Palbociclib

Pronunciation

(pal boe SYE klib)

Index Terms

• Palbociclib Isethionate
• PD 0332991
• PD-0332991
• PD-332991

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral:

Ibrance: 75 mg, 100 mg, 125 mg

Brand Names: U.S.

• Ibrance

Pharmacologic Category

• Antineoplastic Agent, Cyclin-Dependent Kinase Inhibitor

Pharmacology

Palbociclib is a reversible small molecule cyclin-dependent kinase (CDK) inhibitor which is selective for CDK 4 and 6. CDKs have a role in regulating progression through the cell cycle at the G1/S phase by blocking retinoblastoma (Rb) hyperphosphorylation (Finn 2015). Palbociclib reduces proliferation of breast cancer cell lines by preventing progression from the G1 to the S cell cycle phase. The combination of palbociclib and letrozole provides for increased inhibition of Rb phosphorylation, downstream signaling, and tumor growth compared with each agent alone.

Absorption

Increased with high-fat, high-calorie food

Distribution

V_d (mean): 2,583 L

Metabolism

Extensively hepatic; Major pathways: Oxidation and sulfonation, primarily by CYP3A and sulfotransferase (SULT) enzyme SULT2A1; Minor pathways: Acylation and glucuronidation

Excretion

Feces (~74%, primarily as metabolites); Urine (~18%; primarily as metabolites)

Time to Peak

6 to 12 hours

Half-Life Elimination

29 ± 5 hours

Protein Binding

~85%

Use: Labeled Indications

US labeling:

Breast cancer, advanced (initial endocrine-based therapy): Treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer (in combination with letrozole) in postmenopausal women as initial endocrine-based therapy

Breast cancer, advanced (second-line endocrine-based therapy): Treatment of HR-positive, HER2-negative advanced or metastatic breast cancer (in combination with fulvestrant) in women with disease progression following endocrine therapy

Canadian labeling:

Breast cancer, advanced (initial endocrine-based therapy): Treatment of estrogen receptor (ER)-positive, HER2-negative metastatic breast cancer (in combination with letrozole) in postmenopausal women as initial endocrine-based therapy

Contraindications

US labeling: There are no contraindications listed in the manufacturer’s labeling.

Canadian labeling: Hypersensitivity to palbociclib or any component of the formulation

Dosing: Adult

Note: Refer to letrozole and fulvestrant monographs for respective dosing in combination with palbociclib.

Breast cancer, advanced, initial endocrine-based therapy: Females (HER-2 negative): Oral: 125 mg once daily for 21 days, followed by a 7-day rest period to complete a 28-day treatment cycle (in combination with continuous letrozole); continue until disease progression or unacceptable toxicity (Finn 2015).

Breast cancer, advanced, second-line endocrine-based therapy: Females (HER-2 negative): Oral: 125 mg once daily for 21 days, followed by 7 days off, repeat every 28 days (in combination with fulvestrant [and an LHRH agonist (eg, goserelin) if pre- or perimenopausal]); continue until disease progression or unacceptable toxicity (Turner 2015).

Missed/vomited doses: If a dose is vomited or missed, an additional dose should not be taken that day. Resume dosing with the next scheduled daily dose.

Dosage adjustment for concomitant therapy:

Strong CYP3A inhibitors:

US labeling: Avoid concomitant use with strong CYP3A inhibitors (eg, azole antifungals, clarithromycin, nefazodone, protease inhibitors, telithromycin, verapamil, grapefruit or grapefruit juice) and consider alternatives with no or minimal CYP3A inhibition. If coadministration with a strong CYP3A inhibitor cannot be avoided, reduce palbociclib dose to 75 mg once daily. If the strong inhibitor is discontinued, increase palbociclib dose (after 3 to 5 inhibitor half-lives have elapsed) to the dose used prior to initiating the strong CYP3A inhibitor.

Canadian labeling: Avoid concomitant use with strong CYP3A inhibitors.

CYP3A inducers: Avoid concomitant use with strong CYP3A inducers; the Canadian labeling also recommends avoiding concomitant use with moderate CYP3A inducers.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

CrCl 30 to <90 mL/minute:

US labeling: There are no dosage adjustments provided in the manufacturer’s labeling, although palbociclib exposure is not increased.

