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The following information helps you to find FDA Alerts and Pharmacist’s Applications to Practice quickly and easily. In cooperation with the Food and Drug Administration (FDA), and as a service to our members, HOPA periodically distributes information about newly approved therapies for cancer patients from FDA’s Office of Oncology Drug Products Director, Dr. Richard Pazdur to inform oncologists and professionals in oncology-related fields in a timely manner. Links to product labels will take you to relevant clinical information on the indication, contraindications, dosing, and safety. In sending this information, HOPA does not endorse any product or therapy and does not take any position on the safety or efficacy of the product or therapy described.

Along with HOPA’s Publications Committee, members also review new drug updates and provide analysis and research on the application of these new drugs or indications. Pharmacist’s Applications to Practice, or PAP, are listed after drugs that include the additional analysis. If you are interested in helping the Publications Committee with creating a Pharmacist's Application to Practice, please contact Jeff Price at jprice@hoparx.org.

You can also find additional information on FDA Alerts and Updates by listening to FDA Drug Safety Podcasts.


July 18, 2018—Ribociclib (Kisqali): expanded indication in combination with an aromatase inhibitor for pre- and perimenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)–negative advanced or metastatic breast cancer as initial endocrine-based therapy. (With Pharmacist's Application to Practice)

March 13, 2017–Ribociclib (KISQALI®) approved for treatment of postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer.(With Pharmacist's Application to Practice)


         July 18, 2018 with PAP

https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/209092s001lbl.pdf.

On July 18, 2018, the Food and Drug Administration expanded the indication for ribociclib (Kisqali, Novartis Pharmaceuticals Corporation) in combination with an aromatase inhibitor for pre/perimenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer, as initial endocrine-based therapy.

FDA also approved ribociclib in combination with fulvestrant for postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer, as initial endocrine-based therapy or following disease progression on endocrine therapy.

Ribociclib was previously approved for postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer in combination with an aromatase inhibitor as initial endocrine therapy. 

The efficacy of ribociclib in combination with an aromatase inhibitor for pre/perimenopausal women was based on MONALEESA-7 (NCT02278120), a randomized, double-blind, placebo-controlled trial. Pre/perimenopausal women were randomized to ribociclib plus either a non-steroidal aromatase inhibitor (NSAI) or tamoxifen and goserelin versus placebo plus either an NSAI or tamoxifen and goserelin. Results from the pre-specified NSAI-only subgroup of 495 pre/peri-menopausal women with HR-positive, HER2-negative, advanced breast cancer who received no prior endocrine therapy for advanced disease showed an estimated median progression-free survival (PFS, RECIST 1.1) of 27.5 months for patients on the ribociclib arm compared with 13.8 months for those on the placebo arm (HR 0.569; 95% CI: 0.436, 0.743). Ribociclib is not indicated for concomitant use with tamoxifen.

The efficacy of ribociclib in combination with fulvestrant was demonstrated in MONALEESA-3 (NCT02422615), a randomized double-blind, placebo-controlled trial of ribociclib in combination with fulvestrant in 726 postmenopausal women with HR-positive, HER2-negative, advanced breast cancer who received no or only one line of prior endocrine treatment. The estimated median PFS was 20.5 months for patients taking ribociclib compared with 12.8 months for those who received placebo (HR 0.593; 95% CI: 0.480, 0.732; p<0.0001).

The most common adverse reactions in at least 20% of patients were neutropenia, nausea, infections, fatigue, diarrhea, leukopenia, vomiting, alopecia, headache, constipation, rash and cough.

The recommended starting ribociclib dose is 600 mg orally (three 200 mg tablets) once daily with or without food for 21 consecutive days followed by 7 days off treatment.

View full prescribing information for Kisqali.

This is the first FDA approval using the Real Time Oncology Review and the Assessment Aid, pilot programs that enabled the FDA review team to begin analyzing data before the application submission. The FDA was able to approve the application less than one month after it was submitted.

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 or by calling 1-800-FDA-1088.

Pharmacist’s Applications to Practice

Ribociclib (Kisqali): Expanded Indication in Combination with an Aromatase Inhibitor for Pre- and Perimenopausal Women with Hormone Receptor (HR)–Positive, Human Epidermal Growth Factor Receptor 2 (HER2)–Negative Advanced or Metastatic Breast Cancer as Initial Endocrine-Based Therapy

Author: Yasmine Ayoub, PharmD
Clinical Pharmacy Specialist, Hematology/Oncology
VA Northeast Ohio Healthcare System
Cleveland, OH

What is the potential role for ribociclib in the treatment of HR-positive, HER2-negative advanced or metastatic breast cancer?

