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TRASTUZUMAB

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Trastuzumab, a recombinant DNA-derived humanized monoclonal antibody, selectively binds with high affinity in a cell-based assay to the extracellular domain of the human epidermal growth factor receptor 2 protein, HER2.

Specific Substances

    1) HER-2 Monoclonal Antibody
    2) rhuMAb HER2
    3) Trastuzumabum
    4) Traxanoxum
    5) CAS 180288-69-1

Available Forms Sources

    A) FORMS
    1) Trastuzumab is available as a lyophilized, sterile powder nominally containing 440 mg Trastuzumab per vial. Reconstitution with the supplied 20 milliliters of Bacteriostatic Water for Injection, USP, containing 1.1% benzyl alcohol as a preservative yields a solution containing 21 mg/mL trastuzumab (Prod Info HERCEPTIN(R) intravenous solution, 2005).
    B) USES
    1) Trastuzumab is used alone in patients with metastatic breast cancer whose tumors overexpress the HER2 protein and who have received one or more chemotherapy regimens for their metastatic disease. It is also used in combination with paclitaxel to treat patients with metastatic breast cancer whose tumors overexpress the HER2 protein and who have not received chemotherapy for their metastatic disease (Prod Info HERCEPTIN(R) intravenous solution, 2005).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Trastuzumab is used alone in patients with metastatic breast cancer whose tumors overexpress the HER2 protein and who have received one or more chemotherapy regimens for their metastatic disease. It has also been used in combination with other chemotherapeutic agents (ie, paclitaxel, docetaxel, cisplatin and capecitabine or 5-fluorouracil (5-FU), doxorubicin, cyclophosphamide) to treat patients with HER2 overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma, as adjuvant breast cancer therapy or in metastatic breast cancer.
    B) PHARMACOLOGY: In some patients with breast cancer and other malignancies (eg; ovarian, lung), trastuzumab, a recombinant DNA-derived humanized monoclonal antibody, selectively binds with high affinity to the extracellular domain of the human epidermal growth factor receptor 2 protein (HER2). The antibody is an IgG1 kappa that contains human framework regions with murine antibody (4D5) complementarity-determining regions. Trastuzumab causes antibody-dependent cell-mediated cytotoxicity (ADCC) and does not affect cells not overexpressing p185-HER2.
    C) EPIDEMIOLOGY: Overdose is uncommon.
    D) WITH THERAPEUTIC USE
    1) CARDIOVASCULAR: Severe ventricular dysfunction and congestive heart failure have been reported following trastuzumab administration. The incidence and severity of cardiac dysfunction is higher in patients 60 years of age and older, patients who have received cardiotoxic therapy (anthracyclines [a cumulative anthracycline dose equal or greater than 400 mg/m(2)], cyclophosphamide), prior chest wall radiation, and preexisting cardiac disease. Peripheral edema and hypotension have also been reported.
    2) HEMATOLOGIC: Myelosuppression is infrequent following the administration of trastuzumab as a single agent. An increase in anemia, leukopenia, grade 3/4 neutropenia or febrile neutropenia have been observed in patients treated with trastuzumab and other chemotherapeutic agents (ie, capecitabine, 5-FU, cisplatin).
    3) RESPIRATORY: Cough, dyspnea, rhinitis, sinusitis, bronchospasm, pleural effusions, pulmonary infiltrates, acute lung injury, and pulmonary insufficiency and hypoxia have occurred with trastuzumab.
    4) OTHER: Other events include: nausea, vomiting, abdominal pain, diarrhea, fever, infusion reactions, headache, fatigue, dyspnea, rash, acne, renal dysfunction, asthenia, headache, and insomnia may develop.
    5) RARE: Rare cases of severe infusion reactions (ie, anaphylaxis, bronchospasm, angioedema and/or hypotension), including some fatalities have occurred with trastuzumab administration. Symptoms usually occurred during the infusion or within 24 hours of administration. Fever and chills are common during an infusion. Other flu-like symptoms reported during/after an infusion include: headache, nausea, vomiting, back pain, asthenia, rigors, dizziness, hypotension, and rash.
    E) WITH POISONING/EXPOSURE
    1) OVERDOSE: Limited data. The signs and symptoms of an acute overdose are expected to be similar to excessive pharmacologic effects.
    2) MILD TO MODERATE TOXICITY: Nausea, vomiting, abdominal pain, diarrhea, fever, infusion reactions, headache, fatigue, dyspnea, rash, and myalgia may develop.
    3) SEVERE TOXICITY: Cardiotoxicity (ie, congestive heart failure, cardiomyopathy, dysrhythmias) may develop following a significant exposure. Pulmonary toxicity and serious or fatal infusion reactions may occur.
    0.2.20) REPRODUCTIVE
    A) Postmarketing case reports suggest that trastuzumab use during pregnancy may result in an increased risk of oligohydramnios and of oligohydramnios sequence, manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death. No reports describing the use of trastuzumab during human lactation or measuring the amount, if any, of the drug excreted into milk have been located. In animal studies, trastuzumab did not impair female fertility; the effects on male fertility were not studied.
    0.2.21) CARCINOGENICITY
    A) In clinical trials, the incidence of isolated brain metastases was higher in the trastuzumab group (trastuzumab and chemotherapy [doxorubicin plus cyclophosphamide followed by paclitaxel for 4 cycles]) than in the control group (chemotherapy; started with paclitaxel and continued for 1 year).

