SIZE XSSIZE SMSIZE MDSIZE LG

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


February 7, 2018

https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/202379s024lbl.pdf

On February 7, 2018, the Food and Drug Administration (FDA) approved abiraterone acetate (Zytiga®, Janssen Biotech Inc.) tablets in combination with prednisone for metastatic high-risk castration-sensitive prostate cancer (CSPC).

FDA initially approved abiraterone acetate with prednisone in 2011 for patients with metastatic castration-resistant prostate cancer (CRPC) who had received prior chemotherapy, and expanded the indication in 2012 for patients with metastatic CRPC.

Today’s approval was based on LATITUDE (NCT01715285), a placebo controlled international clinical trial that randomized 1,199 patients with metastatic high-risk CSPC. Patients received either abiraterone acetate, 1,000 mg orally once daily with prednisone 5 mg once daily (n=597), or placebos orally once daily (n=602). Patients in both arms received a gonadotropin releasing hormone or had a bilateral orchiectomy. The major efficacy endpoint was overall survival (OS). Median OS was not estimable and 34.7 months in the abiraterone acetate and placebos arms, respectively (HR 0.621; 95% CI: 0.509, 0.756; p<0.0001). The median time-to-initiation of chemotherapy was not reached for patients on abiraterone acetate with prednisone and 38.9 months for those receiving placebos (HR 0.44; 95% CI: 0.35, 0.56; p<0.0001).

The most common adverse reactions in at least 5% of patients receiving abiraterone acetate on LATITUDE were hypertension, hot flush, hypokalemia, increased alanine aminotransferase or aspartate aminotransferase, headache, urinary tract infection, upper respiratory tract infection, and cough.

The most common adverse reactions reported for afatinib (≥20%) across clinical trials are diarrhea, rash/acneiform dermatitis, stomatitis, paronychia, dry skin, decreased appetite, nausea, vomiting, and pruritus.

The recommended dose for Zytiga for metastatic CSPC is 1,000 mg orally once daily with prednisone 5 mg orally once daily. Patients receiving ZYTIGA should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy.

Full prescribing information is available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/202379s024lbl.pdf

FDA granted priority review for this application and it was approved more than a month ahead of the due 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

Abiraterone Acetate for the Treatment of Metastatic Castration-Sensitive Prostate Cancer

Authors: Kourtney D. LaPlant, PharmD BCOP
Clinical Pharmacy Program Manager for Oncology
Veterans Integrated Service Network 8 Pharmacy Benefits Management
Department of Veterans Affairs
Gainesville, FL

Tanja Lepir, PharmD BCOP
Clinical Oncology Pharmacist
Miami VA Healthcare System
Miami, FL

What is the potential role for abiraterone acetate in the treatment of metastatic castration-sensitive prostate cancer (CSPC)?

  • Abiraterone acetate is an oral CYP17 inhibitor given in combination with prednisone for the treatment of metastatic CSPC. The U.S. Food and Drug Administration (FDA) gave approval for this indication in February 2018.1
    • Abiraterone acetate is also approved to treat metastatic castration-resistant prostate cancer (CRPC) either before or after cytotoxic chemotherapy with docetaxel. This approval was given in April 2011, with further label expansion occurring in December 2012.1
  • Recently, the STAMPEDE and LATITUDE trials investigated whether incorporation of abiraterone acetate in the CSPC setting would improve survival in the newly diagnosed high-risk patient population prior to treatment with hormone therapy.
    • The STAMPEDE trial demonstrated that men treated with abiraterone acetate and androgen deprivation therapy (ADT) had a significantly higher survival advantage than those treated with ADT alone (3-year survival 83% vs. 76%, 95% confidence interval [CI], 0.52–0.76; p < .001). Failure-free survival was also improved in the combination arm (3-year failure-free survival 75% vs. 45%, 95% CI, 0.25–0.34; p < .001).2
    • The LATITUDE trial demonstrated an increase in overall survival in the abiraterone acetate group vs. placebo (3-year survival not reached vs. 34.7 months, 95% CI, 0.51–0.76; p < .001). Those in the abiraterone acetate group also had significant improvement in radiographic progression-free survival (33 months vs. 14.8 months, 95% CI, 0.39–0.55; p < .001).3
      • Additionally, the LATITUDE trial demonstrated clinically meaningful and significant decreases in time to pain progression, next symptomatic skeletal event, and chemotherapy initiation.3
  • The National Comprehensive Cancer Network (NCCN) and the European Society for Medical Oncology guidelines currently incorporate abiraterone acetate with prednisone as a category 1 recommendation for patients with metastatic CSPC in conjunction with standard ADT (orchiectomy or luteinizing hormone-releasing hormone (LHRH) agonist or LHRH antagonist).4,5
  • Treatment with enzalutamide, an agent currently used in the same setting as abiraterone acetate in castrate-resistant disease, is currently being studied in clinical trials in the castrate-sensitive setting and is not yet approved for this indication.6
  • Docetaxel 75 mg/m2 for 6 cycles plus ADT is also a recommended therapy option for metastatic CSPC (NCCN category 1 recommendation).4 The CHAARTED trial demonstrated a survival benefit of docetaxel plus ADT vs. ADT alone (median overall survival 57.6 months vs. 44 months, 95% CI, 0.47–0.80; p < .001).4,5,7
    • The choice between abiraterone acetate and docetaxel would be best made by reviewing patient factors such as comorbidities (including hyperglycemia, neuropathy, liver dysfunction, and cardiac dysfunction), current interacting medications, performance status, and desired length of therapy.
      • For example, patients with uncontrolled hyperglycemia and hypertension may not be ideal candidates, given the need for concomitant prednisone administration because of the mineralocorticoid effects of abiraterone acetate. Patients with baseline peripheral neuropathy may not be good candidates for therapy with docetaxel and may have better tolerance to abiraterone acetate.
      • Therapy with docetaxel is limited to 6 cycles (18 weeks) in this setting; abiraterone acetate was given until the disease progressed or intolerance was reached, resulting in extended treatment durations.
      • An arm of the STAMPEDE trial is currently directly comparing docetaxel and abiraterone acetate in treating this patient population.

