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FDA Alerts

Pharmacist's Applications to Practice

HOPA, through the Publications Committee, will review new drug updates and provide analysis and research on the application of these new drugs or indications.

The letters “PAP” after drugs listed below indicates that they include this additional analysis.  


March 31, 2017–Palbociclib (IBRANCE®, Pfizer Inc.) approved for treatment of 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.

February 19, 2016–Palbociclib (IBRANCE® Capsules) approved in combination with fulvestrant for the treatment of women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer with disease progression following endocrine therapy.

February 3, 2015–Palbociclib (IBRANCE®) approved for use in combination with letrozole for the treatment of postmenopausal women with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer as initial endocrine-based therapy for their metastatic disease.


March 31, 2017 (with PAP)

https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/207103s004lbl.pdf

On March 31, 2017, the U.S. Food and Drug Administration granted regular approval to palbociclib (IBRANCE®, Pfizer Inc.) for the treatment of 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.

FDA granted palbociclib accelerated approval in February 2015, in combination with letrozole for the treatment of estrogen receptor (ER)-positive, HER2-negative advanced breast cancer as initial endocrine based therapy in postmenopausal women. FDA granted palbociclib regular approval in February 2016, in combination with fulvestrant for the treatment of HR-positive, HER2-negative advanced or metastatic breast cancer in women with disease progression following endocrine therapy.

The current approval was based on data from an international, randomized, double-blind, placebo-controlled, clinical trial (PALOMA-2) that randomized 666 postmenopausal women (2:1) to palbociclib plus letrozole or placebo plus letrozole. Palbociclib 125 mg or placebo was administered orally once daily for 21 consecutive days, followed by 7 days off. Letrozole 2.5 mg was administered orally once daily. Treatment continued until disease progression or unacceptable toxicity. The median progression-free survival (PFS) was 24.8 months in the palbociclib plus letrozole arm and 14.5 months in the placebo plus letrozole arm (HR=0.576, 95% CI: 0.463, 0.718, p<0.0001). Overall survival data are immature.

Safety data was evaluated in 444 patients who received palbociclib plus letrozole. Neutropenia was the most frequently reported adverse reaction in PALOMA-2 with an incidence of 80%. The most common adverse reactions observed in 10% or more of patients taking palbociclib 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 or greater adverse reactions in patients receiving palbociclib plus letrozole were neutropenia, leukopenia, infections, and anemia. The palbociclib prescribing information recommends monitoring complete blood counts prior to starting therapy and at the beginning of each cycle, as well as on day 15 of the first 2 cycles.

In combination with an aromatase inhibitor or fulvestrant, the recommended palbociclib dose is a 125 mg capsule taken orally once daily with food for 21 consecutive days followed by 7 days off treatment. Please refer to the full prescribing information for the dose and schedule recommendation for the aromatase inhibitor or fulvestrant.

Full prescribing information is available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/207103s004lbl.pdf.

FDA granted this application Priority Review and Breakthrough Therapy Designation. FDA approved this action approximately one month ahead of the goal date. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics, available at: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).


Pharmacist’s Applications to Practice - March 31, 2017

Palbociclib (Ibrance) for Hormone Receptor Positive (HR+), Human Epidermal Growth Factor Receptor 2 (HER-2)/neu Negative Metastatic Breast Cancer (MBC)

Authors: Rodney J. Hunter, PharmD BCOP
Assistant Professor, Texas Southern University
Clinical Pharmacy Specialist, UTHealth, Memorial Hermann Cancer
Center
Houston, TX

Judith A. Smith, PharmD BCOP
Associate Professor, UTHealth, McGovern Medical School
Oncology Clinical Pharmacy Specialist, UTHealth, Memorial Hermann Cancer Center
Houston, TX

What is the potential role for palbociclib in the treatment of HR+, HER-2/neu negative metastatic breast cancer?

  • Palbociclib is a first-in-class cyclin-dependent kinase 4/6 (CDK 4/6) inhibitor for HR+, HER-2/neu negative MBC.
  • In patients with HR+ breast cancer, increased estrogen activity leads to increased formation of the CDK 4/6 cyclin D1 complex. The complex causes the transition from the G1 to the S phase of the cell cycle. Palbociclib induces cellular senescence and decreases cellular proliferation.1-4
  • Postmenopausal patients being treated in the first-line setting with palbociclib had a median progression-free survival (PFS) of 24.8 months (95% CI: 22.1, not estimable) versus 14.5 months (95% CI: 12.9–17.1) in the letrozole-alone arm, observed hazard ratio in the PALOMA-2 trial was 0.58 (95% CI: 0.46–0.72; p < .001).3
  • In premenopausal and postmenopausal patients being treated with palbociclib and fulvestrant following endocrine therapy progression, median PFS was 9.5 months (95% CI: 13.8–27.5) versus 4.6 months (95% CI: 3.5–5.6) in the letrozole-alone arm, observed hazard ratio in the PALOMA-3 trial from the stratified analysis was 0.461 (95% CI: 0.360–0.591; p < .0001).4
  • Palbociclib is a first-in-class CDK 4/6 inhibitor for the treatment of metastatic breast cancer. Palbociclib is the first of two CDK4/6 inhibitors (the other is ribociclib) to be FDA approved for metastatic breast cancer in combination endocrine therapy.1,5,6

What role can the pharmacist play in the management of patients on palbociclib?