  • Ribociclib is a cyclin-dependent kinase 4 and 6 (CDK) inhibitor. Cyclin-dependent kinases regulate retinoblastoma protein phosphorylation, which plays a role in breast cancer cell proliferation.1,2
  • On July 18, 2018, the U.S. Food and Drug Administration (FDA) expanded the approval of ribociclib in combination with an aromatase inhibitor to include pre- and perimenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer as initial endocrine-based therapy.1,2
  • This expanded approval was based on the results of MONALEESA-7.
    • MONALEESA-7 was a multicenter randomized double-blind placebo-controlled phase 3 trial that compared endocrine therapy plus ribociclib with placebo in premenopausal women with HR-positive, HER2-negative advanced breast cancer. Patients could have received prior endocrine therapy and chemotherapy in the adjuvant or neoadjuvant setting and up to one line of chemotherapy for advanced disease. Patients were randomized (1:1) to ribociclib 600 mg/day on a 3-weeks-on, 1-week-off schedule or matching placebo. All patients received oral endocrine therapy with either tamoxifen 20 mg daily or a nonsteroidal aromatase inhibitor (letrozole 25 mg daily or anastrozole 1 mg daily). The primary endpoint, investigator-assessed progression-free survival (PFS), was significantly longer in the ribociclib group (23.8 months) than in the placebo group (13 months, hazard ratio [HR] 0.55, 95% confidence interval [CI] 0.44–0.69). Serious adverse events occurred in 18% of patients in the ribociclib group and in 12% of patients in the placebo group. Treatment was discontinued because of adverse events for 4% of patients in the ribociclib group and for 3% of patients in the placebo group. Overall survival was a key secondary endpoint; however, data were not mature at the time of publication.3
  • The National Comprehensive Cancer Network (NCCN) guidelines list ribociclib in combination with an aromatase inhibitor and ovarian suppression or ablation as one of the preferred regimens for pre- and perimenopausal HR-positive, HER2-negative advanced or metastatic breast cancer (category 1).4
  • Other CDK inhibitors, including abemaciclib and palbociclib, have been studied in pre- and perimenopausal women and are listed in NCCN guidelines as preferred agents in combination with an aromatase inhibitor and ovarian ablation or suppression. However, ribociclib is the only CDK inhibitor that is FDA approved for use in pre- and perimenopausal women.
    • PALOMA-3 showed that palbociclib plus fulvestrant versus placebo plus fulvestrant improved PFS in pre- and postmenopausal women with previously treated HR-positive, HER2-negative metastatic breast cancer.5
    • MONARCH-2 showed abemaciclib plus fulvestrant versus placebo plus fulvestrant improved PFS in pre- and postmenopausal women with previously treated HR-positive, HER2-negative metastatic breast cancer.6

What role can the pharmacist play in the management of patients on ribociclib?1-3

