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SAFETY

Boxed WARNINGS and Additional Important Safety Information

  • Herceptin administration can result in sub-clinical and clinical cardiac failure. The incidence and severity was highest in patients receiving Herceptin with anthracycline-containing chemotherapy regimens. In a pivotal adjuvant breast cancer trial, one patient who developed CHF died of cardiomyopathy
  • Evaluate cardiac function prior to and during treatment. For adjuvant breast cancer therapy, also evaluate cardiac function after completion of Herceptin. Discontinue Herceptin for cardiomyopathy
  • Herceptin can result in serious and fatal infusion reactions and pulmonary toxicity. Discontinue Herceptin for anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome
  • Exposure to Herceptin during pregnancy can result in oligohydramnios, in some cases complicated by pulmonary hypoplasia and neonatal death
  • Exacerbation of chemotherapy-induced neutropenia has also occurred
  • Detection of HER2 protein overexpression is necessary for selection of patients appropriate for Herceptin therapy
  • The most common adverse reactions associated with Herceptin in breast cancer were fever, nausea, vomiting, infusion reactions, diarrhea, infections, increased cough, headache, fatigue, dyspnea, rash, neutropenia, anemia, and myalgia
  • The most common adverse reactions associated with Herceptin in metastatic gastric cancer were neutropenia, diarrhea, fatigue, anemia, stomatitis, weight loss, upper respiratory tract infections, fever, thrombocytopenia, mucosal inflammation, nasopharyngitis, and dysgeusia

Safety First! Before you start exploring, take the time to read the Important Safety Information. Roll over to read more.

Adjuvant Breast Cancer Treatment Side Effects

Boxed WARNINGS and Additional Important Safety Information

Cardiomyopathy

  • Herceptin administration can result in sub-clinical and clinical cardiac failure. The incidence and severity was highest in patients receiving Herceptin with anthracycline-containing chemotherapy regimens. In a pivotal adjuvant breast cancer trial, one patient who developed CHF died of cardiomyopathy
  • Herceptin can cause left ventricular cardiac dysfunction, arrhythmias, hypertension, disabling cardiac failure, cardiomyopathy, and cardiac death
  • Herceptin can also cause asymptomatic decline in LVEF
  • Discontinue Herceptin treatment in patients receiving adjuvant breast cancer therapy and withhold Herceptin 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 Herceptin
  • 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 Herceptin treatment
  • Monitor more frequently if Herceptin is withheld for significant left ventricular cardiac dysfunction

Infusion Reactions

  • Herceptin administration can result in serious and fatal infusion reactions
  • Symptoms usually occur during or within 24 hours of Herceptin administration
  • Interrupt Herceptin infusion for dyspnea or clinically significant hypotension
  • Monitor patients until symptoms completely resolve
  • Discontinue Herceptin 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 Herceptin during pregnancy can result in oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death
  • Advise women of the potential hazard to the fetus resulting from Herceptin exposure during pregnancy and provide counseling to women of childbearing potential to use effective contraceptive methods during treatment and for a minimum of six months following Herceptin
  • Advise nursing mothers treated with Herceptin to discontinue nursing or discontinue Herceptin, taking into account the importance of the drug to the mother
  • Encourage women who are exposed to Herceptin during pregnancy to enroll in MotHER—the Herceptin Pregnancy Registry by calling 1-800-690-6720

Pulmonary Toxicity

  • Herceptin administration 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 Herceptin 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 Herceptin in combination with myelosuppressive chemotherapy as compared to those who received chemotherapy alone. The incidence of septic death was similar among patients who received Herceptin and those who did not

HER2 Testing

  • Detection of HER2 protein overexpression is necessary for selection of patients appropriate for Herceptin therapy because these are the only patients studied and for whom benefit has been shown. Due to differences in tumor histopathology, use FDA-approved tests for the specific tumor type (breast or gastric/gastroesophageal adenocarcinoma) to assess HER2 overexpression and HER2 gene amplification. Tests should be performed by laboratories with demonstrated proficiency in the specific technology being utilized

Most Common Adverse Reactions

  • The most common adverse reactions associated with Herceptin in breast cancer were fever, nausea, vomiting, infusion reactions, diarrhea, infections, increased cough, headache, fatigue, dyspnea, rash, neutropenia, anemia, and myalgia
  • The most common adverse reactions associated with Herceptin in metastatic gastric cancer were neutropenia, diarrhea, fatigue, anemia, stomatitis, weight loss, upper respiratory tract infections, fever, thrombocytopenia, mucosal inflammation, nasopharyngitis, and dysgeusia

Please see Herceptin full Prescribing Information for Boxed WARNINGS and additional important safety information.