  • Palbociclib requires close monitoring, particularly for neutropenia. The incidence of neutropenia has been reported at 75% and 83% (PALOMA-1 and PALOMA-3, respectively). The median onset of any grade of neutropenia was reported as 15 days, and the median duration of grade 3 or above neutropenia was 7 days.2,4
  • It is recommended that patients be screened for possible CYP3A4 inhibitors, inducers, and substrates because of interaction with palbociclib.1,7
  • In the event that CYP3A4 inhibitors cannot be avoided during therapy, dose reduction of palbociclib to 75 mg is recommended. When palbociclib is used in combination with a CYP3A4 inducer, the palbociclib exposure decreases, with no clear dosing recommendation. When palbociclib is administered with CYP3A substrates, consider decreasing the dosage of the CYP3A4 substrate (calcineurin inhibitors, mammalian target of rapamycin inhibitors, and fentanyl).1,7
  • Monitor the patient for hematologic and nonhematologic toxicities for the need for dose modifications.7
  • Nonhematologic adverse effects (all grades) in the PALOMA-1 study reported by patients on palbociclib and letrozole: fatigue (41%), upper respiratory infections (31%), nausea (25%), stomatitis (25%), alopecia (22%), diarrhea (21%), decreased appetite (16%), asthenia (13%), peripheral neuropathy (13%), and epistaxis (11%).2
  • Monitor patients for signs and symptoms of febrile neutropenia, pulmonary embolism, and asthenia.2,3,4
  • Evaluate patients’ menopausal status when using palbociclib in combination with fulvestrant for the need for goserelin in the therapeutic plan.1,4,5
  • Patients should be counseled on the importance of taking this medication with food.7

Clinical Pearls

  • A complete blood count with differential should be assessed at the beginning of each cycle and on day 14 of the first two cycles. For patients with grade 3 neutropenia on day 14 in the first two cycles, repeat labs should be drawn on day 21, and a dose reduction should be considered.1,7
  • Palbociclib is administered 3 weeks on and 1 week off, secondary to the timing of the neutrophil recovery, which is consistent when palbociclib is used in the first-line setting or when it is used following relapse or progression on endocrine therapy.1,2,3
  • The Pfizer Copay One assistance program ensures that commercially insured patients have affordable copays, and the Pfizer RxPathways program can help provide assistance for underinsured or uninsured patients.
  • Patients in the first-line setting should be treated with palbociclib and letrozole, and when they are being treated following progression on endocrine therapy treatment, the treatment should include palbociclib and fulvestrant with the addition of goserelin if the patient is premenopausal.2,3,4

References

  1. Ibrance (Palbociclib) [package insert]. New York, NY: Pfizer Labs; March 2017.
  2. Finn RS, Crown JP, Lang I, et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncology. 2015 Jan;16(1):25-35.
  3. Finn RS, Martin M, Rugo HS, et al. Palbociclib and letrozole in advanced breast cancer. N Engl J Med.2016;375(20):1925-36.
  4. Cristofanilli M, Turner NC, Bondarenko I, et al. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncology.2016 Apr;17(4):425-39.
  5. Breast Cancer. Version 2.2017. National Comprehensive Cancer Network. Available at: https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed July 15, 2017.
  6. ClinicalTrials.gov Registry. National Institutes of Health. Available at:www.Clinicaltrials.gov. Accessed July 10, 2017.
  7. Lexi-Drugs Online, Hudson, OH: Lexi-Comp, Inc.; 2013; Accessed July 11, 2017.

February 19, 2016

http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/207103s002lbl.pdf

On February 19, 2016, the U. S. Food and Drug Administration approved palbociclib (IBRANCE® Capsules, Pfizer, Inc.) in combination with fulvestrant for the treatment of women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer with disease progression following endocrine therapy.

In February 2015, FDA granted accelerated approval for palbociclib in combination with letrozole for the treatment of HR-positive, HER2-negative advanced breast cancer as initial endocrine based therapy in postmenopausal women.

Today’s approval is based on the demonstration of an improvement in progression - free survival (PFS) in an international, randomized, double-blind, parallel group, multicenter study comparing palbociclib plus fulvestrant to placebo plus fulvestrant. Women enrolled had HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression on or after prior adjuvant or metastatic endocrine therapy.

A total of 521 pre- and postmenopausal women were randomized (2:1) to either palbociclib plus fulvestrant or placebo plus fulvestrant until disease progression or unacceptable toxicity. Palbociclib was administered orally at a dose of 125 mg daily for 21 consecutive days followed by 7 days off treatment. Fulvestrant was administered intramuscularly at a dose of 500 mg on days 1, 15, 29 and once monthly thereafter. Pre- or perimenopausal women were enrolled in the study and received the LHRH agonist, goserelin, for at least 4 weeks prior to and for the study’s duration.