  • The FDA-approved dosing of ribociclib is 600 mg orally once daily for 21 days, followed by a 7-day break. Each treatment-cycle length is 28 days.
  • Renal dose adjustments
    • Creatinine clearance (CrCl) 30–90: No dose adjustment is necessary.
    • CrCl 15–30: Reduce initial dose to 200 mg once daily.
    • CrCl < 15: No dosage adjustment is provided in the manufacturer’s labeling.
  • Hepatic dose adjustments
    • Hepatic impairment at treatment initiation
      • Mild impairment (Child-Pugh class A): No adjustment is necessary.
      • Moderate or severe impairment (Child-Pugh class B or C): Initial dose 400 mg once daily
    • Hepatic toxicity during treatment
      • Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) elevations without total bilirubin increase > 2 times upper limit of normal (ULN)
        • Grade 1 (ALT and/or AST elevated > 1 to 3 times ULN): No dosage adjustment is necessary.
        • Grade 2 (ALT and/or AST elevated > 3 to 5 times ULN): If baseline was below grade 2, interrupt ribociclib until recovered to baseline and then resume at the same dose. If a recurrent grade-2 elevation occurs, interrupt ribociclib until recovered to baseline and then resume at the next lower dose level. If baseline was at grade 2, no dosage adjustment is necessary.
        • Grade 3 (ALT and/or AST elevated > 5 to 20 times ULN): Interrupt ribociclib until recovery to baseline or lower and then resume at the next lower dose level. For recurrent grade-3 elevations, discontinue ribociclib.
        • Grade 4 (ALT and/or AST elevated > 20 times ULN): Discontinue ribociclib.
      • Combined ALT and/or AST elevations > 3 times ULN and total bilirubin increase > 2 times ULN (in the absence of cholestasis), regardless of baseline grade: Discontinue ribociclib.
  • Dose adjustments for toxicities
    • Starting dose: 600 mg/day
    • First dose reduction: Reduce to 400 mg/day.
    • Second dose reduction: Reduce to 200 mg/day.
    • If further dose reduction below 200 mg/day is needed, discontinue ribociclib.
  • Drug interactions
    • Ribociclib is a major substrate of cytochrome P450 3A4 (CYP3A4). It is recommended that concomitant use of ribociclib with strong CYP3A4 inhibitors be avoided. If coadministration must be done, it is recommended that ribociclib be reduced to 400 mg once daily. If the strong inhibitor is discontinued, change the ribociclib dose to the prior dose after at least five half-lives of the strong inhibitor. It is recommended that concomitant use of ribociclib with strong CYP3A4 inducers be avoided. Ribociclib is a moderate inhibitor of CYP3A4.
    • Ribociclib can cause QT prolongation. Avoid concomitant use with QTc-prolonging agents. Concomitant use of ribociclib with CYP3A4 inhibitors may increase ribociclib concentrations and subsequently increase the risk of QT prolongation.
    • Concurrent use of ribociclib with tamoxifen is not indicated because of QTc prolongation.
  • Warnings
    • QTc prolongation
      • Ribociclib is associated with QT prolongation in a concentration-dependent manner. Routine monitoring of QTc is required. Refer to the ribociclib prescribing information for additional information.
    • Bone marrow suppression
      • Neutropenia is common with ribociclib. Neutropenic fever has been reported. Routine monitoring of complete blood counts (CBCs) is required.
    • Hepatotoxicity
      • Hepatotoxicity, including AST and ALT elevations, has occurred. Routine monitoring of liver function tests is required.
  • Adverse events
    • The most common grade 3–4 adverse events reported in MONALEESA-7 were neutropenia (61%), leucopenia (14%), and ALT elevation (5%). Febrile neutropenia was reported in 2% of patients.
  • Monitoring
    • CBC: baseline, every 2 weeks for the first 2 cycles, at the beginning of every subsequent 4 cycles, and as clinically necessary
    • Liver function tests: baseline, every 2 weeks for the first 2 cycles, at the beginning of every subsequent 4 cycles, and as clinically necessary
    • Serum electrolytes (including potassium, magnesium, calcium, and phosphorous): baseline, at the beginning of the first 6 cycles, and as clinically necessary
    • ECG: baseline, on day 14 of cycle 1, at the beginning of cycle 2, and as clinically necessary
    • Pregnancy test prior to treatment (in females with reproductive potential)

Clinical Pearls1,2

  • Ribociclib is available as 200-mg film-coated tablets. It comes in blister packs of 21 tablets (200-mg dose), 42 tablets (400-mg dose) and 63 tablets (600-mg dose). Tablets should be swallowed whole and not chewed or crushed. It can be given with or without food at the same time each day.
  • Patients should avoid grapefruit and grapefruit juice.
  • Ribociclib should be stored at room temperature in the original package.
  • Pre- and perimenopausal women should also receive a luteinizing hormone-releasing hormone (LHRH) agonist in combination with ribociclib and an aromatase inhibitor.
  • Patient assistance is available through the KISQALI Care program. The program provides patient support and copay assistance for those patients who meet insurance coverage and income requirements. Additional information may be found at https://www.hcp.novartis.com/products/kisqali/metastatic-breast-cancer/patient-support-access/.

References

  1. Ribociclib (Kisqali) [package insert]. East Hanover, NJ: Novartis Pharmaceutical Corp.; 2018.
  2. Ribociclib. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at http://online.lexi.com. Accessed September 30, 2018.
  3. Tripathy D, Im SA, Colleoni M, et al. Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): a randomised phase 3 trial. Lancet Oncol. 2018;19:904-915.
  4. National Comprehensive Cancer Network. Breast Cancer. Version 3.2018. Available at https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed November 8, 2018.
  5. 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 Oncol. 2016;17:425-439.
  6. Sledge GW Jr, Toi M, Neven P, et al. MONARCH 2: Abemaciclib in combination with fulvestrant in women with HR+/HER2- advanced breast cancer who had progressed while receiving endocrine therapy. J Clin Oncol. 2017;35:2875-2884.

          March 13, 2017 with PAP

http://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209092s000lbl.pdf

On March 13, 2017, the U.S. Food and Drug Administration approved ribociclib (KISQALI®, Novartis Pharmaceuticals Corp.), a cyclin-dependent kinase 4/6 inhibitor, in combination with an aromatase inhibitor as initial endocrine-based therapy for the treatment of postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer.

Approval was based on a randomized, double-blind, placebo-controlled, international clinical trial (MONALEESA-2), in post-menopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer who received no prior therapy for advanced disease. A total of 668 patients were randomized to receive either ribociclib plus letrozole (n=334) or placebo plus letrozole (n=334). Ribociclib 600 mg or placebo was administered orally once daily for 21 consecutive days, followed by 7 days off, with letrozole 2.5 mg administered orally once daily for 28 days. Treatment continued until disease progression or unacceptable toxicity.

