Questions and Answers About Biosimilars

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

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

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 2006.3-5

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.2,6

Required data include7:

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

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Animal studies including an assessment of toxicity

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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.3

Yes. Truxima was initially approved in the US, November 2018 for certain indications, has demonstrated biosimiliarity to Rituxan (rituximab) through a totality of evidence, and has no clinically meaningful differences in terms of safety, purity, and potency.8-10

TRUXIMA is approved for oncology indications in over 25 European countries.11*

*Approved indications of TRUXIMA vary by country and indications may be different from those approved in the US.

TRUXIMA is a treatment alternative to Rituxan for the indications listed below.8,9

Offering competitive pricing for TRUXIMA is our key priority.

When considering rituximab, choose TRUXIMA for NHL and CLL.8

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

TRUXIMA is indicated for the treatment of adult patients with:

Non-Hodgkin’s Lymphoma (NHL)

  • Relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL as a single agent
  • Previously untreated follicular, CD20-positive, B-cell NHL in combination with first-line chemotherapy and, in patients achieving a complete or partial response to a rituximab product in combination with chemotherapy, as single-agent maintenance therapy
  • Non-progressing (including stable disease), low-grade, CD20-positive, B-cell NHL as a single agent after first-line cyclophosphamide, vincristine, and prednisone (CVP) chemotherapy
  • Previously untreated diffuse large B-cell, CD20-positive NHL in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or other anthracycline-based chemotherapy regimens

Chronic Lymphocytic Leukemia (CLL)

  • In combination with fludarabine and cyclophosphamide (FC), for the treatment of adult patients with previously untreated CD20-positive CLL

IMPORTANT SAFETY INFORMATION

BOXED WARNINGS

WARNING: FATAL INFUSION-RELATED REACTIONS, SEVERE MUCOCUTANEOUS REACTIONS, HEPATITIS B VIRUS REACTIVATION and PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY

  • Infusion-Related Reactions: Administration of rituximab products, including TRUXIMA, can result in serious, including fatal, infusion-related reactions. Deaths within 24 hours of rituximab infusion have occurred. Approximately 80% of fatal infusion-related reactions occurred in association with the first infusion. Monitor patients closely. Discontinue TRUXIMA infusion for severe reactions and provide medical treatment for Grade 3 or 4 infusion-related reactions
  • Severe Mucocutaneous Reactions: Severe, including fatal, mucocutaneous reactions can occur in patients receiving rituximab products
  • Hepatitis B Virus (HBV) Reactivation: HBV reactivation can occur in patients treated with rituximab products, in some cases resulting in fulminant hepatitis, hepatic failure, and death. Screen all patients for HBV infection before treatment initiation, and monitor patients during and after treatment with TRUXIMA. Discontinue TRUXIMA and concomitant medications in the event of HBV reactivation
  • Progressive Multifocal Leukoencephalopathy (PML), including fatal PML, can occur in patients receiving rituximab products

WARNINGS AND PRECAUTIONS

Infusion-Related Reactions

  • Rituximab products can cause severe, including fatal, infusion-related reactions. Severe reactions typically occurred during the first infusion with time to onset of 30–120 minutes. Rituximab product-induced infusion-related reactions and sequelae include urticaria, hypotension, angioedema, hypoxia, bronchospasm, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, cardiogenic shock, anaphylactoid events, or death
  • Premedicate patients with an antihistamine and acetaminophen prior to dosing. Institute medical management (e.g. glucocorticoids, epinephrine, bronchodilators, or oxygen) for infusion-related reactions as needed. Depending on the severity of the infusion-related reaction and the required interventions, temporarily or permanently discontinue TRUXIMA. Resume infusion at a minimum 50% reduction in rate after symptoms have resolved. Closely monitor the following patients: those with pre-existing cardiac or pulmonary conditions, those who experienced prior cardiopulmonary adverse reactions, and those with high numbers of circulating malignant cells (≥25,000/mm3)