Laboratory Monitoring

    A) Monitor vital signs.
    B) Institute continuous cardiac monitoring and obtain an ECG.
    C) Monitor serum electrolytes, renal function, CBC and troponin concentrations after significant overdose.
    D) Obtain a chest radiograph and monitor pulse oximetry and/or arterial blood gases in patients with respiratory signs or symptoms.
    E) Obtain an echocardiogram following a significant exposure to assess left ventricular ejection fraction.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) Trastuzumab is available only for intravenous use.
    B) Treatment should include recommendations listed in the PARENTERAL EXPOSURE section when appropriate.
    0.4.6) PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Treat persistent nausea and vomiting with several antiemetics of different classes and IV fluids as needed. Treat significant diarrhea with antidiarrheal agents. Monitor for dyspnea or clinically significant hypotension.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. CARDIOVASCULAR: Cardiac dysfunction is the most significant toxicity that can occur with trastuzumab therapy. A decrease in left ventricular ejection fraction can occur. Treat congestive heart failure with ACE inhibitors, beta-blockers, diuretics, aldosterone receptor antagonists. Other therapies for heart failure may include anticoagulants and antiarrhythmic agents as clinically necessary. Obtain an echocardiogram to assess left ventricular ejection fraction.
    C) INTRATHECAL INJECTION
    1) BACKGROUND: Intrathecal trastuzumab has been used in a limited number of patients with leptomeningeal carcinomatosis in HER2-overexpressing metastatic breast cancer. It has been used as monotherapy or given concurrently with intrathecal thiotepa or methotrexate. The typical schedule is 20 to 30 mg weekly (range: 5 to 100 mg); the doses were well tolerated. There have been no reports of inadvertent intrathecal injection with trastuzumab. THERAPY: The following recommendations are based on experience with other antineoplastic drugs in the event of an overdose. If a large intrathecal overdose occurs, keep the patient upright and immediately drain at least 20 mL of CSF; drainage of up to 70 mL has been tolerated in adults. Follow with CSF exchange (remove serial 20 mL aliquots CSF and replace with equivalent volumes of warmed, preservative free saline). Consult a neurosurgeon for placement of a ventricular catheter and begin ventriculolumbar perfusion (infuse warmed preservative free normal saline through ventricular catheter, drain fluid from lumbar catheter; typical volumes 80 to 150 mL/hr for 24 hours). Dexamethasone 4 mg IV every 6 hours to prevent arachnoiditis.
    D) DECONTAMINATION
    1) Gastrointestinal decontamination is not necessary as trastuzumab is administered intravenously. For dermal exposures, clean skin with soap and water, and for eye exposures, flush with water.
    E) AIRWAY MANAGEMENT
    1) Intubate if patient is unable to protect airway or if unstable due to cardiac toxicity, an infusion reaction, severe respiratory distress syndrome, or CNS depression.
    F) ANTIDOTE
    1) None.
    G) NAUSEA AND VOMITING
    1) Treat severe nausea and vomiting with agents from several different classes. For example: dopamine (D2) receptor antagonists (eg, metoclopramide), phenothiazines (eg, prochlorperazine, promethazine), 5-HT3 serotonin antagonists (eg, dolasetron, granisetron, ondansetron), benzodiazepines (eg, lorazepam), corticosteroids (eg, dexamethasone), and antipsychotics (eg, haloperidol, olanzapine).
    H) MUCOSITIS
    1) Treat mild mucositis with bland oral rinses with 0.9% saline, sodium bicarbonate, and water. For moderate cases with pain, consider adding a topical anesthetic (eg, lidocaine, benzocaine, dyclonine, diphenhydramine, or doxepin). Treat moderate to severe mucositis with topical anesthetics and systemic analgesics. Patients with mucositis and moderate xerostomia may receive sialagogues (eg, sugarless candy/mints, pilocarpine/cevimeline, or bethanechol) and topical fluorides to stimulate salivary gland function. Consider prophylactic antiviral and antifungal agents to prevent infections. Topical oral antimicrobial mouthwashes, rinses, pastilles, or lozenges may be used to decrease the risk of infection. Palifermin is indicated to reduce the incidence and duration of severe oral mucositis in patients with hematologic malignancies receiving myelotoxic therapy requiring hematopoietic stem cell support. It has not been studied in the setting of chemotherapy overdose. In patients with trastuzumab overdose, consider administering palifermin 60 mcg/kg/day IV bolus injection starting 24 hours after the overdose for 3 consecutive days.
    I) ENHANCED ELIMINATION
    1) It is unlikely that hemodialysis would be useful after overdose because of the size of trastuzumab.
    J) PATIENT DISPOSITION
    1) HOME CRITERIA: There is no data to support home management.
    2) ADMISSION CRITERIA: Patients should be closely monitored in an inpatient setting, with frequent monitoring of vital signs (every 4 hours for the first 24 hours), cardiac monitoring, and daily monitoring of CBC.
    3) CONSULT CRITERIA: Consult an oncologist, medical toxicologist and/or poison center for assistance in managing patients with an overdose.
    4) TRANSFER CRITERIA: Patients with large overdoses or severe neutropenia may benefit from early transfer to a cancer treatment or bone marrow transplant center.
    K) PITFALLS
    1) Symptoms of overdose are likely similar to reported side effects of trastuzumab. Early symptoms of overdose may be delayed or not evident (ie, congestive heart failure), so reliable follow-up is imperative. Patients taking trastuzumab may have severe co-morbidities and may be receiving other drugs that may produce synergistic effects (ie, cardiotoxicity, myelosuppression).
    L) PHARMACOKINETICS
    1) Trastuzumab is a humanized IgG1 kappa monoclonal antibody that selectively binds with high affinity to the extracellular domain of the human epidermal growth factor receptor 2 protein, HER2. It is produced by recombinant DNA. Volume of distribution is 44 mL/kg. METASTATIC BREAST CANCER: In women with metastatic breast cancer receiving intravenous infusions of 10 to 500 mg, the half-life averaged 2 and 12 days, respectively. In general, mean half-life increased and clearance decreased with increasing dose level. ADJUVANT THERAPY: In women receiving an initial dose of 8 mg/kg followed by a dose of 6 mg/kg every 3 weeks, a mean half-life of 16 days (range: 11 to 23 days) was observed.
    M) DIFFERENTIAL DIAGNOSIS
    1) Clinical events may be related to other chemotherapeutic agents that may be used in combination with trastuzumab therapy (ie, cardiac toxicity (eg, anthracyclines) or myelosuppression (eg, paclitaxel). Preexisting heart disease or a borderline or low left ventricular ejection fraction.

Range Of Toxicity

    A) TOXICITY: A lethal human dose has not been established.
    B) THERAPEUTIC DOSE: INTRAVENOUS: ADULT: Therapeutic dose is 4 mg/kg infused intravenously over 90 minutes followed by weekly infusions 2 mg/kg over 30 minutes. Maximum: Single doses higher than 8 mg/kg have not been administered. INTRATHECAL: Limited experience. Intrathecal trastuzumab has been used in a limited number of patients with leptomeningeal carcinomatosis (a rare manifestation of metastatic breast cancer) in HER2-overexpressing metastatic breast cancer. It has been used as monotherapy or given concurrently with intrathecal thiotepa or methotrexate. The typical schedule is 20 to 30 mg weekly (range: 5 to 100 mg); doses were well tolerated. PEDIATRIC: The safety and efficacy of trastuzumab in pediatric patients has not been established.

