palbociclib

Palbociclib is a chemotherapy drug used to treat HER2-negative and HR-positive breast cancers in women and men, which are advanced or have spread to other organs (metastatic), in combination with an anti-estrogenic drug.

In breast cancers that are human epidermal growth factor receptor 2 (HER2)-negative, tumor growth is not promoted by HER2, a protein that aids the growth of some breast cancers. Hormone receptor (HR)-positive breast cancers refer to those that grow in the presence of estrogen and/or progesterone, the female sex hormones.

Palbociclib belongs to a class of medications known as cyclin-dependent kinase (CDK) inhibitors. CDKs are enzymes that are involved in the proliferation of cells and regulate the cell cycle progression. Cell cycle is a process with multiple stages by which cells grow and divide into two daughter cells.

Palbociclib selectively blocks CDK 4 and 6 which prevents the cell cycle progressing from G1 phase to the next S phase, resulting in cell cycle arrest and control of cancer cell proliferation. The combination of palbociclib with an anti-estrogenic drug, letrozole or fulvestrant, is more effective in controlling cancer cell growth than monotherapy with either of the drug class.

• Palbociclib therapy can cause a drop in neutrophil count and lead to neutropenia. Monitor the patient’s complete blood counts before starting therapy, at the beginning of each chemotherapy cycle, and on day 15 of the first 2 cycles. Delay treatment or adjust dosage in patients who develop grade 3 or 4 neutropenia.
• A higher incidence of grade 3 and 4 infections has been reported in patients receiving combination therapy of palbociclib and antiestrogen, than with antiestrogen therapy alone. Monitor patients and institute appropriate treatment, should the patients develop signs and symptoms of infection.
• Palbociclib treatment can lead to severe, fatal, or life-threatening interstitial lung disease (ILD) or pneumonitis. Monitor patients for development of respiratory symptoms and discontinue the drug if they develop severe ILD or pneumonitis.
• Palbociclib can cause fetal harm:
  • Advise women patients to practice effective contraception during treatment and for at least 3 weeks after.
  • Advise male patients with women partners who may get pregnant to practice effective contraception during treatment and for 3 months after.
• Advise nursing mothers to avoid breastfeeding during therapy and for 3 weeks after the last dose.
• Palbociclib may cause male infertility.
• Avoid concurrent use of drugs that are strong CYP3A inhibitors or inducers.

Common side effects of palbociclib/letrozole or fulvestrant combination therapy include:

• Blood disorders including:
  • Low count neutrophil immune cells (neutropenia)
  • Low count of leukocyte immune cells (leukopenia)
  • Low red blood cell count (anemia)
  • Low platelet count (thrombocytopenia)
  • Febrile neutropenia
• Infections
• Fatigue
• Weakness (asthenia)
• High temperature (pyrexia)
• Nausea
• Vomiting
• Diarrhea
• Oral inflammation (stomatitis)
• Decreased appetite
• Increase in liver enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST)
• Taste disorder (dysgeusia)
• Hair loss (alopecia)
• Rash
• Dry skin
• Blurred vision
• Increased tearing of eyes (lacrimation)
• Dry eye syndrome
• Nasal bleeding (epistaxis)
• Interstitial lung disease
• Lung inflammation (pneumonitis)

Call your doctor immediately if you experience any of the following symptoms or serious side effects while using this drug:

• Serious heart symptoms include fast or pounding heartbeats, fluttering in your chest, shortness of breath, and sudden dizziness;
• Severe headache, confusion, slurred speech, severe weakness, vomiting, loss of coordination, feeling unsteady;
• Severe nervous system reaction with very stiff muscles, high fever, sweating, confusion, fast or uneven heartbeats, tremors, and feeling like you might pass out; or
• Serious eye symptoms include blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights.

This is not a complete list of all side effects or adverse reactions that may occur from the use of this drug. Call your doctor for medical advice about serious side effects or adverse reactions. You may also report side effects or health problems to the FDA at 1-800-FDA-1088.

Capsule

• 75 mg
• 100 mg
• 125 mg

Tablet

• 75 mg
• 100 mg
• 125 mg

Adult:

Breast Cancer

Indication

• Indicated for the treatment of men or pre-/peri/postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer as follows:
  • Use in combination with an aromatase inhibitor as initial endocrine-based therapy
  • Use in combination with fulvestrant in men or women with disease progression following endocrine therapy

Combination therapy with an aromatase inhibitor

• Palbociclib 125 mg orally once daily for days 1-21 of each 28-day cycle
• Continue until disease progression or unacceptable toxicity
• Men treated with combination palbociclib plus aromatase inhibitor therapy, consider treatment with a luteinizing hormone-releasing hormone (LHRH) agonist according to current clinical practice standards
• Pre/perimenopausal women treated with the combination palbociclib plus aromatase inhibitor should also be treated with an LHRH agonist according to current clinical practice standards

Combination therapy with fulvestrant

• Palbociclib 125 mg orally once daily for days 1-21 of each 28-day cycle
• Fulvestrant 500 mg intramuscular (IM) on days 1, 15, and 29, and then once monthly thereafter
• Continue until disease progression or unacceptable toxicity
• Pre/perimenopausal women treated with the combination palbociclib plus fulvestrant should also be treated with an LHRH agonist according to current clinical practice standards