Severe Mucocutaneous Reactions

  • Mucocutaneous reactions, some with fatal outcome, can occur in patients treated with rituximab products. These reactions include paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis. The onset of these reactions has been variable and includes reports with onset on the first day of rituximab exposure. Discontinue TRUXIMA in patients who experience a severe mucocutaneous reaction. The safety of re-administration of rituximab products to patients with severe mucocutaneous reactions has not been determined

Hepatitis B Virus Reactivation

  • Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, can occur in patients treated with drugs classified as CD20-directed cytolytic antibodies, including rituximab products. Cases have been reported in patients who are hepatitis B surface antigen (HBsAg) positive and also in patients who are HBsAg negative but are hepatitis B core antibody (anti-HBc) positive. Reactivation also has occurred in patients who appear to have resolved hepatitis B infection (i.e., HBsAg negative, anti-HBc positive and hepatitis B surface antibody [anti-HBs] positive)
  • HBV reactivation is defined as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA levels or detection of HBsAg in a person who was previously HBsAg negative and anti-HBc positive. Reactivation of HBV replication is often followed by hepatitis, i.e., increase in transaminase levels. In severe cases increase in bilirubin levels, liver failure, and death can occur
  • Screen all patients for HBV infection by measuring HBsAg and anti-HBc before initiating treatment with TRUXIMA. For patients who show evidence of prior hepatitis B infection (HBsAg positive [regardless of antibody status] or HBsAg negative but anti-HBc positive), consult with physicians with expertise in managing hepatitis B regarding monitoring and consideration for HBV antiviral therapy before and/or during TRUXIMA treatment
  • Monitor patients with evidence of current or prior HBV infection for clinical and laboratory signs of hepatitis or HBV reactivation during and for several months following TRUXIMA therapy. HBV reactivation has been reported up to 24 months following completion of rituximab therapy
  • In patients who develop reactivation of HBV while on TRUXIMA, immediately discontinue TRUXIMA and any concomitant chemotherapy, and institute appropriate treatment. Insufficient data exist regarding the safety of resuming TRUXIMA treatment in patients who develop HBV reactivation. Resumption of TRUXIMA treatment in patients whose HBV reactivation resolves should be discussed with physicians with expertise in managing HBV

Progressive Multifocal Leukoencephalopathy (PML)

  • JC virus infection resulting in PML and death can occur in rituximab product-treated patients with hematologic malignancies. The majority of patients with hematologic malignancies diagnosed with PML received rituximab in combination with chemotherapy or as part of a hematopoietic stem cell transplant. Most cases of PML were diagnosed within 12 months of their last infusion of rituximab
  • Consider the diagnosis of PML in any patient presenting with new-onset neurologic manifestations. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture
  • Discontinue TRUXIMA and consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy in patients who develop PML

Tumor Lysis Syndrome (TLS)

  • Acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, or hyperphosphatemia from tumor lysis, sometimes fatal, can occur within 12–24 hours after the first infusion of rituximab products in patients with NHL. A high number of circulating malignant cells (≥25,000/mm3) or high tumor burden, confers a greater risk of TLS
  • Administer aggressive intravenous hydration and anti-hyperuricemic therapy in patients at high risk for TLS. Correct electrolyte abnormalities, monitor renal function and fluid balance, and administer supportive care, including dialysis as indicated

Infections

  • Serious, including fatal, bacterial, fungal, and new or reactivated viral infections can occur during and following the completion of rituximab product-based therapy. Infections have been reported in some patients with prolonged hypogammaglobulinemia (defined as hypogammaglobulinemia >11 months after rituximab exposure). New or reactivated viral infections included cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster virus, West Nile virus, and hepatitis B and C. Discontinue TRUXIMA for serious infections and institute appropriate anti-infective therapy. TRUXIMA is not recommended for use in patients with severe, active infections