Clinical Effects

Summary Of Exposure

    A) USES: Trastuzumab is used alone in patients with metastatic breast cancer whose tumors overexpress the HER2 protein and who have received one or more chemotherapy regimens for their metastatic disease. It has also been used in combination with other chemotherapeutic agents (ie, paclitaxel, docetaxel, cisplatin and capecitabine or 5-fluorouracil (5-FU), doxorubicin, cyclophosphamide) to treat patients with HER2 overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma, as adjuvant breast cancer therapy or in metastatic breast cancer.
    B) PHARMACOLOGY: In some patients with breast cancer and other malignancies (eg; ovarian, lung), trastuzumab, a recombinant DNA-derived humanized monoclonal antibody, selectively binds with high affinity to the extracellular domain of the human epidermal growth factor receptor 2 protein (HER2). The antibody is an IgG1 kappa that contains human framework regions with murine antibody (4D5) complementarity-determining regions. Trastuzumab causes antibody-dependent cell-mediated cytotoxicity (ADCC) and does not affect cells not overexpressing p185-HER2.
    C) EPIDEMIOLOGY: Overdose is uncommon.
    D) WITH THERAPEUTIC USE
    1) CARDIOVASCULAR: Severe ventricular dysfunction and congestive heart failure have been reported following trastuzumab administration. The incidence and severity of cardiac dysfunction is higher in patients 60 years of age and older, patients who have received cardiotoxic therapy (anthracyclines [a cumulative anthracycline dose equal or greater than 400 mg/m(2)], cyclophosphamide), prior chest wall radiation, and preexisting cardiac disease. Peripheral edema and hypotension have also been reported.
    2) HEMATOLOGIC: Myelosuppression is infrequent following the administration of trastuzumab as a single agent. An increase in anemia, leukopenia, grade 3/4 neutropenia or febrile neutropenia have been observed in patients treated with trastuzumab and other chemotherapeutic agents (ie, capecitabine, 5-FU, cisplatin).
    3) RESPIRATORY: Cough, dyspnea, rhinitis, sinusitis, bronchospasm, pleural effusions, pulmonary infiltrates, acute lung injury, and pulmonary insufficiency and hypoxia have occurred with trastuzumab.
    4) OTHER: Other events include: nausea, vomiting, abdominal pain, diarrhea, fever, infusion reactions, headache, fatigue, dyspnea, rash, acne, renal dysfunction, asthenia, headache, and insomnia may develop.
    5) RARE: Rare cases of severe infusion reactions (ie, anaphylaxis, bronchospasm, angioedema and/or hypotension), including some fatalities have occurred with trastuzumab administration. Symptoms usually occurred during the infusion or within 24 hours of administration. Fever and chills are common during an infusion. Other flu-like symptoms reported during/after an infusion include: headache, nausea, vomiting, back pain, asthenia, rigors, dizziness, hypotension, and rash.
    E) WITH POISONING/EXPOSURE
    1) OVERDOSE: Limited data. The signs and symptoms of an acute overdose are expected to be similar to excessive pharmacologic effects.
    2) MILD TO MODERATE TOXICITY: Nausea, vomiting, abdominal pain, diarrhea, fever, infusion reactions, headache, fatigue, dyspnea, rash, and myalgia may develop.
    3) SEVERE TOXICITY: Cardiotoxicity (ie, congestive heart failure, cardiomyopathy, dysrhythmias) may develop following a significant exposure. Pulmonary toxicity and serious or fatal infusion reactions may occur.

