Trastuzumab

Take this medication exactly as prescribed by your doctor. Follow the directions on your prescription label carefully. The dose your doctor recommends may be based on the following:

• the condition being treated
• other medical conditions you have
• other medications you are taking
• how you respond to this medication
• your weight
• your height
• your age
• your gender

Adjuvant Treatment of HER2-Overexpressing Breast Cancer

• Option 1: Starting dose of 4 mg/kg over 90 minute IV (into the vein) infusion, then 2 mg/kg over 30 minute IV infusion weekly for 52 weeks.
• Option 2: Starting dose of 8 mg/kg over 90 minutes IV (into the vein) infusion, then 6 mg/kg over 30–90 minutes IV infusion every three weeks for 52 weeks.

Metastatic HER2-Overexpressing Breast Cancer

• Starting dose of 4 mg/kg as a 90 minute IV infusion followed by subsequent weekly doses of 2 mg/kg as 30 minute IV infusions.

Metastatic HER2-overexpressing Gastric Cancer

• Starting dose of 8 mg/kg over 90 minutes IV infusion, followed by 6 mg/kg over 30 to 90 minutes IV infusion every 3 weeks.

If you take too much trastuzumab, call your healthcare provider or local Poison Control Center, or seek emergency medical attention right away.

If trastuzumab is administered by a healthcare provider in a medical setting, it is unlikely that an overdose will occur. However, if overdose is suspected, seek emergency medical attention.

Some side effects may occur during the injection. Tell your caregiver right away if you feel dizzy, nauseated, light-headed, weak, short of breath, or if you have a headache, fever, chills, sudden chest pain, wheezing, dry cough, hives, or swelling of your face, lips, tongue, or throat.

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

• shortness of breath (even with mild exertion or while lying down);

• rapid or shallow breathing, grunting, gasping for breath, pain when you breathe;

• blue-colored skin or lips;

• sudden chest pain or discomfort, wheezing, new or worsening cough;

• pounding heartbeats or fluttering in your chest;

• swelling, rapid weight gain;

• fever, swollen gums, painful mouth sores, pain when swallowing, skin sores, cold or flu symptoms; or

• heart attack symptoms--chest pain or pressure, pain spreading to your jaw or shoulder, nausea, sweating.

Common side effects may include:

• nausea, diarrhea, weight loss;

• headache, sleep problems (insomnia), tiredness;

• mouth sores;

• fever, chills, cough, or other signs of infection;

• skin rash, bruising, pale skin;

• altered sense of taste; or

• cold symptoms such as stuffy nose, sinus pain, sore throat.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Other drugs may interact with trastuzumab, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell your doctor about all your current medicines and any medicine you start or stop using.

Warnings/Precautions

Warnings

Risk of cardiotoxicity (e.g., dyspnea [including paroxysmal nocturnal], increased cough, peripheral edema, S3 gallop, cardiomyopathy, CHF, and reduced ejection fraction [decrease of >10%]).1 4 CHF1 may be severe and may result in disabling heart failure, mural thrombosis and stroke, and/or death.1

Discontinue therapy if a clinically important decrease in left ventricular function or CHF occurs.1 18 19 If trastuzumab is used in early breast cancer, therapy interruption may be needed in patients experiencing asymptomatic decreases in left ventricular function.31 Institute appropriate medical therapy if cardiac dysfunction occurs.1 21

Monitor patients closely for signs of cardiotoxicity.1 Perform baseline cardiac evaluation including history, physical examination, and cardiac function tests (i.e., ECG, echocardiogram and/or MUGA scan) prior to initiating therapy.1 Monitor cardiac function frequently.1 14 Closely monitor patients who develop asymptomatic decreases in ejection fraction for signs and symptoms of heart failure.1

Increased risk of cardiac dysfunction in geriatric patients, patients with preexisting cardiac disease, and patients who have had prior cardiotoxic therapy (e.g., anthracycline therapy or radiation therapy to the chest area).1

Extreme caution is advised during trastuzumab therapy for metastatic breast cancer in patients with preexisting cardiac dysfunction.1

Risk of severe and rarely fatal infusion-related reactions (e.g., bronchospasm, dyspnea, hypoxia, severe hypotension) generally with the first dose (possibly during or immediately following the infusion).1 24

Risk of symptoms worsening progressively and leading to further pulmonary complications.1

Risk of marked clinical deterioration following initial improvement in those with acute signs and symptoms.1

Risk of delayed adverse events with rapid clinical deterioration occurring following completion of trastuzumab infusion.1

Severe infusion-related reactions may result in death within hours of the infusion or up to 1 week after the infusion.1

Interrupt infusion and administer supportive therapy (e.g., oxygen, IV fluids, β-adrenergic agonists, corticosteroids) if severe infusion-related reactions occur.1

Subsequent infusions may be tolerated following complete recovery, typically accompanied by prophylactic treatment (e.g., antihistamines and/or corticosteroids); severe reactions may recur despite the use of premedication.1

Preexisting pulmonary compromise may increase risk of serious infusion-related adverse effects.24

