and selective inhibitor of cyclin-dependent kinase (CDK) 4 and 6.^{1 2 3 5 6 7 10}

• 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.^{2 8}

• Inhibits the G1 into S phase of the cell cycle and reduces cellular proliferation of estrogen receptor-positive breast cancer cells.¹

• Increased cell growth arrest in breast cancer cells treated with palbociclib and antiestrogens compared with either drug alone.¹

• Increased cell senescence for up to 6 days following discontinuance of therapy in estrogen receptor-positive breast cancer cells treated with palbociclib and antiestrogens.¹

• 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.¹

Advice to Patients

• Importance of taking palbociclib with food.¹ Avoid grapefruit and grapefruit juice while taking the drug.¹

• Importance of advising patients to swallow capsules whole and not to chew, crush, or open capsules.¹

• 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.¹

• Risk of myelosuppression or infection.¹ 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.¹

• Risk of pulmonary embolism.¹ Importance of contacting clinician promptly if signs or symptoms of pulmonary embolism (e.g., shortness of breath, chest pain, tachypnea, tachycardia) occur.¹

• Risk of fetal harm.¹ Necessity of advising 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.¹ Importance of women informing clinicians if they are or plan to become pregnant.¹ If pregnancy occurs, advise patient of potential fetal risk.¹

• Risk of serious adverse reactions in nursing infants.¹ Importance of advising women to discontinue nursing during treatment and for 3 weeks following drug discontinuance.¹

• 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.¹

• Importance of informing patients of other important precautionary information.¹ (See Cautions.)

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.

Distribution of palbociclib is restricted.⁴ (See Restricted Distribution under Dosage and Administration.)