Canadian labeling: No dosage adjustment necessary.

CrCl <30 mL/minute: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Dosing: Hepatic Impairment

Mild impairment (total bilirubin ≤ULN and AST >ULN or total bilirubin >1 to 1.5 times ULN and any AST):

US labeling: There are no dosage adjustments provided in the manufacturer’s labeling, although palbociclib exposure is not increased.

Canadian labeling: No dosage adjustment necessary.

Moderate to severe impairment (total bilirubin >1.5 times ULN and any AST): There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Dosing: Adjustment for Toxicity

May require treatment interruption/delay, dose reduction, or discontinuation for some adverse reactions. The recommended first dose reduction is to 100 mg daily; if a second reduction is required, reduce dose to 75 mg daily. If dose reduction below 75 mg daily is required, discontinue treatment.

Hematologic toxicity (except lymphopenia unless associated with clinical events [eg, opportunistic infection]), according to Common Toxicity Criteria for Adverse Events Version 4:

Grade 1 or 2: No dosage adjustment required.

Grade 3:

Day 1 of cycle: Withhold palbociclib therapy and repeat CBC with differential within 1 week. When improved to ≤ grade 2, initiate the next cycle at the same dose.

Day 14 of first 2 cycles: Continue palbociclib therapy at current dose to complete the cycle. Repeat CBC with differential on day 21. Consider dose reduction in future cycles if recovery from grade 3 neutropenia is prolonged (>1 week) or for recurrent grade 3 neutropenia in subsequent cycles.

Grade 3 (ANC 500/mm³ to <1,000/mm³) plus fever ≥38.5 °C and/or infection: Withhold palbociclib treatment until resolved to ≤ grade 2. Resume at next lower dose upon restarting.

Grade 4: Withhold palbociclib treatment until resolved to ≤ grade 2. After resolution, resume at next lower dose.

Nonhematologic toxicity (according to Common Toxicity Criteria for Adverse Events Version 4):

Grade 1 or 2: No dosage adjustment required.

Grade 3 or higher (if persistent despite optimal medical management): Withhold palbociclib until symptoms resolve to ≤ grade 1 or ≤ grade 2 (if toxicity is not a safety risk); after resolution, resume at the next lower dose.

Administration

Oral: Administer with food. Take at approximately the same time each day. Swallow whole, do not crush, chew, or open capsules prior to swallowing (do not ingest if capsules are broken, cracked, or not fully intact). Hazardous agent; use appropriate precautions for handling and disposal (meets NIOSH 2014 criteria). NIOSH recommends single gloving for administration of an intact capsule (NIOSH 2014).

Dietary Considerations

Avoid grapefruit.

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F).

Drug Interactions

Aprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

ARIPiprazole: CYP3A4 Inhibitors (Weak) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole pharmacologic effects. Aripiprazole dose adjustments may or may not be required based on concomitant therapy and/or indication. Consult full interaction monograph for specific recommendations. Monitor therapy

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

CYP3A4 Inducers (Moderate): May decrease the serum concentration of Palbociclib. Management: The US label does not provide specific recommendations concerning use with moderate CYP3A4 inducers, but the Canadian label recommends avoiding use of moderate CYP3A4 inducers. Consider therapy modification

CYP3A4 Inducers (Strong): May decrease the serum concentration of Palbociclib. Avoid combination

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Palbociclib. Avoid combination

CYP3A4 Substrates: Palbociclib may increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Dofetilide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Dofetilide. Monitor therapy

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Flibanserin: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Flibanserin. Monitor therapy

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Grapefruit Juice: May increase the serum concentration of Palbociclib. Avoid combination

HYDROcodone: CYP3A4 Inhibitors (Weak) may increase the serum concentration of HYDROcodone. Monitor therapy

Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Ivacaftor: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Lomitapide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Lomitapide. Management: Patients on lomitapide 5 mg/day may continue that dose. Patients taking lomitapide 10 mg/day or more should decrease the lomitapide dose by half. The lomitapide dose may then be titrated up to a max adult dose of 30 mg/day. Consider therapy modification

Luliconazole: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Netupitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

NiMODipine: CYP3A4 Inhibitors (Weak) may increase the serum concentration of NiMODipine. Monitor therapy

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Pimozide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Pimozide. Avoid combination

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

St John's Wort: May decrease the serum concentration of Palbociclib. Avoid combination

Stiripentol: May increase the serum concentration of CYP3A4 Substrates. Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Avoid combination

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Avoid combination

Adverse Reactions

Percentages reported as part of combination therapy.

