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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.  


December 1, 2017

https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761074s000lbl.pdf

On December 1, 2017, the Food and Drug Administration approved Ogivri (trastuzumab-dkst, Mylan) as a biosimilar to Herceptin (trastuzumab, Genentech, Inc.) for the treatment of patients with HER2-overexpressing breast or metastatic stomach cancer (gastric or gastroesophageal junction adenocarcinoma).

Health care professionals should review the prescribing information in the labeling for detailed information about the approved uses:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761074s000lbl.pdf

Approval was based on comparisons of extensive structural and functional product characterization, animal data, human pharmacokinetic and pharmacodynamic data, and clinical studies including clinical immunogenicity between Ogivri and U.S.-licensed Herceptin. These data demonstrate that Ogivri is highly similar to U.S.-licensed Herceptin and that there are no clinically meaningful differences between the products. Ogivri has been approved as a biosimilar, not as an interchangeable product.

Common expected side effects of Ogivri for the treatment of HER2+ breast cancer include headache, diarrhea, nausea, chills, fever, infection, congestive heart failure, insomnia, cough, and rash. Common expected side effects of Ogivri for the treatment of HER2+ metastatic stomach cancer include neutropenia, diarrhea, fatigue, anemia, stomatitis, weight loss, upper respiratory tract infections, fever, thrombocytopenia, mucosal inflammation, nasopharyngitis, and dysgeusia. Serious expected side effects of Ogivri include worsening of chemotherapy-induced neutropenia.

Like Herceptin, the labeling for Ogivri contains a Boxed Warning to alert health care professionals and patients about increased risks of cardiomyopathy, infusion reactions, pulmonary toxicity, and embryo-fetal toxicity.

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

Trastuzumab-dkst (Ogivri) for the Treatment of HER2-Overexpressing Breast Cancer and HER2-Overexpressing Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma

Author: Leah Edenfield, PharmD BCOP BCPS
Hematology/Oncology Clinical Specialist
Wake Forest Baptist Health
Winston-Salem, NC

What is the potential role for trastuzumab-dkst in the treatment of HER2-overexpressing breast cancer and HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma?

  • Trastuzumab-dkst (Ogivri) is a biosimilar approved by the U.S. Food and Drug Administration (FDA) for the same indications as trastuzumab (Herceptin), which include the following:1,2
    • adjuvant treatment of HER2-overexpressing breast cancer as part of a regimen containing doxorubicin, cyclophosphamide, and a taxane; as part of a regimen containing docetaxel and carboplatin; or as a single agent after anthracycline-based therapy
    • initial treatment of HER2-overexpressing metastatic breast cancer in combination with paclitaxel or use as a single agent for HER2-overexpressing metastatic breast cancer that has been previously treated
    • initial treatment of HER2-overexpressing metastatic gastric or gastroesophageal adenocarcinoma in combination with cisplatin and capecitabine or 5-fluorouracil.
  • This biological product has demonstrated similarity to the trastuzumab reference product in the Heritage study, a phase 3 trial of patients receiving initial therapy for HER2-overexpressing metastatic breast cancer.3
    • In this multicenter double-blind randomized parallel-group phase 3 equivalence study, patients were randomized to receive trastuzumab-dkst plus a taxane or trastuzumab plus a taxane.
    • Among the 458 women evaluated for the primary end point of overall response rate (ORR) at 24 weeks, the ORR was 69.6% (95% confidence internal [CI], 63.62%–75.51%) for trastuzumab-dkst compared to 64% (95% CI, 57.81%–70.26%) for trastuzumab. The ORR ratio of 1.09 was within the prespecified equivalence boundary of 0.81 to 1.24.
    • At 48 weeks, progression-free survival was not significantly different at 44.3% for trastuzumab-dkst versus 44.7% for trastuzumab (-0.4%; 95% CI, -9.4%–8.7%). Overall survival was not significantly different at 89.1% for trastuzumab-dkst and 85.1% for trastuzumab (4.0%; 95% CI, -2.1%–10.3%).
  • Trastuzumab-dkst is the first trastuzumab biosimilar product approved by the FDA, though several others are under investigation.1,4
  • Long-term efficacy and safety data are limited for trastuzumab-dkst compared to the reference product, though studies to date support similar potency, pharmacokinetics, immunogenicity, safety, and efficacy.1,3
  • Though biosimilars are not expressly addressed in the National Comprehensive Cancer Network (NCCN) Guidelines, current recommendations support the addition of trastuzumab to first-line chemotherapy for HER2-overexpressing metastatic gastric adenocarcinoma.4,5 NCCN guidelines also recommend the addition of trastuzumab to adjuvant chemotherapy for HER2-overexpressing breast cancer. HER2-directed therapy is recommended for HER-2 positive recurrent or metastatic breast cancer, and trastuzumab is one of the suggested agents.4,6

What role can the pharmacist play in the management of patients on trastuzumab-dkst?

