Clinical Efficacy

**A head-to-head, comparative-equivalence clinical study supported equivalent clinical efficacy with Herceptin (trastuzumab)¹**

Learn about:

Study design²

To support biosimilarity to Herceptin, ONTRUZANT was evaluated in the largest clinical trial among biosimilars^1,2

Approval of ONTRUZANT is based on the rigorous evaluation of the “totality of evidence,” which included structural, functional, and clinical data.

European Union (EU)–sourced Herceptin was used for the purpose of this study.¹

Definitions

EBC = early breast cancer
FEC = fluorouracil, epirubacin, and cyclophosphamide
HER2 = human epidermal growth factor receptor 2
HER2+ = HER2-positive
LABC = locally advanced breast cancer
LVEF = left ventricular ejection fraction

Key inclusion criteria¹:

Female, aged 18–65 years
Eastern Cooperative Oncology Group performance status of 0 or 1
Nonmetastatic, unilateral, primary breast cancer
Stage II to III, including inflammatory breast cancer
Tumor size ≥2 cm
Primary invasive adenocarcinoma of the breast
HER2 positive
LVEF ≥55%

Key exclusion criteria³:

Metastatic (stage IV) or bilateral breast cancer or 2 clinically detectable separate masses
History of any prior invasive breast carcinoma^f
Past or current history of malignant neoplasms within 5 years of randomization^g
Pregnant or lactating women
Concurrent hormonal therapy
Previous history of radiation therapy, immunotherapy, chemotherapy, or biotherapy
Major surgery within 4 weeks of randomization
Minor surgery within 2 weeks of randomization
Serious cardiac, pulmonary, or other illness or infection
Abnormal laboratory tests

^aA common dosing schedule was used in the ONTRUZANT and Herceptin arms.¹
^bDocetaxel 75 mg/m².¹
^cFluorouracil 500 mg/m², epirubicin 75 mg/m², and cyclophosphamide 500 mg/m².¹
^dEuropean Union (EU)–sourced Herceptin was used for the purposes of this study.¹
^ePrimary end point was pathologic complete response (pCR) in breast tumor.¹
^fExcept for patients with a past history of ductal carcinoma in situ and/or lobular carcinoma in situ treated with surgery only.³
^gExcept for curatively treated carcinoma in situ of uterine cervix, basal cell carcinoma of the skin, or squamous cell carcinoma of the skin (malignant neoplasms occurring >5 years before randomization were permitted if curatively treated with surgery only).³

Study purpose and end point¹

A head-to-head study to demonstrate the equivalent clinical efficacy of ONTRUZANT to Herceptin.

Primary end point¹

Efficacy:

Breast pathologic complete response (bpCR): defined as no histologic evidence of residual invasive tumor cells in the breast
- Demonstration of clinical efficacy equivalence required that the confidence intervals of either ratio or difference of bpCR rates fell within predefined equivalence margins

Pathologic complete response in the breast (bpCR) in the per-protocol set^h

Demonstration of clinical efficacy equivalence required that the confidence intervals of either ratio or difference of bpCR rates fall within predefined equivalence margins, as defined by: 95% CI of the ratio of bpCR rates (0.785–1.546); 95% CI of the difference of bpCR rates (−13%, 13%)¹
Adjusted difference: 10.7% (95% CI, 4.13%–17.26%)¹

In the 95% confidence interval of adjusted difference, the lower margin was contained within and the upper margin was outside the predefined equivalence margin.¹

Adjusted rate ratio: 1.259 (95% CI, 1.085–1.460)¹

95% confidence interval of adjusted rate ratio was within the margin of predefined equivalence.

^hPer-protocol set is defined as all randomized subjects who completed 8 cycles of neoadjuvant therapy and surgery without major prespecified protocol deviations.¹
ⁱEuropean Union (EU)–sourced Herceptin was used for the purposes of this study.¹

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Indications and Selected Safety Information

Indications

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 a 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

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.

Definitions

MUGA = multigated acquisition
NCI-CTC = National Cancer Institute-Common Terminology Criteria
PK = pharmacokinetics

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 trademarks of their respective owners.

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 a 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

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.

Definitions

MUGA = multigated acquisition
NCI-CTC = National Cancer Institute-Common Terminology Criteria
PK = pharmacokinetics

Brands mentioned are trademarks of their respective owners.

Indications

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 a 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

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.

Definitions

MUGA = multigated acquisition
NCI-CTC = National Cancer Institute-Common Terminology Criteria
PK = pharmacokinetics

Brands mentioned are trademarks of their respective owners.