A pre-planned interim efficacy analysis demonstrated an improvement in PFS (investigator-assessed) with hazard ratio of 0.556 (95% CI: 0.429, 0.720; p<0.0001). The estimated median PFS had not been reached in the ribociclib-containing arm and was 14.7 months in the placebo-containing arm. Objective response rate (ORR) in patients with measurable disease was 52.7% (95% CI: 46.6, 58.9) in the ribociclib plus letrozole arm and 37.1% (95% CI: 31.1, 43.2) in the placebo plus letrozole arm. Overall survival data are immature.

The most common adverse reactions (ARs) observed in 20% or more of patients taking ribociclib were neutropenia, nausea, fatigue, diarrhea, leukopenia, alopecia, vomiting, constipation, headache, and back pain. The most common grade 3 or 4 ARs (reported in >2%) were neutropenia, leukopenia, abnormal liver function tests, lymphopenia, and vomiting. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner (refer to details in Warning and Precautions section of the label).

The recommended starting dose of ribociclib is 600 mg orally (three 200 mg tablets) taken once daily with or without food for 21 consecutive days followed by 7 days off treatment.

Full prescribing information for ribociclib is available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209092s000lbl.pdf

FDA granted this application a priority review and breakthrough therapy designation. 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 Application to Practice

Ribociclib (Kisqali) for Hormone Receptor (HR)–Positive, Human Epidermal Growth Factor Receptor 2 (HER2)–Negative Advanced or Metastatic Breast Cancer

Author: Sandra Cuellar, PharmD BCOP
University of Illinois Hospital and Health Sciences System
Chicago, IL

What is the potential role for ribociclib in the management of HR-positive metastatic breast cancer?1

  • Ribociclib is the second cyclin-dependent kinase (CDK) 4/6 inhibitor approved in the first-line setting in combination with an aromatase inhibitor for postmenopausal women with HR-positive metastatic breast cancer.
  • The magnitude of benefit of combination therapy is unquestionable compared to monotherapy with an aromatase inhibitor. Patients on the combination arm in the MONALEESA-2 trial had superior outcomes in terms of progression-free survival and overall response rate compared to monotherapy with letrozole, and the benefit of the addition of ribociclib was seen within 8 weeks.
  • The toxicity profile of combination therapy is manageable and predictable. Given these compelling data, an aromatase inhibitor combined with a CDK 4/6 inhibitor should be standard first-line treatment for the majority of postmenopausal patients with advanced HR-positive breast cancer.

What role can the pharmacist play in the management of patients on ribociclib?2, 3

  • Both ribociclib and letrozole are oral agents that present opportunities for pharmacists to optimize care via assistance with access to medication, counseling, and medication adherence.
  • Management of side effects is crucial to ensure that patients remain on oral therapy. Although most adverse events are grade 1 or 2, they can have an impact on a patient’s daily life, especially because these agents are administered daily (ribociclib on days 1–21 and letrozole on days 1–28 of a 28-day cycle). In particular, adverse events such as diarrhea, nausea, vomiting, and arthralgias need specific supportive-care action plans to assist patients to identify, manage, and notify healthcare staff regarding the tolerability of therapy.
  • Ribociclib is metabolized via cytochrome P450 3A4 (CYP 3A4); pharmacists therefore need to evaluate the risk of drug-drug interactions as well as drug-drug interactions with other concomitant medications that have the potential to prolong the QTc interval.

Clinical Pearls2,3

  • There are no head-to-head data comparing palbociclib to ribociclib; however, their efficacy is superior to monotherapy with an aromatase inhibitor. Their side-effect profile is similar, with the exception of prolongation of QTc with ribociclib. At this time, the National Comprehensive Cancer Network (NCCN) guidelines list them both as category 1 recommendations.
  • Electrocardiogram monitoring is recommended at baseline, after 2 weeks from initiation, and at the beginning of each cycle.
  • Monitor electrolytes (potassium, magnesium, calcium, phosphorus) because of the potential for cardiotoxicity.
  • Ribociclib comes in a blister pack of 200 mg tablets. This packaging allows for dosing adjustments to occur in 200 mg increments, without the need to dispense another prescription. In addition, ribociclib is not a restricted-access drug; therefore, pharmacies can order and dispense it.
  • Ribociclib can be combined with any aromatase inhibitor (letrozole, anastrozole, or exemestane).

References

  1. Hortobagy GN, Stemmer SM, Burris HA, et al. Ribociclib as first-line therapy for HR-positive, advanced breast cancer. N Engl J Med 2016;375:1738-48.
  2. Breast Cancer. Version 2.2017. National Comprehensive Cancer Network. Retrieved from: https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed April 17, 2017.
  3. Kisqali® (Ribociclib) tablets [package insert]. East Hanover, NJ: Novartis, Inc.; March 2017.
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