Vital Signs

    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) Fever is a common adverse event of trastuzumab therapy (Prod Info HERCEPTIN(R) intravenous infusion, 2010). Fever and chills have been reported in up to 40% of patients following trastuzumab therapy (Yeon & Pegram, 2005; Emens, 2005; Marty et al, 2005).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) CARDIOMYOPATHY
    1) WITH THERAPEUTIC USE
    a) SUMMARY
    1) Severe ventricular dysfunction and congestive heart failure have been reported following trastuzumab administration. The incidence and severity of cardiac dysfunction is higher in patients 60 years of age and older, patients who have received cardiotoxic therapy (anthracyclines [a cumulative anthracycline dose equal or greater than 400 mg/m(2)], cyclophosphamide), prior chest wall radiation, and preexisting cardiac disease. Patients may develop asymptomatic declines in left ventricular ejection fraction (LVEF), clinically manageable congestive heart failure (CHF) or severe CHF (Prod Info HERCEPTIN(R) intravenous infusion, 2010; Telli et al, 2007; Emens, 2005; Youssef & Links, 2005).
    2) The cardiotoxicity with trastuzumab is not dose-related. In clinical trials, the incidence of cardiac dysfunction (symptomatic and asymptomatic) following the concurrent therapy of trastuzumab with an anthracycline and cyclophosphamide was approximately 28% as compared with approximately 8% with anthracycline and cyclophosphamide alone. The incidence of cardiac dysfunction following the concurrent therapy of trastuzumab and paclitaxel was 13% as opposed to 1% when paclitaxel was given alone (Youssef & Links, 2005).
    3) Although the pathogenesis of trastuzumab-related cardiac dysfunction is poorly understood, it may be through a direct cardiotoxic effect via interaction with the cardiac HER-2/neu receptor. Another study suggested that trastuzumab is not cardiotoxic by itself but interferes with remodeling after anthracycline-induced injury (Prod Info HERCEPTIN(R) intravenous solution, 2005; Emens, 2005; Youssef & Links, 2005). In a meta-analysis (5 trials with 515 eligible patients) to assess the benefit and toxicity of trastuzumab combined with neoadjuvant chemotherapy in HER2-positive breast cancer, less than 1% of patients with neoadjuvant trastuzumab presented with congestive heart failure. In most eligible studies, trastuzumab was combined with anthracyclines (Valachis et al, 2011).
    a) RISK FACTORS: Based on a systematic review of the literature, potential risk factors associated with the development of trastuzumab-induced cardiotoxicity include: older age, concurrent or prior use of anthracycline(s), and previous history of cardiac disease. The sequence in which chemotherapy is given may also affect the development of cardiotoxicity (Sengupta et al, 2008).
    4) PREVALENCE: The prevalence of trastuzumab-induced cardiotoxicity was 10%, based on a pooled analysis from randomized controlled trials and case controlled studies. This compared to a 2% pooled prevalence in the comparator arm of those patients not receiving trastuzumab. In another metaanalysis of 5 randomized controlled trials, patients treated with trastuzumab for one year were at increased risk to develop severe CHF as compared to the control group. An absolute difference of 1.61% (p less than .00001) was observed (or, if 62 patients were treated one would develop an adverse effect) (Sengupta et al, 2008).
    5) OUTCOME: In a review of the literature, of those patients that developed cardiotoxicity most patients improved once therapy was discontinued. In a study of 38 patients with trastuzumab-induced cardiotoxicity, mean time to recovery of left ventricular function was 1.5 months after therapy was discontinued. Cardiac deaths related to trastuzumab therapy are rare (Sengupta et al, 2008).
    b) ADJUVANT BREAST CANCER
    1) BENEFIT VS RISK: In a review of the major adjuvant trastuzumab trials (ie, National Surgical Adjuvant Breast and Bowel Project B-31 (NSABP B-31), North Central Cancer Treatment Group trial N9831, Herceptin Adjuvant [HERA] trial, Breast Cancer International Research group [BCIRG] trial and the Finland Herceptin [FinHER] trial), up to 4% of patients developed severe CHF during trastuzumab therapy. The NSABP B-31 trial found that for every 30 women treated with trastuzumab, one woman would develop a cardiac event (ie, cardiac death or severe NYHA class III/IV CHF at 3 years). Cardiac dysfunction will also occur in 1 of 5 women requiring discontinuation of therapy. The course of trastuzumab cardiotoxicity remains unknown and its difficult to determine the 10-year risk of a cardiac event (Telli et al, 2007).
    2) According to a combined interim analysis of data from the National Surgical Adjuvant Breast and Bowel Project B-31 (NSABP-B31) and North Central Cancer Treatment Group trial N9831, an increased incidence of cardiotoxicity has been observed in patients treated with trastuzumab in conjunction with standard chemotherapy as compared to patients who received chemotherapy alone. In the randomized phase III trials, women with operable, HER2-overexpressing breast cancer and without active cardiac disease or history of such disease received a chemotherapy regimen which included 4 cycles of doxorubicin and cyclophosphamide followed by 4 cycles of paclitaxel at 3-week intervals; patients were assigned to treatment with 1 year of trastuzumab therapy (at the approved dose and schedule) in addition to and following paclitaxel therapy (n=1672) or to paclitaxel therapy alone (n=1679). A significantly greater 3-year cumulative incidence of New York Heart Association (NYHA) class III or IV congestive heart failure (CHF) or death from cardiac causes was seen in trastuzumab-treated patients as compared with the control group (4.1% vs 0.8%, respectively). Of the 31 patients in the trastuzumab group who developed CHF, 27 were followed for at least 6 months after the onset and only 1 reported persistent symptoms. In N9831, the 3-year cumulative incidence of NYHA class III or IV CHF or death from cardiac causes was 0% in the control group versus 2.9% in the trastuzumab group. All of these patients had CHF, while 1 died of cardiomyopathy (Romond et al, 2005). In addition, 30.5% of evaluable trastuzumab-treated patients in the NSABP-B31 trial needed at least 1 dose delay due to an asymptomatic reduction in left ventricular ejection fraction (LVEF) and 18.6% of patients in the trastuzumab group stopped therapy as a result of asymptomatic decreased LVEF and symptomatic cardiac dysfunction or other cardiac toxicity. No cardiac deaths occurred in trastuzumab-treated patients, while one death was reported in the control group (Anon, 2005).
    3) Interim analysis from the Herceptin Adjuvant (HERA) trial reported an increased incidence of severe congestive heart failure (CHF) in patients who received trastuzumab (administered every 3 weeks) sequentially for 1 year after chemotherapy (n=1677) compared to patients who received chemotherapy without trastuzumab (n=1710). Severe CHF, defined as New York Heart Association class III or IV and a decrease in the left ventricular ejection fraction (LVEF) of 10 percentage points or more from baseline to an LVEF of less than 50%, occurred in 0.54% of patients who received trastuzumab versus 0% of patients in the control group (p=0.002). Symptomatic CHF, including severe CHF, occurred in 1.73% and 0.06% in the trastuzumab and control groups, respectively (p less than 0.001). A decrease in the LVEF of 10 percentage points or more from baseline to an LVEF of less than 50% at any time occurred in 7.08% of patients in the trastuzumab group compared to 2.21% of patients in the control group (p less than 0.001) (Piccart-Gebhart et al, 2005).