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Exclusion from Herceptin adjuvant clinical trials based on certain cardiac criteria1

Cardiac exclusion criteria in adjuvant breast cancer trials

In adjuvant breast cancer patients who received Herceptin, certain risk factors were found to be significantly associated with CHF in the Joint Analysis2

Potential risk factors with Herceptin for adjuvant breast cancer treatment

*Defined as New York Heart Association Class III or possible/probable cardiac death.

References
  1. Herceptin Prescribing Information. Genentech, Inc. October 29, 2010.
  2. Tan-Chiu E, Yothers G, Romond E, et al. Assessment of cardiac dysfunction in a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel, with or without trastuzumab as adjuvant therapy in node-positive, human epidermal growth factor receptor 2-overexpressing breast cancer: NSABP B-31. J Clin Oncol. 2005;23:7811-7819.

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Herceptin was associated with lower cardiac-related discontinuation rates when used in a non-anthracycline-containing regimen1

Discontinuation of adjuvant breast cancer treatment with Herceptin due to cardiac-related events1

Discontinuation of adjuvant breast cancer treatment with Herceptin due to cardiac-related events

AC=anthracycline (doxorubicin) plus cyclophosphamide.
T=Taxotere® (docetaxel) (in BCIRG 006) or paclitaxel (in the Joint Analysis).
C=carboplatin (in the TCH regimen).
H=Herceptin.
Taxotere is a registered trademark of sanofi-aventis U.S. LLC.

Discontinuation of Herceptin treatment in BCIRG 006 by phase due to cardiotoxicity1

  • In the AC→TH arm:
    • 1.5% of patients discontinued during the chemotherapy phase
    • 4.2% of patients discontinued during the Herceptin monotherapy phase
  • In the TCH arm:
    • 1.5% of patients discontinued during the chemotherapy phase
    • 1.4% of patients discontinued during the Herceptin monotherapy phase
References
  1. Herceptin Prescribing Information. Genentech, Inc. October 29, 2010.

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Potential cardiotoxicities and their mechanisms1-4

Discontinuation of Herceptin due to symptomatic cardiomyopathy

  • In the HERA trial, 2.6% of patients (44/1678) discontinued Herceptin due to cardiotoxicity1
  • In the BCIRG 006 trial, grade 3/4 cardiac ischemia/infarction was higher in Herceptin-containing regimens (0.3% in AC→TH and 0.2% in TCH) when compared with AC→;T (0%)1
  • In the Joint Analysis, a total of 32 patients receiving Herceptin developed CHF and approximately half of the surviving patients had recovery to a normal LVEF (defined as ≥ 50%) on continuing medical management at the time of last follow-up1

Proposed mechanisms of cardiotoxicity for Herceptin2-4

  • Cardiac pathogenesis is believed to be driven by blocking HER2-initiated cell-repair pathways, preventing damaged myocytes from recovering2,3
  • Cardiotoxicity with Herceptin does not appear to be dose-dependent4

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 Herceptin in combination with myelosuppressive chemotherapy as compared to those who received chemotherapy alone. The incidence of septic death was similar among patients who received Herceptin and those who did not
References
  1. Herceptin Prescribing Information. Genentech, Inc. October 29, 2010.
  2. Ewer MS, Vooletich MT, Durand J-B, et al. Reversibility of trastuzumab-related cardiotoxicity: new insights based on clinical course and response to medical treatment. J Clin Oncol. 2005;23:7820-7826.
  3. Chien KR. Herceptin and the heart-a molecular modifier of cardiac failure. N Engl J Med. 2006;354:789-790.
  4. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344:783-792.