Risk of mild to moderate infusion-related symptoms1 (e.g., chills,1 2 fever,1 2 nausea,1 vomiting,1 pain [including at tumor sites],1 rigors,1 headache,1 dizziness,1 dyspnea,1 hypotension,1 rash,1 asthenia)1 occurring during the first infusion or possibly with subsequent infusions.1 4 Administer acetaminophen, diphenhydramine, and/or meperidine, and reduce infusion rate if such infusion-related symptoms occur.1 4 Discontinuance of therapy is required infrequently.1

Risk of severe and rarely fatal adverse respiratory effects (e.g., dyspnea, wheezing, pulmonary infiltrates, pleural effusions, noncardiogenic pulmonary edema, pulmonary insufficiency, hypoxia); may require supplemental oxygen or ventilatory support.1 24 ARDS also may occur.1 (See Boxed Warning.)

Possible increased risk of serious or fatal adverse pulmonary reactions in patients with clinically important preexisting pulmonary compromise secondary to intrinsic lung disease (e.g., asthma, COPD) and/or malignant pulmonary involvement (e.g., lymphangitic spread of tumor, pleural effusions, parenchymal masses) resulting in dyspnea at rest.1 24 Administer with extreme caution in such patients; carefully weigh the risks and benefits of therapy.24

Possible exacerbation of chemotherapy-induced neutropenia (including fatal sepsis associated with neutropenia) in patients receiving trastuzumab in combination with myelosuppressive chemotherapy.1

Risk of leukopenia and anemia especially in those receiving trastuzumab in combination with paclitaxel.1 These reactions occur frequently with combination chemotherapy, but rarely in those receiving monotherapy;1 they are mild to moderate in severity, reversible, and do not require discontinuance of therapy.1

Sensitivity Reactions

Risk of severe hypersensitivity reactions (e.g., fatal anaphylaxis).1 24 Signs and symptoms of hypersensitivity reactions include anaphylaxis, urticaria, bronchospasm, angioedema, and/or hypotension.1 Onset usually during initial infusion, but may occur following completion of an infusion.1

If a severe hypersensitivity reaction occurs, interrupt infusion and administer appropriate medical therapy (e.g., epinephrine, corticosteroids, diphenhydramine, bronchodilators, oxygen).1 Monitor patients carefully until signs and symptoms have resolved completely.1 Discontinuance of therapy should be considered strongly in patients who develop anaphylaxis or angioedema.1 Additional infusions may be tolerated following complete recovery, typically accompanied by prophylactic treatment (e.g., antihistamines, corticosteroids); severe reactions may occur despite the use of premedication.1

Administer with caution in patients with known hypersensitivity to trastuzumab, Chinese Hamster Ovary (CHO) cell proteins, or any component of the formulation.1

General Precautions

Assess breast tumors for HER2 overexpression prior to initiating therapy.1 Fluorescent in situ hybridization (FISH) (e.g., PathVysion), which measures amplification of the HER2 oncogene, and immunohistochemistry (IHC) assays (e.g., HercepTest), which measure overexpression of the HER2 protein are tests most commonly used.9

Ensure accuracy of prescriptions;1001 1002 1005 1006 similarity in generic name of Herceptin (trastuzumab) and Kadcyla (ado-trastuzumab emtansine) may result in medication errors.1001 1004 1005 1006 Such errors may be associated with severe toxicity or lack of appropriate therapy.1001 1004 1005 (See Special Alerts.)

Specific Populations

Category B.1

Distributed into milk in monkeys; not known whether distributed into human milk.1 Discontinue nursing during trastuzumab therapy and for 6 months following the last dose of the drug because of potential risk to nursing infants.1

Safety and efficacy not established in children <18 years of age.1 18

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.1 18 19 Possible increased frequency of cardiotoxicity and cardiac dysfunction compared with younger adults.1 Pharmacokinetics not affected by age.1

Pharmacokinetics are not affected by increased Scr concentrations up to 2 mg/dL.1

Common Adverse Effects

Fever, diarrhea, infections, chills, increased cough, headache, rash, insomnia.1

Specific Drugs

• Inhibits proliferation of tumor cells that overexpress HER2.1 7 The HER2 proto-oncogene encodes a 185-kd transmembrane tyrosine kinase receptor known as p185HER2 or human epidermal growth factor receptor 2 (HER2).1 4 19

• Binds specifically to the extracellular domain of the HER2 receptor or HER2 protein.1

• The HER2 receptor participates in receptor-receptor interactions that regulate cell differentiation, growth, and proliferation.6 7 Overexpression of the HER2 receptor contributes to the process of neoplastic transformation.6 7

• Trastuzumab-mediated antibody-dependent cellular cytotoxicity (ADCC) has been demonstrated and occurs preferentially in cells that overexpress the HER2 protein compared with cells that do not.1

Use this medicine as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• It is given as an infusion into a vein over a period of time.
• Acetaminophen and diphenhydramine may be given before trastuzumab to lower fever and chills.

