FDA Approves Herzuma

FDA Approves Herzuma (trastuzumab-pkrb), a Biosimilar to Herceptin

INCHEON, South Korea & JERUSALEM--(BUSINESS WIRE) December 14, 2018 --Celltrion, Inc. and Teva Pharmaceutical Industries Ltd. today announced that the U.S. Food and Drug Administration (FDA) has approved Herzuma (trastuzumab-pkrb), a HER2/neu receptor antagonist biosimilar to Herceptin®1(trastuzumab) for the following indications:

• Adjuvant Breast Cancer 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
• Metastatic Breast Cancer
  • 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.

• In these indications, patients should be selected for therapy based on an FDA-approved companion diagnostic for a trastuzumab product

“Biosimilars are of growing importance to the oncology community and the approval of Herzuma may provide more patients access to this important therapy,” stated Woosung Kee, Chief Executive Officer of Celltrion. “This is our second oncology biosimilar approval in the United States in the past month, which reinforces the goal for all of our approved products -- providing broader treatment options for patients and the providers who treat them.”

• Herzuma meets the FDA’s rigorous standards as a biosimilar to the reference product for the approved indications based on a totality of evidence. The FDA approval is based on a review of a comprehensive data package inclusive of foundational analytical similarity data, nonclinical data, clinical pharmacology, immunogenicity, clinical efficacy and safety data. The results of the clinical development program for Herzuma demonstrated that there were no clinically meaningful differences in purity, potency and safety between Herzuma and Herceptin for the treatment of HER2-overexpressing breast cancer for the approved indications.

  “We are excited about building Teva’s presence in biosimilars,” said Brendan O’Grady, Executive Vice President and Head of North America Commercial at Teva. “The addition of Herzuma to our biosimilars portfolio will allow us to leverage our strengths from Oncology and Generics.”

  Trastuzumab products have a Boxed Warning which states that treatment with trastuzumab may be associated with cardiomyopathy, infusion reactions, pulmonary toxicity and embryo-fetal toxicity. Please see the full Boxed Warning and additional Important Safety Information in this release and accompanying Prescribing Information.

  Celltrion and Teva Pharmaceutical Industries Ltd. entered into an exclusive partnership in October 2016 to commercialize Herzuma in the U.S. and Canada.

  Important Safety Information and 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 Herzuma 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.

  Cardiomyopathy

  • 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).
  • There is a 4–6-fold increase in the incidence of symptomatic myocardial dysfunction among patients receiving trastuzumab products as a single agent or in combination therapy compared with those not receiving trastuzumab products. The highest absolute incidence occurs when a trastuzumab product is administered with an anthracycline.
  • Withhold Herzuma for ≥ 16% absolute decrease in LVEF from pre-treatment values or an LVEF value below institutional limits of normal and ≥ 10% absolute decrease in LVEF from pretreatment values. The safety of continuation or resumption of Herzuma in patients with trastuzumab product-induced left ventricular cardiac dysfunction has not been studied.
  • Patients who receive anthracycline after stopping Herzuma may also be at increased risk of cardiac dysfunction.

  Cardiac Monitoring

  • Conduct thorough cardiac assessment, including history, physical examination, and determination of LVEF by echocardiogram or MUGA scan. The following schedule is recommended:
    • Baseline LVEF measurement immediately prior to initiation of Herzuma.
    • LVEF measurements every 3 months during and upon completion of Herzuma.
    • Repeat LVEF measurement at 4 week intervals if Herzuma is withheld for significant left ventricular cardiac dysfunction.
    • LVEF measurements every 6 months for at least 2 years following completion of Herzuma as a component of adjuvant therapy.

  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.
  • In post-marketing reports, serious and fatal infusion reactions have been reported. Severe reactions, which include bronchospasm, anaphylaxis, angioedema, hypoxia, and severe hypotension, were usually reported during or immediately following the initial infusion. However, the onset and clinical course were variable, including progressive worsening, initial improvement followed by clinical deterioration, or delayed post-infusion events with rapid clinical deterioration. For fatal events, death occurred within hours to days following a serious infusion reaction.
  • Interrupt Herzuma infusion in all patients experiencing dyspnea, clinically significant hypotension, and intervention of medical therapy administered (which may include epinephrine, corticosteroids, diphenhydramine, bronchodilators, and oxygen). Patients should be evaluated and carefully monitored until complete resolution of signs and symptoms. Permanent discontinuation should be strongly considered in all patients with severe infusion reactions.
  • There are no data regarding the most appropriate method of identification of patients who may safely be retreated with trastuzumab products after experiencing a severe infusion reaction. Prior to resumption of trastuzumab infusion, the majority of patients who experienced a severe infusion reaction were pre-medicated with antihistamines and/or corticosteroids. While some patients tolerated trastuzumab infusions, others had recurrent severe infusion reactions despite pre-medications.

  Embryo-Fetal Toxicity

  • Trastuzumab products can cause fetal harm when administered to a pregnant woman. In post marketing reports, use of trastuzumab during pregnancy resulted in cases of oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death.
  • 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.

  Pulmonary Toxicity

  • • Trastuzumab product use can result in serious and fatal pulmonary toxicity. Pulmonary toxicity 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.

    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.

    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.