    c) METASTATIC BREAST CANCER
    1) SUMMARY
    a) A retrospective analysis of the phase II trial (Cobleigh et al, 1999) and phase III trial (Slamon et al, 2001) upon which the indication for the use of trastuzumab is based was performed by an independent Cardiac Review and Evaluation Committee (CREC). Cardiac dysfunction was defined as any 1 of the following: 1) cardiomyopathy with a fall in cardiac ejection fraction that was either global or more severe in the septum; 2) symptoms of congestive heart failure; 3) signs of congestive heart failure, including but not limited to, S3 gallop and/or tachycardia; 4) decline in cardiac ejection fraction of at least 5 points below 55% with signs and symptoms, or decline in cardiac ejection fraction of at least 10 points below 55% without signs and symptoms (Pers Comm, 2002).
    2) MONOTHERAPY
    a) LACK OF EFFECT: In one study, 116 patients received trastuzumab as a first-line agent with no other known cardiotoxic agents given. No clinical evidence of heart failure or LV dysfunction were observed in any patient (Sengupta et al, 2008).
    b) In a phase II trial of single-agent trastuzumab as first-line therapy of metastases of HER2+ breast cancer (n=113), cardiac dysfunction developed in 3 patients (2.6%). Prior adjuvant chemotherapy was reported in 68% of patients; 51% of patients had received anthracyclines as adjuvant therapy. Trastuzumab was discontinued in 2 of the 3 patients with cardiac dysfunction due to adverse events (Pers Comm, 2002; Vogel et al, 2001).
    c) In a study of patients with HER2+ metastatic breast cancer that had progressed after chemotherapy (n=222), cardiac dysfunction developed in 4.7% (n=10) patients after treatment with single- agent trastuzumab. Nine patients had received prior anthracycline therapy and 6 patients had received a cumulative anthracycline dose of more than 400 mg/m(2) of doxorubicin; the tenth patient had significant cardiac disease without prior anthracycline exposure at study entry. Six of 8 patients who continued to receive trastuzumab maintained stable cardiac function. Two patients had asymptomatic decline in left ventricular ejection fraction (LVEF). One patient with cumulative doxorubicin dose of 450 mg/m(2) and baseline LVEF of 60% experienced 2 episodes of severe cardiac dysfunction after 18 weekly doses of trastuzumab; she responded to medical therapy but died 2 days after her last trastuzumab infusion presumably due to a ventricular arrhythmia (Pers Comm, 2002; Cobleigh et al, 1999).
    3) COMBINATION THERAPY
    a) A pilot trial examined the cardiac effects of PACLITAXEL plus TRASTUZUMAB PRIOR TO DOXORUBICIN plus CYCLOPHOSPHAMIDE in stage II breast cancer patients (n=234). Patients were HER-2-positive (immunohistochemical staining 2+ or 3+) and received paclitaxel (175 mg/m(2) every 3 weeks for 4 courses) plus trastuzumab (4 mg/m(2) loading dose followed by 2 mg/m(2) weekly for 9 weeks). A decrease in left ventricular ejection fraction (LVEF) of 10% or greater from baseline developed in 9.5% of patients following paclitaxel and trastuzumab; LVEF dropped to below the lower limit of normal in 4 of 189 patients. Patients then received either 4 cycles of standard doses of doxorubicin plus cyclophosphamide or weekly trastuzumab for 52 weeks. Decreases of 10% or greater in LVEF occurred in 12.5% of patients after doxorubicin and cyclophosphamide; LVEF dropped to below the lower limit of normal in 7 of 128 patients (Sledge et al, 2001).
    b) Other phase II and III studies have also reported cardiotoxicity when trastuzumab was used with or without chemotherapy (Slamon et al, 2001; Tripathy et al, 2001; Seidman et al, 2001).
    B) CARDIAC ARREST
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 58-year-old previously healthy woman with HER2 positive metastatic breast cancer was initially treated with epirubicin for 6 months with no evidence of cardiac toxicity. Seven months after diagnosis, she had evidence of relapse with jaundice and metastatic liver disease. Further therapy included capecitabine followed by trastuzumab (3 cycles of 430 mg every 3 weeks). Cardiac studies prior to therapy were normal with no history of cardiac disease. Four weeks after completing her third course of trastuzumab therapy, the patient developed sudden ventricular fibrillation cardiac arrest; no prior cardiac symptoms. The patient was resuscitated, but suffered hypoxic brain injury. Care was withdrawn and the patient died 5 days later. Autopsy showed a normal heart and coronary vessels with no evidence of tumor. Electron microscopy showed intracellulare edema and the accumulation of lipid droplets in the cytoplasm of myocytes but no evidence of anthracycline toxicity (no vacuolated cells) (Suvarna, 2008).
    C) PERIPHERAL EDEMA
    1) WITH THERAPEUTIC USE
    a) Peripheral edema, as a sign of cardiac dysfunction has been reported in patients treated with trastuzumab (Prod Info HERCEPTIN(R) intravenous infusion, 2010).
    D) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Hypotension has occurred with trastuzumab administration (Anon, 2000).
    E) MITRAL VALVE REGURGITATION
    1) WITH THERAPEUTIC USE
    a) CASE REPORTS: A 43-year-old woman with ductal breast carcinoma and no cardiovascular risk factors was treated with 8 courses (6 mg/kg every 3 weeks) of trastuzumab therapy. A baseline, echocardiography was normal, and a repeat study done after 8 courses revealed a normal ejection fraction, but a new onset of mitral regurgitation (MR). No chordae tendineae rupture was observed. Eccentric MR was thought to be due to a delay of the postmedullary muscle that developed secondary to a decrease posterior wall strain. Trastuzumab was discontinued and at follow-up 14 weeks later, an echocardiography showed that mitral failure was mild (Karabay et al, 2010).
    1) In a second case, a woman with ductal breast cancer and no cardiovascular risk factors was initially treated with a total of 175 mg/m(2) of doxorubicin and was then treated with 8 courses (6 mg/kg every 3 weeks) of trastuzumab. Following the 8 week course, echocardiography showed a normal ejection fraction with moderate posterior eccentric MR. Other studies were normal. The patient had a delayed posterior papillary strain which led to eccentric mitral failure. Trastuzumab was stopped and mild mitral failure was observed at 10 weeks (Karabay et al, 2010).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) RESPIRATORY FINDING
    1) WITH THERAPEUTIC USE
    a) Pulmonary events, including adult respiratory distress syndrome and death have been reported with trastuzumab administration. Bronchospasm, dyspnea, wheezing, pleural effusions, pulmonary infiltrates, noncardiogenic pulmonary edema, and pulmonary insufficiency and hypoxia requiring supplemental oxygen or ventilatory support have been reported with trastuzumab. Most patients with fatal events had significant preexisting pulmonary compromise secondary to intrinsic lung disease and/or malignant pulmonary involvement (Prod Info HERCEPTIN(R) intravenous infusion, 2010; Ahamed et al, 2009; Yeon & Pegram, 2005; Anon, 2005).(Emens, 2005; Anon, 2000).
