Questions and Answers About Biosimilars

What is a biosimilar?
A biosimilar is defined as a large, complex molecule that is highly similar to and has no clinically meaningful differences in safety, purity, and potency from the reference product.1
Why biosimilars?
In 2009, The Biologics Price Competition and Innovation Act (BPCIA) created a therapeutic approval pathway for biosimilars. This abbreviated pathway was established as a way to provide more treatment options, increase access to lifesaving medications, and potentially lower healthcare costs through price competition.2

In 2020, NCCN Guidelines® for Breast Cancer recommend FDA-approved biosimilars as appropriate substitutes for trastuzumab.3

Are biosimilars new?
Although more recent in the United States, other therapeutic biosimilars have been in use in the European Union and worldwide for more than a decade, with the first biosimilar approved in 2006.4-6
What is the process for approval?

To meet the rigorous standards set by the FDA, manufacturers must supply an extensive data package for biosimilars. In addition, a biologic medicine typically has around 250 in-process tests during manufacturing to assure quality and consistency.7,8

Required data include1:

Analytical studies to demonstrate that the biologic is highly similar to the reference product, notwithstanding minor differences in clinically inactive components

Animal studies including an assessment of toxicity

Clinical studies to demonstrate there are no clinically meaningful differences in safety and potency for the proposed biosimilar product

The goal of a biosimilar development program for gaining FDA approval is demonstrating high similarity between the proposed biosimilar product and the reference product—not to independently establish the safety and efficacy of the proposed product.7

Is HERZUMA an approved biosimilar?

Yes. HERZUMA was initially approved in the United States in December 2018 for certain indications, has demonstrated biosimilarity to Herceptin® (trastuzumab) through a totality of evidence, and has no clinically meaningful differences in terms of safety, purity, and potency.1,7,9,10

HERZUMA is approved for oncology indications in over 30 European countries.11*

*Approved indications for HERZUMA vary by country and indications may be different from those approved in the US (adjuvant breast cancer, metastatic breast cancer, metastatic gastric cancer).

What does this mean for you?

HERZUMA is a treatment alternative to Herceptin for the indications listed below.9,10

Offering competitive pricing for HERZUMA is our key priority.

When considering a trastuzumab, choose HERZUMA.

Additional biosimilar resources

Visit tevabiosimilars.com

or these non-profit member organizations and regulatory bodies for more information on biosimilars.

Click on a logo below to visit the website

INDICATIONS

Adjuvant Breast Cancer

HERZUMA is indicated for the adjuvant treatment of HER2-overexpressing node-positive or node-negative (ER/PR negative or with one high-risk feature) breast cancer

  • as part of a treatment regimen consisting of doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel
  • as part of a treatment regimen with docetaxel and carboplatin
  • as a single agent following multi-modality anthracycline based therapy

Select patients for therapy based on an FDA-approved companion diagnostic for a trastuzumab product

Metastatic Breast Cancer

HERZUMA is indicated:

  • In combination with paclitaxel for first-line treatment of HER2-overexpressing metastatic breast cancer
  • As a single agent for treatment of HER2-overexpressing breast cancer in patients who have received one or more chemotherapy regimens for metastatic disease

Select patients for therapy based on an FDA-approved companion diagnostic for a trastuzumab product

Metastatic Gastric Cancer

HERZUMA is indicated:

  • In combination with cisplatin and capecitabine or 5-fluorouracil, for the treatment of patients with HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma who have not received prior treatment for metastatic disease

Select patients for therapy based on an FDA-approved companion diagnostic for a trastuzumab product

IMPORTANT SAFETY INFORMATION

BOXED WARNINGS

WARNING: CARDIOMYOPATHY, INFUSION REACTIONS, EMBRYO FETAL TOXICITY, AND PULMONARY TOXICITY

Cardiomyopathy - Administration of trastuzumab products can result in sub-clinical and clinical cardiac failure. The incidence and severity was highest in patients receiving trastuzumab with anthracycline containing chemotherapy regimens.

Evaluate left ventricular function in all patients prior to and during treatment with HERZUMA. Discontinue HERZUMA treatment in patients receiving adjuvant therapy and withhold HERZUMA in patients with metastatic disease for clinically significant decrease in left ventricular function.

Infusion Reactions; Pulmonary Toxicity - Administration of trastuzumab products can result in serious and fatal infusion reactions and pulmonary toxicity. Symptoms usually occur during or within 24 hours of administration. Interrupt HERZUMA infusion for dyspnea or clinically significant hypotension. Monitor patients until symptoms completely resolve. Discontinue HERZUMA for anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome.

