Side Effects of Ibrance (palbociclib)

Ibrance (palbociclib) is a kinase inhibitor used to treat adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer in combination with an aromatase inhibitor as initial endocrine-based therapy in postmenopausal women or in men, or in combination with fulvestrant in patients with disease progression following endocrine therapy.

Common side effects of Ibrance include

• anemia,
• weakness,
• fatigue,
• anemia,
• upper respiratory infection,
• nausea,
• inflammation of the mouth and lips,
• mouth sores,
• hair thinning or loss,
• diarrhea,
• low blood platelets,
• decreased appetite,
• vomiting,
• numbness or tingling in extremities,
• nosebleed,
• blurred vision,
• dry or watery eyes,
• headache,
• changes in taste,
• constipation,
• rash,
• dry skin, and
• fever.

Serious side effects of Ibrance include

• low white blood cell count (neutropenia),
• interstitial lung disease, and
• pneumonitis.

Drug interactions of Ibrance include

• azole antifungals,
• antiviral medications,
• macrolide antibiotics,
• nefazodone,
• verapamil,
• grapefruit or grapefruit juice,
• antiseizure medications,
• rifampin,
• St John's wort,
• bosentan,
• modafinil,
• nafcillin,
• midazolam,
• alfentanil,
• cyclosporine,
• dihydroergotamine,
• ergotamine,
• everolimus,
• fentanyl,
• pimozide,
• quinidine,
• sirolimus, and
• tacrolimus.

Ibrance can cause fetal harm when administered to a pregnant woman. Females of reproductive potential are advised to use effective contraception during treatment with Ibrance and for at least 3 weeks after the last dose.

There is no information regarding the presence of Ibrance in breast milk, its effects on milk production, or the breastfed infant. Because of the potential for serious adverse reactions in breastfed infants from Ibrance, breastfeeding women are advised not to breastfeed during treatment with Ibrance and for 3 weeks after the last dose.

Neutropenia

• Neutropenia was the most frequently reported adverse reaction in Study 1 (PALOMA-2) with an incidence of 80% and Study 2 (PALOMA-3) with an incidence of 83%.
• A Grade ≥3 decrease in neutrophil counts was reported in 66% of patients receiving Ibrance plus letrozole in Study 1 and 66% of patients receiving Ibrance plus fulvestrant in Study 2.
• In Study 1 and 2, the median time to first episode of any grade neutropenia was 15 days and the median duration of Grade ≥3 neutropenia was 7 days.
• Monitor complete blood counts prior to starting Ibrance therapy and at the beginning of each cycle, as well as on Day 15 of the first 2 cycles, and as clinically indicated.
• Dose interruption, dose reduction, or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia.
• Febrile neutropenia has been reported in 1.8% of patients exposed to Ibrance across Studies 1 and 2.
• One death due to neutropenic sepsis was observed in Study 2. Physicians should inform patients to promptly report any episodes of fever.

Embryo-Fetal Toxicity

• Based on findings from animal studies and its mechanism of action, Ibrance can cause fetal harm when administered to a pregnant woman.
• In animal reproduction studies, administration of palbociclib to pregnant rats and rabbits during organogenesis resulted in embryo-fetal toxicity at maternal exposures that were ≥4 times the human clinical exposure based on area under the curve (AUC).
• Advise pregnant women of the potential risk to a fetus.
• Advise females of reproductive potential to use effective contraception during treatment with Ibrance and for at least 3 weeks after the last dose.

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Neutropenia
• ILD/Pneumonitis

Clinical Studies Experience

Because clinical trials are conducted under varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice.

Study 1: Ibrance Plus Letrozole

Patients With Estrogen Receptor (ER)-positive, HER2-negative Advanced Or Metastatic Breast Cancer For Initial Endocrine Based Therapy

The safety of Ibrance (125 mg/day) plus letrozole (2.5 mg/day) versus placebo plus letrozole was evaluated in Study 1 (PALOMA-2).

The data described below reflect exposure to Ibrance in 444 out of 666 patients with ER-positive, HER2-negative advanced breast cancer who received at least 1 dose of Ibrance plus letrozole in Study 1.

The median duration of treatment for Ibrance plus letrozole was 19.8 months while the median duration of treatment for placebo plus letrozole arm was 13.8 months.

Dose reductions due to an adverse reaction of any grade occurred in 36% of patients receiving Ibrance plus letrozole. No dose reduction was allowed for letrozole in Study 1.

Permanent discontinuation associated with an adverse reaction occurred in 43 of 444 (9.7%) patients receiving Ibrance plus letrozole and in 13 of 222 (5.9%) patients receiving placebo plus letrozole. Adverse reactions leading to permanent discontinuation for patients receiving Ibrance plus letrozole included neutropenia (1.1%) and alanine aminotransferase increase (0.7%).

The most common adverse reactions (≥10%) of any grade reported in patients in the Ibrance plus letrozole arm by descending frequency were

• neutropenia,
• infections,
• leukopenia,
• fatigue,
• nausea,
• alopecia,
• stomatitis,
• diarrhea,
• anemia,
• rash,
• asthenia,
• thrombocytopenia,
• vomiting,
• decreased appetite,
• dry skin,
• pyrexia, and
• dysgeusia.