    b) Cough (26%), dyspnea (22%), rhinitis (14%), and sinusitis (9%) have been reported in breast cancer patients receiving single-agent trastuzumab at the recommended dosing regimen (Prod Info HERCEPTIN(R) intravenous infusion, 2010; Cobleigh et al, 1998; Cobleigh, 1998a).
    c) Rare reports of pneumonitis and pulmonary fibrosis have been reported in patients treated with trastuzumab (Prod Info HERCEPTIN(R) intravenous infusion, 2010).
    d) CASE REPORT: A 56-year-old woman with a history of breast cancer had been recently treated with radiotherapy and a 3-weekly adjuvant trastuzumab therapy (4 previous courses of trastuzumab), presented with fever and cough with diminished breath sounds. Chest x-ray showed consolidation in the left lower lobe. She was empirically treated with antibiotics with no improvement. Blood and sputum cultures and serology studies were negative. A high resolution CT was consistent with bilateral organizing pneumonia. A bronchoscopy showed moderate acute and chronic inflammatory changes and chronic inflammatory infiltrates (lymphocytes and plasma cells); no endobronchial lesion was found. Organizing pneumonia associated with trastuzumab was successfully treated with steroid therapy; she was successfully rechallenged with trastuzumab (Ahamed et al, 2009).
    B) INTERSTITIAL PNEUMONIA
    1) WITH THERAPEUTIC USE
    a) In the National Surgical Adjuvant Breast and Bowel Project B-31 (NSABP-B31) in which women received chemotherapy (doxorubicin plus cyclophosphamide followed by paclitaxel for 4 cycles) with or without trastuzumab (started with paclitaxel and continued for 1 year) for the adjuvant treatment of early breast cancer, 4 patients in the trastuzumab group (n=864) developed interstitial pneumonitis with the death of 1 patient. No patients in the control group (n=872) developed interstitial pneumonitis (Romond et al, 2005).
    b) In the North Central Cancer Treatment Group trial N9831 in which women received chemotherapy (doxorubicin plus cyclophosphamide followed by paclitaxel for 4 cycles) with or without trastuzumab (started with paclitaxel and continued for 1 year) for the adjuvant treatment of early breast cancer, 5 patients in the trastuzumab group (n=808) developed grade 3+ interstitial pneumonitis or pulmonary infiltrates, with the death of 1 patient. No patients in the control group (n=807) developed interstitial pneumonitis (Romond et al, 2005).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM FINDING
    1) WITH THERAPEUTIC USE
    a) Asthenia (35% to 42%), headache (26% to 40%), and insomnia (14%) have been reported in breast cancer patients receiving single-agent trastuzumab at the recommended dosing regimen (Yeon & Pegram, 2005; Emens, 2005; Prod Info HERCEPTIN(R) intravenous solution, 2005).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Nausea (33%), vomiting (23%) and abdominal pain (22%) have been reported during or after infusion in breast cancer patients (n=352) receiving single-agent trastuzumab at the recommended dosing regimen (Prod Info HERCEPTIN(R) intravenous infusion, 2010; Yeon & Pegram, 2005; Emens, 2005).
    B) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Diarrhea (25%) has been reported during or after infusion in breast cancer patients (n=352) receiving single-agent trastuzumab at the recommended dosing regimen (Prod Info HERCEPTIN(R) intravenous infusion, 2010).
    C) STOMATITIS
    1) WITH THERAPEUTIC USE
    a) In a clinical trial of patients with metastatic gastric cancer, all grades of stomatitis occurred in 72 (24%) patients (n=294) treated with trastuzumab in combination with a fluoropyrimidine (capecitabine or 5-fluorouracil) compared to 43 (15%) patients (n=290) in the fluoropyrimidine group (Prod Info HERCEPTIN(R) intravenous infusion, 2010).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) NEPHROTIC SYNDROME
    1) WITH THERAPEUTIC USE
    a) Rare cases of nephrotic syndrome have been reported in patients receiving trastuzumab; onset ranged from 4 months to 18 months from initiation of therapy. Pathologic findings included membranous glomerulonephritis, focal glomerulosclerosis, and fibrillary glomerulonephritis. Congestive heart failure and volume overload were complications (Prod Info HERCEPTIN(R) intravenous infusion, 2010).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) HEMATOLOGY FINDING
    1) WITH THERAPEUTIC USE
    a) SINGLE AGENT
    1) Hematologic toxicity is infrequent following the administration of trastuzumab as a single agent, with an incidence of Grade III toxicities for white blood cell, platelets, hemoglobin all less than 1% (Prod Info HERCEPTIN(R) intravenous solution, 2005).
    b) COMBINATION THERAPY
    1) An increased per patient incidence of anemia (28% versus 21%), leukopenia (52% versus 34%), grade 3/4 neutropenia (32% versus 22%) and febrile neutropenia (23% versus 17%) has been observed (Prod Info HERCEPTIN(R) intravenous infusion, 2010; Emens, 2005).
    2) Septic death has been reported in patients with severe neutropenia receiving combination trastuzumab and chemotherapy; clinical trials show no significant increased incidence (Prod Info HERCEPTIN(R) intravenous infusion, 2010).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) DERMATOLOGICAL FINDING
    1) WITH THERAPEUTIC USE
    a) Rash (18%) and acne (2%) have been reported in breast cancer patients receiving single-agent trastuzumab at the recommended dosing regimen (Prod Info HERCEPTIN(R) intravenous infusion, 2010).
    b) Mild eczema has been reported infrequently with trastuzumab therapy (Bonny et al, 2011).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) BONE PAIN
    1) WITH THERAPEUTIC USE
    a) In a phase l dose-escalation study of trastuzumab in patients with metastatic breast cancer (overexpressing the HER2 proto-oncogene) refractory to chemotherapy, one patient with no history of bone metastasis developed severe generalized bone pain (grade 3) after receiving a dose of 8 mg/kg. Symptoms resolved within 8 hours, but therapy was discontinued (Tokuda et al, 1999).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) HYPERSENSITIVITY REACTION
    1) WITH THERAPEUTIC USE
    a) Severe hypersensitivity reactions (anaphylaxis, bronchospasm, angioedema and/or hypotension) have occurred with trastuzumab therapy; reactions are usually seen during the first infusion and some have been fatal. Data are lacking on the retreatment of patients with trastuzumab that have experienced a hypersensitivity reaction. However, most patients that were retreated with trastuzumab received prophylactic premedications (antihistamines and/or corticosteroids) (Prod Info HERCEPTIN(R) intravenous infusion, 2010; Yeon & Pegram, 2005).
    B) IMMUNE SYSTEM FINDING
    1) WITH THERAPEUTIC USE
    a) Formation of neutralizing antibodies following trastuzumab administration is rare (Cobleigh, 1998a) and attributed to humanization of the protein.
    b) No antibody was detected after 748 doses of trastuzumab in one study (weekly dosing for seven months) (Pegram et al, 1998a).