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

  • In the metastatic CSPC setting, the recommended dose of abiraterone acetate is 1,000 mg administered once daily in combination with prednisone 5 mg once daily.1
    • In the metastatic CRPC setting, the recommended dose of abiraterone acetate is the same as in the CSPC setting; however, the recommended prednisone dose is 5 mg given twice daily.1
  • Patients receiving abiraterone acetate should also concurrently receive a gonadotropin-releasing hormone analog (goserelin, histrelin, leuprolide, triptorelin, or degarelix), unless they have had prior bilateral orchiectomy.1
  • Abiraterone acetate must be taken on an empty stomach with water at least 1 hour before or 2 hours after a meal. Food will increase absorption of abiraterone acetate. Tablets should be swallowed whole and not crushed or chewed.1
  • Patients with baseline moderate hepatic impairment (Child-Pugh class B) should have a reduced starting dose of 250 mg once daily. Abiraterone acetate should not be used with severe hepatic impairment (Child-Pugh class C). Dosage adjustment is not necessary in patients with renal impairment.1
  • The most common adverse reactions (occurring in 10% of cases or more) are fatigue, arthralgia, hypertension, nausea, edema, hypokalemia, hot flush, diarrhea, vomiting, upper respiratory infection, cough, and headache.1
  • The most common laboratory abnormalities (greater than 20%) are anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, and hypokalemia.1
  • Co-administration of abiraterone acetate with strong cytochrome P450 3A4 (CYP3A4) inducers should be avoided if possible. If co-administration is required, increase the frequency of abiraterone acetate administration to twice daily and return to once-daily dosing if the concomitant strong CYP3A4 inducer is discontinued.1
  • Patient assistance for prescription costs can be provided through the Janssen CarePath program. This program is not available to individuals who use any state or federal government-subsidized healthcare program to cover a portion of medication costs, such as Medicare, Medicaid, TRICARE, Department of Defense, or Veterans Administration.8

Clinical Pearls

  • Abiraterone acetate may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition. Patients’ blood pressure, potassium, and fluid balance should be monitored at least once a month.1
    • Patients with underlying medical conditions that might be worsened because of increases in blood pressure, hypokalemia or fluid retention (e.g., heart failure, recent myocardial infarction, cardiovascular disease, ventricular arrhythmia) should be closely monitored. Patients with a history of heart failure were excluded from the clinical trials.1
  • Patients should be monitored for signs of adrenocortical insufficiency (e.g., extreme fatigue, weakness, hypotension, and hypoglycemia) and mineralocorticoid excess (hypertension, hypokalemia, and fluid retention). Increased dosage of corticosteroids may be indicated before, during, and after stressful situations.1
  • Abiraterone acetate has been associated with severe hepatic toxicity, including fulminant hepatitis, acute liver failure, and death.
    • Measure serum transaminases (alanine aminotransferase and aspartate aminotransferase) and bilirubin levels prior to starting treatment with abiraterone acetate, every 2 weeks for the first 3 months of treatment, and monthly thereafter.
    • Patients with baseline hepatic impairment will require a reduced starting dose and more frequent monitoring of hepatic function.1
    • For patients who develop hepatotoxicity during treatment, abiraterone acetate should be interrupted or discontinued, depending on the severity of the toxicity.1
  • Because of its mechanism of action, abiraterone acetate may harm a developing fetus.
    • Women who are pregnant or who may become pregnant should not handle uncoated tablets or broken, crushed, or damaged tablets unless they are wearing protection (e.g., gloves).1
    • Men who are sexually active with a pregnant woman must use a condom during and for 1 week after treatment with abiraterone acetate. If their female partner may become pregnant, a condom and another form of birth control must be used during treatment and for 1 week after treatment with abiraterone acetate.1
  • Abiraterone acetate is available in 500 mg and 250 mg tablets.1

References

  1. Zytiga (abiraterone acetate) [package insert]. Horsham, PA: Janssen Biotech, Inc.; February 2018.
  2. James ND, de Bono JS, Spears MR, et al. Abiraterone for prostate cancer not previously treated with hormone therapy. N Engl J Med. 2017;377:338-351.
  3. Fizazi K, Tran NP, Fein L, et al. Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. N Engl J Med. 2017;377:352-360.
  4. National Comprehensive Cancer Network. Prostate Cancer. Version 2.2018. Available at https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf. Accessed April 11, 2018.
  5. European Society for Medical Oncology. eUpdate—Cancer of the Prostate Treatment Recommendations. September 28, 2017. Available at www.esmo.org/Guidelines/Genitourinary-Cancers/Cancer-of-the-Prostate/eUpdate-Treatment-Recommendation. Accessed April 11, 2018.
  6. National Institutes of Health. U.S. National Library of Medicine. ClinicalTrials.gov. https://clinicaltrials.gov/. Accessed April 11, 2018.
  7. Sweeney CJ, Chen Y-H, Carducci M, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med. 2015;373:737-746.
  8. Janssen CarePath Savings Program. Available at https://www.janssencarepath.com/hcp/zytiga. Accessed April 12, 2018.
xs
sm
md
lg