  • Like the trastuzumab reference product, trastuzumab-dkst should be dosed either at 8 mg/kg followed by 6 mg/kg every 3 weeks or at 4 mg/kg followed by 2 mg/kg weekly.
  • Patients receiving anthracyclines after trastuzumab products are at increased risk of cardiotoxicity, so use should be avoided for up to 7 months after administration of trastuzumab-dkst.1
  • The most common treatment-emergent adverse events in the Heritage trial included alopecia (57.5% for trastuzumab-dkst and 54.9% for trastuzumab), neutropenia (57.5% for trastuzumab-dkst and 53.3% for trastuzumab), peripheral neuropathy (23.1% for trastuzumab-dkst and 24.8% for trastuzumab), and diarrhea (20.6% for trastuzumab-dkst and 20.7% for trastuzumab). Changes in left ventricular ejection fraction were not significantly different in either group at week 24.3
  • Serious adverse events in the Heritage trial included neutropenia (27.5% for trastuzumab-dkst and 25.2% for trastuzumab), neutropenia with fever (4.5% for trastuzumab-dkst and 4.1% for trastuzumab), leukopenia (1.6% for trastuzumab-dkst and 4.9% for trastuzumab), and pneumonia (1.6% for trastuzumab-dkst and 2.0% for trastuzumab).3
  • For metastatic gastric cancer, the most common adverse reactions (10% or greater) that were increased by 5% or more in patients receiving trastuzumab included neutropenia, diarrhea, fatigue, anemia, stomatitis, weight loss, upper respiratory tract infections, fever, thrombocytopenia, mucosal inflammation, nasopharyngitis, and dysgeusia.1
  • Boxed warnings for trastuzumab-dkst are the same as for trastuzumab and include cardiomyopathy, infusion reactions, pulmonary toxicity, and embryo-fetal toxicity.1
    • Left ventricular function should be monitored prior to and during treatment, and trastuzumab-dkst should be withheld for significant decreases in left ventricular function (greater than or equal to 16% absolute decrease, or below the limit of normal and greater than or equal to 10% absolute decrease).
    • Trastuzumab-dkst should be discontinued if anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome occur. The infusion should be interrupted for dyspnea or hypotension until symptoms resolve.
  • Cost and patient assistance information are not yet available for trastuzumab-dkst. However, Mylan has promoted the approval of its biosimilars as an opportunity to expand access and reduce costs for these medications.7

Clinical Pearls

  • Assessment of HER2 protein overexpression and gene amplification should be completed using FDA-approved tests specific for the indication.1
  • Trastuzumab-dkst is available as a 420-mg multiple-dose vial. Like trastuzumab, trastuzumab-dkst should be diluted in 250 ml of 0.9% sodium chloride and stored at 2–8 °C for no more than 24 hours.1,2
  • Because of the patent on Herceptin, trastuzumab-dkst is not yet available, and the release date is unknown.8
  • Trastuzumab-dkst is not interchangeable with trastuzumab, but trastuzumab-dkst, as a biosimilar, has the same indications and safety profile.1

References

  1. Ogivri [package insert]. Zurich, Switzerland: Mylan; 2017.
  2. Herceptin [package insert]. South San Francisco, CA: Genentech, Inc.; 2017.
  3. Rugo HS, Barve A, Waller CF, et al. Effect of a proposed trastuzumab biosimilar compared with trastuzumab on overall response rate in patients with ERBB2 (HER2)-positive metastatic breast cancer: a randomized clinical trial. JAMA. 2017;317(1):37-47.
  4. Jackisch C, Lammers P, Jacobs I. Evolving landscape of human epidermal growth factor receptor 2-positive breast cancer treatment and the future of biosimilars. The Breast. 2017;32:19-36.
  5. National Comprehensive Cancer Network. Gastric Cancer. Version 1.2018. https://www.nccn.org/professionals/physician_gls/pdf/gastric.pdf. Accessed March 19, 2018.
  6. National Comprehensive Cancer Network. Breast Cancer. Version 4.2017. https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed March 19, 2018.
  7. Mylan. U.S. FDA Approves Mylan and Biocon’s OgivriTM, the First Biosimilar for Trastuzumab, for the Treatment of HER2-Positive Breast and Gastric Cancers [news release]. http://newsroom.mylan.com/2017-12-01-U-S-FDA-Approves-Mylan-and-Biocons-Ogivri-TM-the-First-Biosimilar-for-Trastuzumab-for-the-Treatment-of-HER2-Positive-Breast-and-Gastric-Cancers. December 1, 2017. Accessed February 4, 2018.
  8. Mylan. Mylan Announces Global Settlement and License Agreements with Genentech and Roche on Herceptin® [news release]. http://newsroom.mylan.com/2017-03-13-Mylan-Announces-Global-Settlement-and-License-Agreements-with-Genentech-and-Roche-on-Herceptin-R. March 13, 2017. Accessed February 6, 2018.
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