Reproductive

    3.20.1) SUMMARY
    A) Postmarketing case reports suggest that trastuzumab use during pregnancy may result in an increased risk of oligohydramnios and of oligohydramnios sequence, manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death. No reports describing the use of trastuzumab during human lactation or measuring the amount, if any, of the drug excreted into milk have been located. In animal studies, trastuzumab did not impair female fertility; the effects on male fertility were not studied.
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY REGISTRY
    1) Prescribers can enroll patients exposed to trastuzumab during pregnancy or within 7 months of conception in the MotHER Registry by calling 1-800-690-6720 or in the Genentech pharmacovigilance program by calling 1-888-835-2555 (Prod Info HERCEPTIN(R) intravenous infusion powder, 2016).
    B) CONTRACEPTION
    1) Advise women that trastuzumab can cause fetal harm when administered during pregnancy. Before beginning treatment, check the pregnancy status of females of reproductive potential and recommend contraception during and for 7 months after ending therapy. (Prod Info HERCEPTIN(R) intravenous infusion powder, 2016).
    C) FETAL COMPLICATIONS
    1) A meta-analysis that included 18 pregnancies and 19 newborns total was performed to evaluate the safety of trastuzumab during pregnancy. A mean total dose of 2853 mg of trastuzumab was administered (range, 523 to 4200 mg). The most common complication reported was oligohydramnios or anhydramnios, which was observed in 11 of 18 pregnancies. Oligohydramnios or anhydramnios was reported in 11 of 15 patients receiving trastuzumab in the second or third trimesters. However, it was not seen in any of the 3 patients receiving trastuzumab in the first trimester only. All 3 newborns who were exposed to trastuzumab during the first trimester were healthy at birth, as well as at the 9-month follow-up. Four of the 16 fetuses exposed to trastuzumab during the second or third trimesters died either at birth or in the first 5 months of life. Likewise, the frequency of trastuzumab administration (weekly vs 3-week intervals) was not statistically associated with fetal complications or mortality (Zagouri et al, 2013).
    D) OLIGOHYDRAMNIOS
    1) According to postmarketing case reports, trastuzumab use during pregnancy can increase the risk of oligohydramnios and of oligohydramnios sequence, manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death. Oligohydramnios was reported in women treated with trastuzumab alone or in combination with chemotherapy. In some cases, the amniotic fluid index increased after trastuzumab was discontinued. In one case report, oligohydramnios recurred when trastuzumab therapy was resumed following amniotic fluid index improvement. The efficacy of IV hydration in the management of oligohydramnios due to trastuzumab treatment is unknown (Prod Info HERCEPTIN(R) intravenous injection, 2015).
    E) SPONTANEOUS ABORTION
    1) In the phase 3 randomized clinical HERA trial of patients who received adjuvant trastuzumab therapy for HER2-positive breast cancer (n=5102), spontaneous abortion occurred in 4/16 patients (25%) who became pregnant during and up to 3 months after treatment (Group 1) and in 7/45 patients (16%) who became pregnant more than 3 months (mean interval, 32 months) after treatment discontinuation (Group 2), compared with no spontaneous abortions in 9 pregnancies of patients who were not exposed to trastuzumab. Fetal measurements (Apgar, weight, and length) were normal across the 3 groups and no oligohydramnios occurred in Groups 1 or 2. One child was born with Down syndrome in Group 2 to a 43-year-old mother more than 5 years after completing trastuzumab therapy. One infant was born with partial fusion of the second and third toes to a mother who was not exposed to trastuzumab (group 3) (Azim et al, 2012).
    F) ANIMAL STUDIES
    1) MONKEYS: No teratogenic effects were seen in the offspring of cynomolgus monkeys administered trastuzumab during organogenesis at exposures up to 25 times the recommended weekly human dose of 2 mg/kg (Prod Info HERCEPTIN(R) intravenous injection, 2015).
    2) MICE: Embryos died in early gestation in mutant mice without HER2 (Prod Info HERCEPTIN(R) intravenous injection, 2015).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) No reports describing the use of trastuzumab during human lactation or measuring the amount, if any, of the drug excreted into milk have been located. However, IgG is excreted in human milk, but has not been shown to enter the neonatal and infant circulation in substantial amounts. Because of the potential for serious adverse reactions in the nursing infant, a decision should be made to either discontinue nursing or discontinue the drug, giving consideration to the elimination half-life of trastuzumab and the importance of the drug to the mother (Prod Info HERCEPTIN(R) intravenous injection, 2015).
    B) ANIMAL STUDIES
    1) SUMMARY
    a) MONKEYS: In lactating cynomolgus monkeys, trastuzumab was excreted in breast milk with maternal doses 12.5 times the recommended weekly human dose. Offspring exposed during early or late fetal development displayed trastuzumab levels 15% to 28% of maternal blood levels. In infant monkeys with detectable trastuzumab levels, there were no adverse effects on development from birth to 3 months of age (Prod Info HERCEPTIN(R) intravenous injection, 2015).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) Studies to assess the fertility effects of trastuzumab on male monkeys have not been conducted. Studies in female monkeys at doses of up to 25 times the recommended weekly human dose found no effect on fertility, as determined by menstrual cycle duration and female hormone levels (Prod Info HERCEPTIN(R) intravenous injection, 2014).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS180288-69-1 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed
    3.21.2) SUMMARY/HUMAN
    A) In clinical trials, the incidence of isolated brain metastases was higher in the trastuzumab group (trastuzumab and chemotherapy [doxorubicin plus cyclophosphamide followed by paclitaxel for 4 cycles]) than in the control group (chemotherapy; started with paclitaxel and continued for 1 year).
    3.21.3) HUMAN STUDIES
    A) LACK OF INFORMATION
    1) At the time of this review, trastuzumab has not been tested for carcinogenic potential (Prod Info HERCEPTIN(R) intravenous infusion, 2010).
    B) SECONDARY MALIGNANT NEOPLASM OF BRAIN
    1) According to a combined interim analysis of data from the National Surgical Adjuvant Breast and Bowel Project B-31 (NSABP-B31) and North Central Cancer Treatment Group trial N9831, in which women (n=3351) received chemotherapy (doxorubicin plus cyclophosphamide followed by paclitaxel for 4 cycles) with or without trastuzumab (started with paclitaxel and continued for 1 year) for the adjuvant treatment of early breast cancer, the incidence of isolated brain metastases was higher in the trastuzumab group than in the control group. Brain metastases, as first events, occurred in 21 patients in the trastuzumab group versus 11 patients in the control group in the the NSABP-B31 trial and 12 patients in the trastuzumab group versus 4 patients in the control group in trial N9831. However, these events were attributed to masking of the incidence of brain metastases in the control group due to earlier development of metastases in other organs, demonstrated by the finding in NSABP-B31 that brain metastases occurred as a first or subsequent event in 28 patients in the trastuzumab group versus 35 patients in the control group (hazard ratio, 0.79; p=0.35) (Romond et al, 2005).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs.
    B) Institute continuous cardiac monitoring and obtain an ECG.
    C) Monitor serum electrolytes, renal function, CBC and troponin concentrations after significant overdose.
    D) Obtain a chest radiograph and monitor pulse oximetry and/or arterial blood gases in patients with respiratory signs or symptoms.
    E) Obtain an echocardiogram following a significant exposure to assess left ventricular ejection fraction.
    4.1.2) SERUM/BLOOD
    A) TROPONIN LEVELS
    1) Assessment of troponin l levels (prior to and during each cycle therapy) have been studied in patients undergoing trastuzumab therapy to evaluate patients at risk for trastuzumab-induced cardiotoxicity. The findings suggest that troponin l levels may be used as an adjunct to detect early cardiac vulnerability along with echocardiogram studies. However, an elevated troponin level is not limited to cardiac disease, and may occur as a result of noncardiac events (ie, pulmonary disease, renal impairment, sepsis) in cancer patients. Further study is being conducted to assess the role of troponin l and other cardiac markers to detect or predict trastuzumab-induced cardiotoxicity (Cardinale et al, 2010; Fallah-Rad et al, 2011; Goel & Beith, 2011).
    a) In a study of 251 women with breast cancer undergoing trastuzumab therapy, troponin levels were evaluated at baseline and after each cycle of therapy, along with evaluation of left ventricular ejection fraction (LVEF). A total of 42 (17%) women developed cardiotoxicity, which was more frequently observed in patients with an elevated troponin l level (62% vs 5%; p less than .001). An elevated troponin level was found in 36 patients (7 were elevated at baseline probably related to prior chemotherapy) and noted shortly after the first dose of trastuzumab. The increase in troponin level may be due to subclinical myocardial injury and useful to identify patients at risk to develop cardiotoxicity (Cardinale et al, 2010).
    b) In another study, troponin l was an independent predictor for the development of cardiotoxicity in trastuzumab-treated patients, while N-terminal pro-B-type natriuretic peptide did not predict cardiotoxicity (Sawaya et al, 2011).
    B) OTHER CARDIAC BIOMARKERS
    1) In a study of 42 consecutive women with HER-2 overexpressing breast cancer, the use of cardiac biomarkers (ie, troponin T, C-reactive protein, and brain natriuretic peptide) to detect early heart failure, a marker of LV dysfunction, did not change over time. At baseline, the cardiac markers were normal for the entire population and at 12 month follow-up there was no significant change in biomarkers between patients who developed cardiotoxicity and those that did not develop cardiotoxicity (Fallah-Rad et al, 2011).

Radiographic Studies

    A) CHEST RADIOGRAPH
    1) Obtain a chest radiograph and monitor pulse oximetry and/or arterial blood gases in patients with respiratory signs or symptoms or evidence of congestive heart failure.
    B) ECHOCARDIOGRAPHY
    1) Echocardiography may be indicated to assess left ventricular function in patients with evidence of cardiotoxicity following exposure, or to assess asymptomatic decline in left ventricular ejection fraction (LVEF) in patients with suspected trastuzumab-induced cardiotoxicity (Sengupta et al, 2008).
    C) ECHOCARDIOGRAM WITH TISSUE VELOCITY IMAGING AND STRAIN VALUES
    1) Tissue velocity imagining (TVI) and strain imaging are noninvasive echocardiographic techniques that have been used to detect subtle early changes in left ventricular (LV) systolic dysfunction before there is evidence of a decrease in left ventricular ejection fraction (LVEF). Tissue velocity imaging has been described as a modification of conventional blood-flow Doppler that images tissue-derived, high-amplitude, and low-velocity Doppler signals. Strain is 2D myocardial imaging that measures myocardial deformation by assessing segmental and global LV function in multiple planes. An early decrease in myocardial strain may predict the later occurrence of cardiotoxicity (Stoodley et al, 2012; Fallah-Rad et al, 2011; Sawaya et al, 2011).
    a) In a study of 42 consecutive women with HER-2 overexpressing breast cancer that had received adjuvant trastuzumab therapy, TVI and strain imaging were similar among the group at baseline and were significantly different at 3 months among patients that developed left ventricular systolic dysfunction and patients without cardiac dysfunction. All 10 patients that developed cardiac toxicity were above the threshold established (ie, difference between baseline and 3-month values for systolic velocities) with sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 93% 99%, 96% and 98%, respectively. A left ventricular ejection fraction decreased by 10% or greater at 6 months and continued to decline up to 9 months later. TVI and strain imaging were able to detect preclinical changes in LV systolic function prior to changes in LVEF (Fallah-Rad et al, 2011).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Monitoring

    A) Monitor vital signs.
    B) Institute continuous cardiac monitoring and obtain an ECG.
    C) Monitor serum electrolytes, renal function, CBC and troponin concentrations after significant overdose.
    D) Obtain a chest radiograph and monitor pulse oximetry and/or arterial blood gases in patients with respiratory signs or symptoms.
    E) Obtain an echocardiogram following a significant exposure to assess left ventricular ejection fraction.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Gastrointestinal decontamination is not necessary as trastuzumab is administered IV.
    6.5.3) TREATMENT
    A) SUPPORT
    1) Treatment should include recommendations listed in the PARENTERAL EXPOSURE section when appropriate.