Embryo-Fetal Toxicity - Exposure to trastuzumab products during pregnancy can result in oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death. Advise patients of these risks and the need for effective contraception.

Warnings and Precautions

Cardiomyopathy

  • Administration of trastuzumab products can result in sub-clinical and clinical cardiac failure. The incidence and severity was highest in patients receiving trastuzumab with anthracycline containing chemotherapy regimens
  • Trastuzumab products can cause left ventricular cardiac dysfunction, arrhythmias, hypertension, disabling cardiac failure, cardiomyopathy, and cardiac death
  • Trastuzumab products can also cause asymptomatic decline in left ventricular ejection fraction (LVEF)
  • Discontinue HERZUMA treatment in patients receiving adjuvant therapy and withhold HERZUMA in patients with metastatic disease for clinically significant decrease in left ventricular function
  • The safety of continuation or resumption of HERZUMA in patients with trastuzumab product-induced LV cardiac dysfunction has not been studied

Cardiac Monitoring

  • Evaluate cardiac function prior to and during treatment. For adjuvant breast cancer therapy, also evaluate cardiac function after completion of HERZUMA
  • Conduct thorough cardiac assessment, including history, physical examination, and determination of LVEF by echocardiogram or MUGA scan
  • Monitor frequently for decreased left ventricular function during and after HERZUMA treatment
  • Monitor more frequently if HERZUMA is withheld for significant left ventricular cardiac dysfunction

Infusion Reactions

  • Administration of trastuzumab products can result in serious and fatal infusion reactions
  • Symptoms usually occur during or within 24 hours of administration
  • Interrupt HERZUMA infusion for dyspnea or clinically significant hypotension
  • Monitor patients until symptoms completely resolve
  • Discontinue HERZUMA for anaphylaxis or angioedema. Strongly consider permanent discontinuation in all patients with severe infusion reactions
  • Infusion reactions consist of a symptom complex characterized by fever and chills, and on occasion included nausea, vomiting, pain (in some cases at tumor sites), headache, dizziness, dyspnea, hypotension, rash, and asthenia

Embryo-Fetal Toxicity

  • Exposure to trastuzumab products during pregnancy can result in oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death. Advise patients of these risks and the need for effective contraception
  • Verify the pregnancy status of females of reproductive potential prior to the initiation of HERZUMA
  • Advise pregnant women and females of reproductive potential that exposure to HERZUMA during pregnancy or within 7 months prior to conception can result in fetal harm
  • Advise females of reproductive potential to use effective contraception during treatment and for 7 months following the last dose of HERZUMA. Advise female patients to contact their healthcare provider with a known or suspected pregnancy
  • Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for HERZUMA treatment and any potential adverse effects on the breastfed child from HERZUMA or from the underlying maternal condition

Pulmonary Toxicity

  • Administration of trastuzumab products can result in serious and fatal pulmonary toxicity, which includes dyspnea, interstitial pneumonitis, pulmonary infiltrates, pleural effusions, non cardiogenic pulmonary edema, pulmonary insufficiency and hypoxia, acute respiratory distress syndrome, and pulmonary fibrosis. Such events can occur as sequelae of infusion reactions
  • Patients with symptomatic intrinsic lung disease or with extensive tumor involvement of the lungs, resulting in dyspnea at rest, appear to have more severe toxicity
  • Discontinue HERZUMA in patients experiencing pulmonary toxicity

Exacerbation of Chemotherapy-Induced Neutropenia

  • In randomized, controlled clinical trials, the per-patient incidences of NCI-CTC Grade 3 to 4 neutropenia and of febrile neutropenia were higher in patients receiving trastuzumab in combination with myelosuppressive chemotherapy as compared to those who received chemotherapy alone. The incidence of septic death was similar among patients who received trastuzumab and those who did not

Most Common Adverse Reactions

Adjuvant Breast Cancer

  • Most common adverse reactions (≥5%) are headache, diarrhea, nausea, and chills

Metastatic Breast Cancer

  • Most common adverse reactions (≥10%) are fever, chills, headache, infection, congestive heart failure, insomnia, cough, and rash

Metastatic Gastric Cancer

  • Most common adverse reactions (≥10%) are neutropenia, diarrhea, fatigue, anemia, stomatitis, weight loss, upper respiratory tract infections, fever, thrombocytopenia, mucosal inflammation, nasopharyngitis, and dysgeusia

Please see full Prescribing Information, including BOXED WARNINGS.