The most frequently reported Grade >3 adverse reactions (≥5%) in patients receiving Ibrance plus letrozole by descending frequency were

• neutropenia,
• leukopenia,
• infections, and
• anemia.

Adverse reactions (≥10%) reported in patients who received Ibrance plus letrozole or placebo plus letrozole in Study 1 are listed in Table 4.

Table 4: Adverse Reactions (≥10%) in Study 1

Additional adverse reactions occurring at an overall incidence of <10.0% of patients receiving Ibrance plus letrozole in Study 1 included

• alanine aminotransferase increased (9.9%),
• aspartate aminotransferase increased (9.7%),
• epistaxis (9.2%),
• lacrimation increased (5.6%),
• dry eye (4.1%),
• vision blurred (3.6%), and
• febrile neutropenia (2.5%).

Table 5: Laboratory Abnormalities in Study 1

Study 2: Ibrance Plus Fulvestrant

Patients with HR-positive, HER2-negative Advanced or Metastatic Breast Cancer Who Have Had Disease Progression On Or After Prior Adjuvant Or Metastatic Endocrine Therapy

The safety of Ibrance (125 mg/day) plus fulvestrant (500 mg) versus placebo plus fulvestrant was evaluated in Study 2 (PALOMA-3). The data described below reflect exposure to Ibrance in 345 out of 517 patients with HR-positive, HER2-negative advanced or metastatic breast cancer who received at least 1 dose of Ibrance plus fulvestrant in Study 2. The median duration of treatment for Ibrance plus fulvestrant was 10.8 months while the median duration of treatment for placebo plus fulvestrant arm was 4.8 months.

Dose reductions due to an adverse reaction of any grade occurred in 36% of patients receiving Ibrance plus fulvestrant. No dose reduction was allowed for fulvestrant in Study 2.

Permanent discontinuation associated with an adverse reaction occurred in 19 of 345 (6%) patients receiving Ibrance plus fulvestrant, and in 6 of 172 (3%) patients receiving placebo plus fulvestrant. Adverse reactions leading to discontinuation for those patients receiving Ibrance plus fulvestrant included

• fatigue (0.6%),
• infections (0.6%), and
• thrombocytopenia (0.6%).

The most common adverse reactions (≥10%) of any grade reported in patients in the Ibrance plus fulvestrant arm by descending frequency were

• neutropenia,
• leukopenia,
• infections,
• fatigue,
•  nausea,
• anemia,
• stomatitis,
• diarrhea,
• thrombocytopenia,
• vomiting,
• alopecia,
• rash,
• decreased appetite, and
•  pyrexia.

The most frequently reported Grade ≥3 adverse reactions (≥5%) in patients receiving Ibrance plus fulvestrant in descending frequency were neutropenia and leukopenia.

Adverse reactions (≥10%) reported in patients who received Ibrance plus fulvestrant or placebo plus fulvestrant in Study 2 are listed in Table 6.

Table 6: Adverse Reactions (≥10%) in Study 2

Additional adverse reactions occurring at an overall incidence of <10.0% of patients receiving Ibrance plus fulvestrant in Study 2 included

• asthenia (7.5%),
• aspartate aminotransferase increased (7.5%),
• dysgeusia (6.7%),
• epistaxis (6.7%),
• lacrimation increased (6.4%),
• dry skin (6.1%),
• alanine aminotransferase increased (5.8%),
• vision blurred (5.8%),
• dry eye (3.8%), and
• febrile neutropenia (0.9%).

Table 7: Laboratory Abnormalities in Study 2

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Ibrance. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Respiratory Disorders: Interstitial lung disease (ILD)/non-infectious pneumonitis.

Male Patients With HR-Positive, HER2-Negative Advanced Or Metastatic Breast Cancer

Based on limited data from postmarketing reports and electronic health records, the safety profile for men treated with Ibrance is consistent with the safety profile in women treated with Ibrance.

• Palbociclib is primarily metabolized by CYP3A and sulfotransferase (SULT) enzyme SULT2A1. In vivo, palbociclib is a time-dependent inhibitor of CYP3A.

Agents That May Increase Palbociclib Plasma Concentrations

Effect Of CYP3A Inhibitors

• Coadministration of a strong CYP3A inhibitor (itraconazole) increased the plasma exposure of palbociclib in healthy subjects by 87%.
• Avoid concomitant use of strong CYP3A inhibitors (e.g., clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, and voriconazole).
• Avoid grapefruit or grapefruit juice during Ibrance treatment.
• If coadministration of Ibrance with a strong CYP3A inhibitor cannot be avoided, reduce the dose of Ibrance.

Agents That May Decrease Palbociclib Plasma Concentrations

Effect Of CYP3A Inducers

• Coadministration of a strong CYP3A inducer (rifampin) decreased the plasma exposure of palbociclib in healthy subjects by 85%.
• Avoid concomitant use of strong CYP3A inducers (e.g., phenytoin, rifampin, carbamazepine, enzalutamide, and St John's Wort).

Drugs That May Have Their Plasma Concentrations Altered By Palbociclib

• Coadministration of midazolam with multiple doses of Ibrance increased the midazolam plasma exposure by 61%, in healthy subjects, compared to administration of midazolam alone.
• The dose of the sensitive CYP3A substrate with a narrow therapeutic index (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, everolimus, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus) may need to be reduced, as Ibrance may increase its exposure.