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Incidence of LVEF decline observed across adjuvant trials1

First LVEF decline of ≥10 percentage points from baseline and to <50%* in pivotal Herceptin trials1

Herceptin adjuvant breast cancer adverse events

Boxed WARNING: Cardiomyopathy

  • Herceptin administration can result in sub-clinical and clinical cardiac failure. The incidence and severity was highest in patients receiving Herceptin with anthracycline-containing chemotherapy regimens. In a pivotal adjuvant breast cancer trial, one patient who developed CHF died of cardiomyopathy
  • Discontinue Herceptin treatment in patients receiving adjuvant breast cancer therapy and withhold Herceptin in patients with metastatic disease for clinically significant decrease in left ventricular function
References
  1. Herceptin Prescribing Information. Genentech, Inc. October 29, 2010.

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Cardiac issues associated with Herceptin therapy1

Incidence of CHF in adjuvant HER2+ breast cancer studies1*

Incidence of CHF in adjuvant HER2+ breast cancer studies

References
  1. Herceptin Prescribing Information. Genentech, Inc. October 29, 2010.

Learn about Herceptin dosing and administration in adjuvant breast cancer ›

Indications

Adjuvant Breast Cancer

Herceptin 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 containing doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel
  • With docetaxel and carboplatin
  • As a single agent following multi-modality anthracycline-based therapy

* High-risk is defined as ER/PR positive with one of the following features: tumor size >2 cm, age <35 years, or tumor grade 2 or 3.

Metastatic Breast Cancer

Herceptin is indicated:

  • In combination with paclitaxel for the 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

Metastatic Gastric Cancer

Herceptin 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.


Boxed WARNINGS and Additional Important Safety Information

Cardiomyopathy

  • Herceptin administration can result in sub-clinical and clinical cardiac failure. The incidence and severity was highest in patients receiving Herceptin with anthracycline-containing chemotherapy regimens. In a pivotal adjuvant breast cancer trial, one patient who developed CHF died of cardiomyopathy
  • Herceptin can cause left ventricular cardiac dysfunction, arrhythmias, hypertension, disabling cardiac failure, cardiomyopathy, and cardiac death
  • Herceptin can also cause asymptomatic decline in LVEF
  • Discontinue Herceptin treatment in patients receiving adjuvant breast cancer therapy and withhold Herceptin 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 Herceptin
  • 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 Herceptin treatment
  • Monitor more frequently if Herceptin is withheld for significant left ventricular cardiac dysfunction

Infusion Reactions

  • Herceptin administration can result in serious and fatal infusion reactions
  • Symptoms usually occur during or within 24 hours of Herceptin administration
  • Interrupt Herceptin infusion for dyspnea or clinically significant hypotension
  • Monitor patients until symptoms completely resolve
  • Discontinue Herceptin 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 Herceptin during pregnancy can result in oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death
  • Advise women of the potential hazard to the fetus resulting from Herceptin exposure during pregnancy and provide counseling to women of childbearing potential to use effective contraceptive methods during treatment and for a minimum of six months following Herceptin
  • Advise nursing mothers treated with Herceptin to discontinue nursing or discontinue Herceptin, taking into account the importance of the drug to the mother
  • Encourage women who are exposed to Herceptin during pregnancy to enroll in MotHER—the Herceptin Pregnancy Registry by calling 1-800-690-6720

Pulmonary Toxicity

  • Herceptin administration 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 Herceptin 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 Herceptin in combination with myelosuppressive chemotherapy as compared to those who received chemotherapy alone. The incidence of septic death was similar among patients who received Herceptin and those who did not

HER2 Testing

  • Detection of HER2 protein overexpression is necessary for selection of patients appropriate for Herceptin therapy because these are the only patients studied and for whom benefit has been shown. Due to differences in tumor histopathology, use FDA-approved tests for the specific tumor type (breast or gastric/gastroesophageal adenocarcinoma) to assess HER2 overexpression and HER2 gene amplification. Tests should be performed by laboratories with demonstrated proficiency in the specific technology being utilized

Most Common Adverse Reactions

  • The most common adverse reactions associated with Herceptin in breast cancer were fever, nausea, vomiting, infusion reactions, diarrhea, infections, increased cough, headache, fatigue, dyspnea, rash, neutropenia, anemia, and myalgia
  • The most common adverse reactions associated with Herceptin in metastatic gastric cancer were neutropenia, diarrhea, fatigue, anemia, stomatitis, weight loss, upper respiratory tract infections, fever, thrombocytopenia, mucosal inflammation, nasopharyngitis, and dysgeusia

Please see Herceptin full Prescribing Information for Boxed WARNINGS and additional important safety information.

Herceptin

Herceptin