Cardiovascular Adverse Reactions

  • Cardiac adverse reactions, including ventricular fibrillation, myocardial infarction, and cardiogenic shock may occur in patients receiving rituximab products. Discontinue infusions for serious or life-threatening cardiac arrhythmias. Perform cardiac monitoring during and after all infusions of TRUXIMA for patients who develop clinically significant arrhythmias, or who have a history of arrhythmia or angina

Renal Toxicity

  • Severe, including fatal, renal toxicity can occur after rituximab product administration in patients with NHL. Renal toxicity has occurred in patients who experience tumor lysis syndrome and in patients with NHL administered concomitant cisplatin therapy during clinical trials. The combination of cisplatin and TRUXIMA is not an approved treatment regimen. Monitor closely for signs of renal failure and discontinue TRUXIMA in patients with a rising serum creatinine or oliguria

Bowel Obstruction and Perforation

  • Abdominal pain, bowel obstruction and perforation, in some cases leading to death, can occur in patients receiving rituximab in combination with chemotherapy. In postmarketing reports, the mean time to documented gastrointestinal perforation was 6 (range 1–77) days in patients with NHL. Evaluate if symptoms of obstruction such as abdominal pain or repeated vomiting occur

Immunization

  • The safety of immunization with live viral vaccines following rituximab product therapy has not been studied and vaccination with live virus vaccines is not recommended before or during treatment

Embryo-Fetal Toxicity

  • Based on human data, rituximab products can cause fetal harm due to B-cell lymphocytopenia in infants exposed to rituximab in-utero. Advise pregnant women of the risk to a fetus. Females of childbearing potential should use effective contraception while receiving TRUXIMA and for 12 months following the last dose of TRUXIMA

Most common adverse reactions in clinical trials of NHL (≥25%) were: infusion-related reactions, fever, lymphopenia, chills, infection, and asthenia

Most common adverse reactions in clinical trials of CLL (≥25%) were: infusion-related reactions and neutropenia

Nursing Mothers

  • There are no data on the presence of rituximab in human milk, the effect on the breastfed child, or the effect on milk production. Since many drugs including antibodies are present in human milk, advise a lactating woman not to breastfeed during treatment and for at least 6 months after the last dose of TRUXIMA due to the potential for serious adverse reactions in breastfed infants

Please see the 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. What is a biosimilar? https://www.fda.gov/downloads/drugs/developmentapprovalprocess/ howdrugsaredevelopedandapproved/approvalapplications/therapeuticbiologicapplications/biosimilars/UCM585738.pdf. Accessed March 5, 2019. 2. US Food and Drug Administration. Biosimilar product regulatory review and approval. https://www.fda.gov/drugs/developmentapprovalprocess/ howdrugsaredevelopedandapproved/approvalapplications/therapeuticbiologicapplications/biosimilars/UCM581309.htm#indication. Accessed March 5, 2019. 3. European Medicines Agency. Biosimilars in the EU. https://www.ema.europa.eu/documents/leaflet/ biosimilars-eu-information-guide-healthcare-professionals_en.pdf. Accessed March 5, 2019. 4. 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. 5. Sandoz Press Release. Available at: https://www.sandoz.com/news/media-releases/sandoz-launches-zarxiotm-filgrastim-sndz-first-biosimilar-united-states. 6. Research Advocacy Network. Introduction to Biosimilar Medicines. https://researchadvocacy.org/sites/default/files/resources/Biosimilar% 20Medicines_Final-download.pdf. Accessed February 5, 2019. 7. US Food and Drug Administration. Labeling for biosimilar products. https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ UCM493439.pdf. Accessed March 5, 2019. 8. TRUXIMA® (rituximab-abbs) Prescribing Information. Incheon, Republic of Korea: Celltrion, Inc. 9. Rituxan® (rituximab) full Prescribing Information, South San Francisco, CA: Genentech, Inc., 2019. 10. US Food and Drug Administration. Scientific considerations in demonstrating biosimilarity to a reference product. https://www.fda.gov/downloads/drugs/guidances/ucm291128.pdf. Accessed March 5, 2019. 11. Data on file. North Wales, PA: Teva Pharmaceuticals USA, Inc.

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