Among the 521 patients, 80% were postmenopausal, all patients had received prior systemic therapy, and 75% had received a previous chemotherapy regimen. Twenty-five percent had not received prior therapy for metastatic disease, 60% had visceral metastases, and 23% had bone only disease.

The major efficacy outcome measure was investigator-assessed PFS evaluated according to RECIST V1.1. The study demonstrated an improvement in PFS with a hazard ratio of 0.46 (95% CI: 0.36, 0.59; p<0.0001). The median PFS was 9.5 versus 4.6 months for patients treated in the palbociclib plus fulvestrant and placebo plus fulvestrant arms, respectively.

Safety data was evaluated in 345 patients who received palbociclib plus fulvestrant. The most common (greater than or equal to 10%) of grade 1-4 adverse reactions were neutropenia, leukopenia, infections, fatigue, nausea, anemia, stomatitis, headache, diarrhea, thrombocytopenia, constipation, vomiting, alopecia, rash, decreased appetite, and pyrexia. The most common (greater than or equal to 5%) grade 3-4 adverse reactions were neutropenia (66%) and leukopenia (31%).

The most frequently reported serious adverse reactions in patients receiving palbociclib plus fulvestrant were infections, pyrexia, neutropenia, and pulmonary embolism). Dose reductions due to an adverse reaction of any grade occurred in 36% of patients and permanent discontinuation associated with an adverse reaction occurred in 6% of patients.

The recommended dose and schedule of palbociclib is 125 mg daily for 21 consecutive days followed by 7 days off treatment in combination with fulvestrant treatment. The dose and schedule of fulvestrant is 500 mg intramuscularly on days 1, 15, 29 and once monthly thereafter.

Palbociclib is being approved prior to the Prescription Drug User Fee Act (PDUFA) goal date of April 15, 2016. This application was granted Priority Review and Breakthrough Therapy Designation. A description of these expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics, available at: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf

Full prescribing information is available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/207103s002lbl.pdf

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).


February 3, 2015

http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/207103s000lbl.pdf

On February 3, 2015, the U. S. Food and Drug Administration granted accelerated approval to palbociclib (IBRANCE®, Pfizer, Inc.) for use in combination with letrozole for the treatment of postmenopausal women with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer as initial endocrine-based therapy for their metastatic disease.

Palbociclib is an inhibitor of cyclin-dependent kinase (CDK) 4 and 6. In vitro palbociclib reduced cellular proliferation of ER-positive breast cancer cell lines by blocking progression of cells from G1 into S phase of the cell cycle.

The approval of palbociclib is based on a randomized, multicenter, open-label trial in postmenopausal women with ER-positive, HER2-negative, advanced (locally advanced or metastatic) breast cancer who had not received previous systemic treatment for advanced disease. The trial enrolled 165 patients randomly allocated to receive either palbociclib (125 mg orally daily for 21 consecutive days, followed by 7 days off treatment) plus letrozole (2.5 mg daily continuously throughout the 28-day cycle) or letrozole alone.

Among the 165 patients, 43% had received chemotherapy and 33% had received anti-hormonal therapy as a neoadjuvant or adjuvant treatment. Forty- nine percent of patients had no prior systemic therapy in the neoadjuvant or adjuvant setting. The majority of patients (98%) had metastatic disease; 48% had visceral disease, 75% had bone disease and 19% had bone only disease.

The major efficacy outcome measure was investigator-assessed progression-free survival (PFS) evaluated according to Response Evaluation Criteria in Solid Tumors Version 1.0 (RECIST). Median investigator-assessed PFS was 20.2 months (95% CI 13.8, 27.5) in the palbociclib plus letrozole arm and 10.2 months (95% CI 5.7, 12.6) in the letrozole alone arm [Hazard Ratio (HR) 0.488 (95% CI 0.319, 0.748)]. The treatment effect of the combination on PFS was also supported by a retrospective radiographic independent review [HR 0.621 (95% CI: 0.378, 1.019).] Overall response rate in patients with measurable disease (investigator assessment) was higher in the palbociclib plus letrozole compared to the letrozole alone arm (55.4% versus 39.4%).

Most common adverse reactions (greater than or equal to 10%) were neutropenia, leukopenia, fatigue, anemia, upper respiratory infection, nausea, stomatitis, alopecia, diarrhea, thrombocytopenia, decreased appetite, vomiting, asthenia, peripheral neuropathy, and epistaxis. The most frequently reported serious adverse reactions in patients receiving palbociclib plus letrozole were pulmonary embolism (3 of 83; 4%) and diarrhea (2 of 83; 2%).

The recommended dose and schedule of palbociclib is 125 mg daily for 21 consecutive days followed by 7 days off treatment with letrozole 2.5 mg daily continuously throughout the 28-day cycle.

FDA granted palbociclib breakthrough therapy designation in April, 2013 based on preliminary evidence of clinical activity in this patient population. This accelerated approval is based on demonstration of an improvement in PFS. Continued approval for this indication may be contingent upon verification and description of clinical benefit in an on-going confirmatory trial.

Full prescribing information is available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/207103s000lbl.pdf

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

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