What do I do if I miss a dose?

• Call your doctor to find out what to do.

• anti-c-erB-2
• anti-ERB-2
• Conventional Trastuzumab
• MOAB HER2
• rhuMAb HER2
• Trastuzumab (Conventional)

Breast cancer, adjuvant treatment: Treatment (adjuvant) of human epidermal growth receptor 2 (HER2)-overexpressing node positive or node negative (estrogen receptor/progesterone receptor negative or with 1 high risk feature) breast cancer as part of a treatment regimen consisting of doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel; with docetaxel and carboplatin; or as a single agent following multimodality anthracycline-based therapy.

Breast cancer, metastatic: First-line treatment of HER2-overexpressing metastatic breast cancer (in combination with paclitaxel); single agent treatment of HER2-overexpressing breast cancer in patients who have received 1 or more chemotherapy regimens for metastatic disease.

Gastric cancer, metastatic: Treatment of HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma (in combination with cisplatin and either capecitabine or 5-fluorouracil) in patients who have not received prior treatment for metastatic disease.

Limitations of use: Patients should be selected for breast and gastric cancer therapy based on an approved companion diagnostic test for tumor specimen for HER2 overexpression or HER2 gene amplification.

HER2-positive metastatic breast cancer (in combination with pertuzumab and docetaxel) in patients who have not received prior anti-HER2 therapy or chemotherapy to treat metastatic disease

Data from a large, randomized, controlled phase III study supports the use of trastuzumab in combination with pertuzumab and docetaxel in the management of metastatic breast cancer [Baselga 2012].

Based on the American Society of Clinical Oncology (ASCO), Systemic Therapy for Patients with Advanced HER2-Positive Breast Cancer guidelines, trastuzumab in combination with pertuzumab and a taxane is recommended as first-line treatment, unless there are contraindications to taxanes.

HER2-positive metastatic breast cancer (in combination with pertuzumab and weekly paclitaxel)

Data from a small phase II study supports the use of trastuzumab in combination with pertuzumab and weekly paclitaxel in the management of metastatic breast cancer [Dang 2015]. Based on the American Society of Clinical Oncology (ASCO), Systemic Therapy for Patients with Advanced HER2-Positive Breast Cancer guidelines, trastuzumab in combination with pertuzumab and a taxane is recommended as first-line treatment, unless there are contraindications to taxanes; paclitaxel is a reasonable alternative in patients who are not good candidates for docetaxel [Giordano 2014].

HER2-positive metastatic breast cancer (in combination with either docetaxel or vinorelbine)

Data from a large phase III study supports the use of trastuzumab (in combination with either docetaxel or vinorelbine) for the treatment of metastatic or locally advanced HER2-positive breast cancer [Andersson 2011]. Additionally, a large randomized phase II trial supports the combination of trastuzumab and docetaxel for the management of metastatic HER2-positive disease [Marty 2005].

HER2 overexpressing metastatic breast cancer (in combination with lapatinib) which had progressed on prior trastuzumab containing therapy

Data from a phase III randomized controlled study supports the use of trastuzumab in combination with lapatinib in the management of metastatic breast cancer which has progressed on prior trastuzumab therapy [Blackwell 2012].

Based on the American Society of Clinical Oncology (ASCO), Systemic Therapy for Patients with Advanced HER2-Positive Breast Cancer guidelines, trastuzumab in combination with lapatinib is a third-line treatment option in patients whose disease has progressed during or after second line or greater HER2-targeted therapy.

Neoadjuvant treatment of HER2-positive locally advanced, inflammatory or early breast cancer

Data from a large randomized phase II study supports the use of trastuzumab in combination with pertuzumab and docetaxel in the neoadjuvant management of HER2-positive locally advanced, inflammatory or early breast cancer [Gianni 2012].

Commonly reported side effects of trastuzumab include: febrile neutropenia, infection, asthenia, dizziness, fever, headache, nausea, pain, skin rash, vomiting, abdominal pain, back pain, diarrhea, flu-like symptoms, insomnia, neutropenia, pharyngitis, rhinitis, chills, and anorexia. Other side effects include: urinary tract infection, anemia, arthralgia, depression, edema, ostealgia, paresthesia, sinusitis, and tachycardia. See below for a comprehensive list of adverse effects.

Administration advice:
-Do not give IV push or bolus.

Storage requirements: Refrigerate

Reconstitution/preparation techniques: The manufacturer product information should be consulted.

IV compatibility:
-Do not mix with other drugs.
-Do not use dextrose (5%) solution.

General:
To prevent medication errors, check the vial labels to ensure that the drug is trastuzumab and not ado-trastuzumab emtansine.

Patient advice:
-Advise patients to immediately report any new onset or worsening shortness of breath, cough, swelling of ankles or legs, swelling of face, palpitations, weight gain of more than 5 pounds in 24 hours, dizziness, or loss of consciousness.
-Advise women that exposure can result in fetal harm.
-Advise women of childbearing potential to use effective contraception during and for a minimum of 6 months after treatment.