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 a 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

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.

Definitions

MUGA = multigated acquisition
NCI-CTC = National Cancer Institute-Common Terminology Criteria
PK = pharmacokinetics

Brands mentioned are trademarks of their respective owners.

**A head-to-head, comparative-equivalence clinical study supported equivalent clinical efficacy with Herceptin (trastuzumab)¹**

Study design²

Definitions

Study purpose and end point¹

Primary end point¹

Pathologic complete response in the breast (bpCR) in the per-protocol set^h

More Biosimilar Data:

Clinical Efficacy

Indications and Selected Safety Information

Indications

Adjuvant Breast Cancer

Metastatic Breast Cancer

Definitions

Selected Safety Information

CARDIOMYOPATHY

INFUSION REACTIONS; PULMONARY TOXICITY

EMBRYO-FETAL TOXICITY

WARNINGS AND PRECAUTIONS

CARDIOMYOPATHY

CARDIAC MONITORING

INFUSION REACTIONS

EMBRYO-FETAL TOXICITY

PULMONARY TOXICITY

EXACERBATION OF CHEMOTHERAPY-INDUCED NEUTROPENIA

DRUG INTERACTIONS

ADVERSE REACTIONS

Definitions

Indications

Selected Safety Information +

A head-to-head, comparative-equivalence clinical study supported equivalent clinical efficacy with Herceptin (trastuzumab)1

Study design2

Definitions

Study purpose and end point1

Primary end point1

Pathologic complete response in the breast (bpCR) in the per-protocol seth

More Biosimilar Data:

Clinical Efficacy

Indications and Selected Safety Information

Indications

Adjuvant Breast Cancer

Metastatic Breast Cancer

Definitions

Selected Safety Information

CARDIOMYOPATHY

INFUSION REACTIONS; PULMONARY TOXICITY

EMBRYO-FETAL TOXICITY

WARNINGS AND PRECAUTIONS

CARDIOMYOPATHY

CARDIAC MONITORING

INFUSION REACTIONS

EMBRYO-FETAL TOXICITY

PULMONARY TOXICITY

EXACERBATION OF CHEMOTHERAPY-INDUCED NEUTROPENIA

DRUG INTERACTIONS

ADVERSE REACTIONS

Definitions

Indications

Selected Safety Information +

Indications

Adjuvant Breast Cancer

Metastatic Breast Cancer

Definitions

Selected Safety Information

CARDIOMYOPATHY

INFUSION REACTIONS; PULMONARY TOXICITY

EMBRYO-FETAL TOXICITY

WARNINGS AND PRECAUTIONS

CARDIOMYOPATHY

CARDIAC MONITORING

INFUSION REACTIONS

EMBRYO-FETAL TOXICITY

PULMONARY TOXICITY

EXACERBATION OF CHEMOTHERAPY-INDUCED NEUTROPENIA

DRUG INTERACTIONS

ADVERSE REACTIONS

Definitions

Indications and Selected Safety Information

Indications

Adjuvant Breast Cancer

Metastatic Breast Cancer

Definitions

Selected Safety Information

CARDIOMYOPATHY

INFUSION REACTIONS; PULMONARY TOXICITY

EMBRYO-FETAL TOXICITY

WARNINGS AND PRECAUTIONS

CARDIOMYOPATHY

CARDIAC MONITORING

INFUSION REACTIONS

EMBRYO-FETAL TOXICITY

PULMONARY TOXICITY

EXACERBATION OF CHEMOTHERAPY-INDUCED NEUTROPENIA

DRUG INTERACTIONS

ADVERSE REACTIONS

Definitions

Selected Safety Information

CARDIOMYOPATHY

INFUSION REACTIONS; PULMONARY TOXICITY

EMBRYO-FETAL TOXICITY

WARNINGS AND PRECAUTIONS

CARDIOMYOPATHY

CARDIAC MONITORING

INFUSION REACTIONS

EMBRYO-FETAL TOXICITY

PULMONARY TOXICITY

EXACERBATION OF CHEMOTHERAPY-INDUCED NEUTROPENIA

DRUG INTERACTIONS

ADVERSE REACTIONS

Definitions

**A head-to-head, comparative-equivalence clinical study supported equivalent clinical efficacy with Herceptin (trastuzumab)¹**

Study design²

Study purpose and end point¹

Primary end point¹

Pathologic complete response in the breast (bpCR) in the per-protocol set^h