ONTRUZANT®

(trastuzumab-dttb) for injection,
for intravenous use 21 mg/mL

Biosimilar Data

Pharmacokinetic (PK) similarity


PK clinical study supported biosimilarity1

Primary PK parameters between ONTRUZANT and Herceptin (trastuzumab)1,a

Pharmacokinetic Clinical Study Supported Biosimilarity Between ONTRUZANT® (trastuzumab-dttb) and Herceptin (trastuzumab).

aPK was assessed based on the evaluation of 3 specific PK parameters: AUC0–∞, AUC0–last, and Cmax. The ratio in geometric least square means of the AUC0–∞, AUC0–last, and Cmax between ONTRUZANT and European Union EU–sourced Herceptin, between ONTRUZANT and US–sourced Herceptin, and between EU-sourced Herceptin and US-sourced Herceptin and the associated 90% CIs were estimated. The PK equivalence was confirmed when the 90% CI for the ratio of geometric least square means of pairwise comparison was within the predefined equivalence margin of 0.8 to 1.25.1

Serum concentration time profiles: ONTRUZANT vs Herceptin1,b,c

A Double-Blind, 3-Arm, Parallel-Group Study to Evaluate the Pharmacokinetic (PK) Equivalence Between ONTRUZANT® (trastuzumab-dttb) and Herceptin (trastuzumab) Sourced in the European Union (EU) and the United States (US).

bThis graph is not meant to imply equivalence at each time point.
cBlood samples for PK analysis were collected at 0 (before infusion), 0.75, 1.5 (end of infusion), 3, 6, 12, 24, 48, 72, 96, 168, 336, 672, 1008, and 1344 hours after the start of infusion. Serum trastuzumab concentrations were measured using a validated enzyme-linked immunosorbent assay.1

Study design1

Single-dose study in 109 healthy male subjects: A double-blind, 3-arm, parallel-group study to evaluate the pharmacokinetic (PK) equivalence between ONTRUZANT and Herceptin sourced in the European Union (EU) and the United States (US) and between EU- and US-sourced Herceptin. Study subjects were aged 18 to 55 years with a body mass index of 18.0 to 29.9 kg/m2 and normal screening results. Subjects with previous exposure to any monoclonal antibody or fusion protein or a history of cardiac disease, cancer, or any clinically significant disease were excluded.

Indications and Usage

Adjuvant Breast Cancer

ONTRUZANT is indicated for 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

ONTRUZANT 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.

Definitions

ER = estrogen receptor
HER2 = human epidermal growth factor receptor 2
PR = progesterone receptor

Selected Safety Information

CARDIOMYOPATHY

  • Administration of trastuzumab products can result in subclinical and clinical cardiac failure. The incidence and severity was highest in patients receiving a trastuzumab product with anthracycline-containing chemotherapy regimens.
  • Evaluate left ventricular function in all patients prior to and during treatment with ONTRUZANT. Discontinue ONTRUZANT treatment in patients receiving adjuvant therapy and withhold ONTRUZANT 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 ONTRUZANT infusion for dyspnea or clinically significant hypotension. Monitor patients until symptoms completely resolve. Discontinue ONTRUZANT 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 subclinical and clinical cardiac failure. The incidence and severity was highest in patients receiving trastuzumab with anthracycline-containing chemotherapy regimens. In a pivotal adjuvant breast cancer trial, one patient who developed congestive heart failure (CHF) died of 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).
  • Discontinue ONTRUZANT treatment in patients receiving adjuvant breast cancer therapy and withhold ONTRUZANT in patients with metastatic disease for clinically significant decrease in left ventricular function.

CARDIAC MONITORING

  • Evaluate cardiac function prior to and during treatment. For adjuvant breast cancer therapy, also evaluate cardiac function after completion of ONTRUZANT.
  • 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 ONTRUZANT treatment.
  • Monitor more frequently if ONTRUZANT 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 ONTRUZANT administration.
  • Interrupt ONTRUZANT infusion for dyspnea or clinically significant hypotension.
  • Monitor patients until symptoms completely resolve.
  • Discontinue ONTRUZANT for infusion reactions manifesting as anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome. 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 include 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 ONTRUZANT.
  • Advise pregnant women and females of reproductive potential that exposure to ONTRUZANT 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 at least 7 months following the last dose of ONTRUZANT.
  • Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for ONTRUZANT treatment and any potential adverse effects on the breastfed child from ONTRUZANT 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, noncardiogenic 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 ONTRUZANT in patients experiencing pulmonary toxicity.

EXACERBATION OF CHEMOTHERAPY-INDUCED NEUTROPENIA

  • In randomized, controlled clinical trials, the per-patient incidences of NCI-CTC grade 3-4 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.

DRUG INTERACTIONS

  • Patients who receive anthracycline after stopping trastuzumab products may be at increased risk of cardiac dysfunction because of trastuzumab's long washout period based on population PK analysis. If possible, physicians should avoid anthracycline-based therapy for up to 7 months after stopping trastuzumab products. If anthracyclines are used, the patient's cardiac function should be monitored carefully.

ADVERSE REACTIONS

ADVERSE REACTIONS

  • The most common adverse reactions associated with trastuzumab products in the adjuvant and metastatic breast cancer setting are fever, nausea, vomiting, infusion reactions, diarrhea, infections, increased cough, headache, fatigue, dyspnea, rash, neutropenia, anemia, and myalgia.

Before prescribing ONTRUZANT, please read the accompanying Prescribing Information, including the Boxed Warning about cardiomyopathy, infusion reactions (pulmonary toxicity), and embryo-fetal toxicity.

Brands mentioned are copyrights of their respective owners.

REFERENCE: 1. Pivot X, Curtit E, Lee YJ, et al. A randomized phase I pharmacokinetic study comparing biosimilar candidate SB3 and trastuzumab in healthy male subjects. Clin Ther. 2016;38(7):1665–1673.
US-SBF-0014309/20