You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch.

Embryo-Fetal Toxicity

  • Exposure to trastuzumab products during pregnancy can result in oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death. Advise patients of these risks and the need for effective contraception
  • Verify the pregnancy status of females of reproductive potential prior to the initiation of HERZUMA
  • Advise pregnant women and females of reproductive potential that exposure to HERZUMA during pregnancy or within 7 months prior to conception can result in fetal harm
  • Advise females of reproductive potential to use effective contraception during treatment and for 7 months following the last dose of HERZUMA. Advise female patients to contact their healthcare provider with a known or suspected pregnancy
  • Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for HERZUMA treatment and any potential adverse effects on the breastfed child from HERZUMA or from the underlying maternal condition

Pulmonary Toxicity

  • Administration of trastuzumab products can result in serious and fatal pulmonary toxicity, which includes dyspnea, interstitial pneumonitis, pulmonary infiltrates, pleural effusions, non cardiogenic pulmonary edema, pulmonary insufficiency and hypoxia, acute respiratory distress syndrome, and pulmonary fibrosis. Such events can occur as sequelae of infusion reactions
  • Patients with symptomatic intrinsic lung disease or with extensive tumor involvement of the lungs, resulting in dyspnea at rest, appear to have more severe toxicity
  • Discontinue HERZUMA in patients experiencing pulmonary toxicity

Exacerbation of Chemotherapy-Induced Neutropenia

  • In randomized, controlled clinical trials, the per-patient incidences of NCI-CTC Grade 3 to 4 neutropenia and of febrile neutropenia were higher in patients receiving trastuzumab in combination with myelosuppressive chemotherapy as compared to those who received chemotherapy alone. The incidence of septic death was similar among patients who received trastuzumab and those who did not

Most Common Adverse Reactions

Adjuvant Breast Cancer

  • Most common adverse reactions (≥5%) are headache, diarrhea, nausea, and chills

Metastatic Breast Cancer

  • Most common adverse reactions (≥10%) are fever, chills, headache, infection, congestive heart failure, insomnia, cough, and rash

Metastatic Gastric Cancer

  • Most common adverse reactions (≥10%) are neutropenia, diarrhea, fatigue, anemia, stomatitis, weight loss, upper respiratory tract infections, fever, thrombocytopenia, mucosal inflammation, nasopharyngitis, and dysgeusia

Please see full Prescribing Information, including BOXED WARNINGS.

You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch.

References: 1. US Food and Drug Administration. Labeling for biosimilar products. Guidance for Industry. July 2018. https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm493439.pdf. Accessed November 4, 2019. 2. US Food and Drug Administration. Biosimilars. https://www.fda.gov/drugs/therapeutic-biologics-applications-bla/biosimilars. Accessed November 4, 2019. 3. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Breast Cancer V3.2020. © National Comprehensive Cancer Network, Inc. 2020. All rights reserved. Accessed March 10, 2020. To view the most recent and complete version of the guideline, go online to NCCN.org. 4. European Medicines Agency. Herzuma assessment report. https://www.ema.europa.eu/documents/assessment-report/ herzuma-epar-public-assessment-report_en.pdf. Published December 14, 2017. Accessed November 4, 2019. 5. Schiestl M, Zabransky M, Sörgel F. Ten years of biosimilars in Europe: development and evolution of the regulatory pathways. Drug Des Devel Ther. 2017;11:1509-1515. 6. Sandoz Press Release. Available at: https://www.sandoz.com/news/media-releases/ sandoz-launches-zarxiotm-filgrastim-sndz-first-biosimilar-united-states. Accessed November 4, 2019. 7. US Food and Drug Administration. Biosimilar product regulatory review and approval. https://www.fda.gov/downloads/drugs/developmentapprovalprocess/howdrugsaredevelopedandapproved/approvalapplications/therapeuticbiologicapplications/biosimilars/ucm581309.pdf. Accessed November 4, 2019. 8. Research Advocacy Network. Introduction to Biosimilar Medicines. http://www. researchadvocacy.org/sites/default/files/resources/ Biosimilar%20Medicines6_4Final.pdf. Accessed November 4, 2019. 9. HERZUMA® (trastuzumab-pkrb) for injection, for intravenous use Prescribing Information. Incheon, Republic of Korea: Celltrion, Inc. 10. Herceptin® (trastuzumab) Prescribing Information. Genentech, Inc. 2018. 11. Data on file. North Wales, PA: Teva Pharmaceuticals USA, Inc.

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