>10%:

Central nervous system: Fatigue (41%), headache (26%), peripheral neuropathy (13%)

Dermatologic: Alopecia (18% to 22%), skin rash (17%)

Gastrointestinal: Nausea (25% to 34%), stomatitis (25% to 28%), diarrhea (21% to 24%), constipation (20%), vomiting (15% to 19%), decreased appetite (16%)

Hematologic & oncologic: Neutropenia (75% to 83%; grade 3: 48% to 55%; grade 4: 6% to 11%), decreased absolute lymphocyte count (81%; grade 3: 17%; grade 4: 1%), anemia (30% to 78%; grade 3: 3% to 5%; grade 4: ≤1%), leukopenia (43% to 53%; grade 3: 19% to 30%; grade 4: ≤1%), thrombocytopenia (17% to 23%; grade 3: 2%; grade 4: ≤1%)

Infection: Infection (47% to 55%)

Neuromuscular & skeletal: Weakness (8% to 13%)

Respiratory: Upper respiratory tract infection (31%), epistaxis (7% to 11%)

Miscellaneous: Fever (13%)

1% to 10%:

Cardiovascular: Pulmonary embolism (1% to 5%)

Dermatologic: Xeroderma (6%)

Gastrointestinal: Dysgeusia (7%)

Hematologic & oncologic: Febrile neutropenia (1%; grade 3: 1%)

Ophthalmic: Blurred vision (6%), increased lacrimation (6%), dry eye syndrome (4%)

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: Neutropenia was commonly observed in clinical studies, including grades 3 and 4 neutropenia. The median time to the first neutropenia episode (any grade) was 15 days; the median duration of grade 3 or higher neutropenia was 7 days. Leukopenia, anemia, lymphocytopenia, thrombocytopenia, neutropenic fever, and neutropenic sepsis have also been reported. Monitor blood counts prior to initiating therapy and at the beginning of each cycle (as well as on day 14 of the first 2 cycles), and as clinically necessary; treatment interruption, delay, or dose reduction is recommended for grade 3 or 4 neutropenia.

• Gastrointestinal toxicity: Nausea, vomiting, diarrhea, and stomatitis (generally grade 1 or 2) were reported from clinical studies.

• Infection: Infections (including grades 3 and 4) were reported more frequently in patients receiving palbociclib and letrozole compared with those receiving only letrozole. Monitor for signs/symptoms of infection and manage appropriately.

• Thromboembolic events: Pulmonary embolism was observed more frequently in patients receiving palbociclib in combination with endocrine therapy compared with those receiving letrozole or fulvestrant alone. Monitor for signs/symptoms of pulmonary embolism and manage appropriately.

Concurrent drug therapy issues :

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (meets NIOSH 2014 criteria).

Monitoring Parameters

CBC with differential (prior to treatment initiation, every 2 weeks for first 2 cycles, then prior to each cycle, and as clinically indicated); monitor for signs/symptoms of infection and pulmonary embolism.

Pregnancy Considerations

Adverse events were observed in animal reproduction studies. Based on the mechanism of action, palbociclib may be expected to cause fetal harm if used during pregnancy. Women of reproductive potential should use effective contraception during treatment 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 at least 3 months after the last dose. Although not approved for use in men, animal data suggests that palbociclib may affect male fertility.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience lack of appetite, diarrhea, hair thinning or loss, mouth sores, nausea, vomiting, constipation, headache, rhinitis, or pharyngitis. Have patient report immediately to prescriber signs of infection, bruising, bleeding, burning or numbness feeling, dizziness, nosebleed, severe loss of strength and energy, angina, coughing up blood, fast breathing, tachycardia, or shortness of breath (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.