Dosage Modifications

Dose reduction for adverse reaction

• First dose reduction: Reduce to 100 mg/day
• Second dose reduction: Reduce to 75 mg/day
• If further dose reduction below 75 mg/day is required, discontinue treatment

Hematologic toxicities

• Grade 1 or 2: No dose adjustment is required
• Grade 3*:
  • Day 1 of the cycle: Withhold dose, repeat CBC within 1 week; when recovered to grade 2 or lower, start next cycle at the same dose
  • Day 15 of first 2 cycles: If grade 3 on Day 15, continue at the current dose to complete the cycle; repeat CBC on Day 22; if grade 4 on Day 22, see grade 4 dose modifications below
  • Prolonged (longer than 1 week) recovery from grade 3 or recurrent grade 3 neutropenia in subsequent cycles: Consider dose reduction
• Grade 3 ANC (less than 1000 to 500/mm³) and fever 38.5ºC or higher and/or infection: Withhold drug until recovery to grade 2 or lower (1000/mm³ or less); resume at next lower dose
• Grade 4*: Withhold drug until recovery to grade 2 or lower; resume at next lower dose
• *Above refers to all hematologic adverse reactions except lymphopenia, unless associated with the clinical event (e.g., opportunistic infections)

Nonhematologic toxicities

• Grade 1 or 2: No dose adjustment is required
• Grade 3 or higher (if persisting despite medical treatment): Withhold until symptoms resolve to grade 1 or lower or grade 2 or lower (if not considered a safety risk for the patient to resume); resume at next lower dose

Coadministration with strong CYP3A inhibitors

• Avoid use with strong CYP3A inhibitors and consider an alternative with no or minimal CYP3A inhibition
• If coadministration cannot be avoided, reduce the palbociclib dose to 75 mg/day
• If the strong inhibitor is discontinued, increase the palbociclib dose (after 3-5 half-lives of the inhibitor) to the dose used prior to the initiation of the strong CYP3A inhibitor

Hepatic impairment

• Mild or moderate (Child-Pugh A or B): No dose adjustment is required
• Severe (Child-Pugh C): Reduce dose to 75 mg/day for days 1-21 of each 28-day cycle

Renal impairment

• Mild, moderate, or severe (creatinine clearance [CrCl] below 15 mL/minute): No dose adjustment is required
• Hemodialysis: Not studied

Interstitial lung disease (ILD) or pneumonitis

• Permanently discontinue treatment in patients with severe ILD/pneumonitis

Dosing Considerations

• Monitor CBC at baseline and at the beginning of each cycle, as well as on day 14 of the first 2 cycles, and as clinically indicated

Pediatric:

Safety and efficacy not established

Overdose

• Palbociclib overdose can damage the DNA and increase the incidence of tumors in the microglial cells, a type of immune cell in the central nervous system (CNS). There is no known antidote for palbociclib overdose. Overdose is treated with general supportive care.

Inform your doctor of all medications you are currently taking, who can advise you on any possible drug interactions. Never begin taking, suddenly discontinue, or change the dosage of any medication without your doctor’s recommendation.

• Palbociclib has no known severe interactions with other drugs.
• Palbociclib has serious interactions with at least 56 different drugs.
• Palbociclib has moderate interactions with at least 75 different drugs.
• Minor interactions of palbociclib include:
  • acetazolamide
  • anastrozole
  • cyclophosphamide
  • larotrectinib

The drug interactions listed above are not all of the possible interactions or adverse effects. For more information on drug interactions, visit the RxList Drug Interaction Checker.

It is important to always tell your doctor, pharmacist, or health care provider of all prescription and over-the-counter medications you use, as well as the dosage for each, and keep a list of the information. Check with your doctor or health care provider if you have any questions about the medication.

• Palbociclib can cause fetal harm if used in pregnant women.
• Women of pregnancy potential should use effective contraception during treatment and at least for 3 weeks following the last dose of palbociclib.
• Male patients with female partners who could become pregnant should practice effective contraception during treatment and at least for 3 months following the last dose.
• Palbociclib may impair fertility in male patients.
• There is no information on the presence of palbocilib in breastmilk, its effects on milk production or the breastfed infant. Nursing mothers should avoid breastfeeding during treatment and for 3 weeks following the final dose, because of the potential for serious adverse reactions in the breastfed infant from drug exposure.

• Take palbociclib exactly as directed.
• Take palbociclib capsules with food, however, tablets may be taken with or without food.
• Swallow the capsule or tablet whole, do not crush, chew or break before swallowing.
• Do not take an additional dose if you vomit or miss a dose.
• Avoid grapefruit juice and other grapefruit products while on palbociclib treatment.
• Report immediately to your healthcare provider if you experience:
  • New or worsening respiratory symptoms such as cough, low tissue oxygen saturation (hypoxia) and/or shortness of breath (dyspnea)
  • Symptoms of bone marrow suppression or infection may include fever, chills, dizziness, shortness of breath, weakness, or increased tendency to bleed and/or bruise
• Store palbociclib safely out of reach of children.
• In case of overdose, seek medical help or contact Poison Control.