Range Of Toxicity

Summary

    A) TOXICITY: A lethal human dose has not been established.
    B) THERAPEUTIC DOSE: INTRAVENOUS: ADULT: Therapeutic dose is 4 mg/kg infused intravenously over 90 minutes followed by weekly infusions 2 mg/kg over 30 minutes. Maximum: Single doses higher than 8 mg/kg have not been administered. INTRATHECAL: Limited experience. Intrathecal trastuzumab has been used in a limited number of patients with leptomeningeal carcinomatosis (a rare manifestation of metastatic breast cancer) in HER2-overexpressing metastatic breast cancer. It has been used as monotherapy or given concurrently with intrathecal thiotepa or methotrexate. The typical schedule is 20 to 30 mg weekly (range: 5 to 100 mg); doses were well tolerated. PEDIATRIC: The safety and efficacy of trastuzumab in pediatric patients has not been established.

Therapeutic Dose

    7.2.1) ADULT
    A) ROUTE OF ADMINISTRATION
    1) INTRAVENOUS
    a) Varies by indication: Initially, 4 mg/kg or 8 mg/kg over 90 min IV infusion; then 2 mg/kg over 30 min IV infusion weekly or 6 mg/kg over 30 to 90 min IV infusion every 3 weeks for 52 weeks. Trastuzumab should not be administered as an IV push or bolus. Do NOT substitute for or with ado-trastuzumab emtansine (Prod Info HERCEPTIN(R) intravenous injection, 2014).
    2) INTRATHECAL
    a) LIMITED EXPERIENCE: Intrathecal trastuzumab has been used in a limited number of patients with leptomeningeal carcinomatosis (a rare manifestation of metastatic breast cancer) in HER2-overexpressing metastatic breast cancer. It has been used as monotherapy or given concurrently with intrathecal thiotepa or methotrexate. The typical schedule is 20 to 30 mg weekly (range: 5 to 100 mg). These doses were well tolerated (Mego et al, 2011).
    7.2.2) PEDIATRIC
    A) SUMMARY
    1) The safety and effectiveness of trastuzumab have not been established in pediatric patients (Prod Info HERCEPTIN(R) intravenous injection, 2014).

Maximum Tolerated Exposure

    A) No lethal human dose has been reported. Single doses higher than 8 mg/kg have not been administered (Prod Info HERCEPTIN(R) intravenous infusion, 2010).

Workplace Standards

    A) ACGIH TLV Values for CAS180288-69-1 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) NIOSH REL and IDLH Values for CAS180288-69-1 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    C) Carcinogenicity Ratings for CAS180288-69-1 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    D) OSHA PEL Values for CAS180288-69-1 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Pharmacology Toxicology

Pharmacologic Mechanism

    A) In some patients with breast cancer and other malignancies (eg; ovarian, lung), trastuzumab, a recombinant DNA-derived humanized monoclonal antibody, selectively binds with high affinity in a cell-based assay to the extracellular domain of the human epidermal growth factor receptor 2 protein (HER2). The antibody is an IgG1 kappa that contains human framework regions with murine antibody (4D5) complementarity-determining regions. Trastuzumab causes antibody-dependent cell-mediate cytotoxicity (ADCC) and does not affect cells not overexpressing p185-HER2 (Prod Info HERCEPTIN(R) intravenous solution, 2005; Cobleigh, 1998; Ohnishi et al, 1995; Tokuda et al, 1996; Anon, 1998).
    B) Amplification of HER2/neu appears involved in the pathogenesis of breast cancer, and is always associated with overexpression of p185-HER2; this overexpression is observed in 25% to 30% of human breast cancers (Baselga et al, 1996; Cobleigh, 1998; Anon, 1998b). Tumors that overexpress p185-HER2 are more often hormone-receptor negative and poorly differentiated, rapidly-progressing, and associated with poor prognosis (eg; disease-free survival, overall survival) (Anon, 1998b; Cobleigh, 1998; Baselga et al, 1996). Thus HER2/neu amplification status is a useful prognostic factor in breast cancer patients. Immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) of fixed tumor blocks are methods used to determine HER2 protein overexpression.
    C) The following mechanisms of action have been reported (Emens, 2005):
    1) CELL PROLIFERATION
    a) Inhibits heterodimer formation with epidermal growth factor receptor (EGFR) (HER-1), HER-3, and HER-4
    b) Blocks metalloproteinase-mediated cleavage of HER-2 extracellular domain (ECD)
    c) Indirectly inhibits signaling through the ras-Raf-mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase/serine threonine kinase (PI3K/Akt) pathway
    d) Directly inhibits signaling through the PI3K/Akt pathway
    e) Blocks cell cycle progression by upregulating p27kip1
    2) CELL DAMAGE AND DEATH
    a) Induces apoptosis
    b) Inhibits DNA repair
    c) Promotes the formation of DNA double-strand breaks
    3) ANTIANGIOGENIC ACTIVITY
    a) Normalizes the phenotype of tumor vasculature
    b) Decreases vascular permeability
    c) Decreases production of proangiogenic factors [vascular endothelial growth factor (VEGF); plasminogen-activator inhibitor-1 (PAI-1); transforming growth factor alpha (TGF-alpha)]
    d) Increases production of antiangiogenic factors [thrombospondin-1 (TSP-1)]
    4) IMMUNOMODULATORY ACTIVITY
    a) Recruits innate immune effectors to mediate antibody-dependent cellular cytotoxicity (ADCC)
    b) Augments antigen processing and presentation
    c) Enhances the activity of CD8+ cytotoxic T lymphocyte (CTL)

Physicochemical

Physical Characteristics

    A) TRASTUZUMAB: A sterile, white to pale yellow, preservative-free lyophilized powder (Prod Info HERCEPTIN(R) intravenous injection, 2014).

Ph

    A) Approximately 6: when reconstituted with bacteriostatic water for injection or sterile water for injection (Prod Info HERCEPTIN(R) intravenous injection, 2014).

Molecular Weight

    A) TRASTUZUMAB: 148 kilodaltons (Prod Info HERCEPTIN(R) intravenous solution, 2005)

References

General Bibliography

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    2) 40 CFR 372.65: Environmental Protection Agency - Toxic Chemical Release Reporting, Community Right-To-Know, Chemicals and Chemical Categories to which this part applies. National Archives and Records Association (NARA) and the Government Printing Office (GPO), Washington, DC. Final rules current as of Apr 3, 2006.
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    9) 67 FR 7164: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2002.
    10) 68 FR 42710: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2003.
    11) 69 FR 54144: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2004.
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