VA Class:AN900

AHFS Class:

• Antineoplastic Agents 10:00

Generic Name(s):

• Trastuzumab

Trastuzumab, a recombinant DNA-derived humanized anti- HER2 monoclonal antibody, is an antineoplastic agent.1,5

Breast Cancer

Overview

Trastuzumab is used as monotherapy for the treatment of metastatic breast cancer that has relapsed following prior chemotherapy in patients with tumors that overexpress the HER2 protein.1,4,5,16,26 Trastuzumab also is used in combination with paclitaxel for the initial treatment of metastatic breast cancer in patients with tumors that overexpress the HER2 protein.1,3,5,25,26 Trastuzumab is used in conjunction with standard adjuvant chemotherapy for the treatment of operable HER2-positive breast cancer.1,26 The benefit of combination therapy with trastuzumab and chemotherapy appears to be largely limited to patients with disease testing 3+ for HER2 overexpression.1 Trastuzumab, the second monoclonal antibody approved for the treatment of cancer and the first monoclonal antibody approved for the treatment of breast cancer, received fast-track and priority review from the US Food and Drug Administration (FDA).17

Although the use of trastuzumab in combination with an anthracycline and cyclophosphamide for the initial treatment of HER2 -overexpressing metastatic breast cancer has been investigated in a large, randomized clinical trial,1,3 the clinical benefit obtained with this regimen did not outweigh the increased risk of serious cardiac toxicity, and an indication for the use of trastuzumab with this combination regimen did not receive approval from the FDA.6,17,19,27

Trastuzumab also is not indicated for the treatment of metastatic breast cancer in patients with tumors that do not overexpress the HER2 protein.1,5

Patients with metastatic breast tumors with 2+ or 3+ overexpression of HER2 protein (based on a 0-3+ scale with 3+ being the highest degree of overexpression) as determined by an immunohistochemical assay using 4D5 and CB11 murine monoclonal anti- HER2 antibodies (known as the Clinical Trial Assay [CTA]) were eligible for enrollment in clinical trials of trastuzumab.1,4 About 33% of women with metastatic breast cancer screened for eligibility for enrollment in clinical trials of trastuzumab were found to have 2+- or 3+ -HER2 -overexpressing tumors;1 among patients enrolled in the pivotal clinical trials, about 75% had 3+-overexpressing tumors and 25% had 2+-overexpressing tumors.4,6 Although these studies were not designed to include stratification by degree of HER2 overexpression, and the small number of patients with 2+-overexpressing tumors limits interpretation of the data,18,19 retrospective analysis of the data from clinical trials suggests that benefit of trastuzumab (i.e., higher response rates, increased time to progression of disease) may be limited to patients with tumors that have 3+ overexpression of the HER2 protein.1 Further study is needed to establish the benefit of trastuzumab in patients with 2+-overexpressing (weakly positive) breast tumors.7,18

Evaluation of HER2/neu in Breast Cancer

The methods of HER2/neu evaluation most commonly used in routine clinical practice and clinical research studies are immunohistochemistry (IHC) assays, which directly measure overexpression of the HER2/neu protein, and fluorescent in situ hybridization (FISH), which measures amplification of the HER2/neu oncogene.1,9 The presence of HER2 overexpression may be inferred when HER2 gene amplification is detected using the FISH assay.1 HercepTest^® and PATHWAY^® (IHC assays) and PathVysion^®, INFORM^®, and HER2 FISH pharmDx^® (FISH assays) are examples of appropriate commercial assays that may be used to identify candidates for trastuzumab therapy.1,43

Findings from small studies show conflicting results for the agreement of IHC and FISH testing, with some studies citing high levels of concordance,9,34 while others report levels as low as 49%.35,36 Some experts argue for use of a FISH assay as the primary screening tool because of greater accuracy35 whereas others argue for use of an IHC assay because of lesser time and cost requirements.9 In addition, overexpression of the HER2 protein has been observed in the absence of detectable HER2 gene amplification (i.e., FISH-negative).1,8,9,15 In a large quality control and quality assurance study in which both FISH and IHC test results were available for 2913 of 2963 breast cancer specimens, the concordance rate was 65% when IHC scores of 2+ and 3+ were grouped together; the concordance rate increased to 96% when results for the IHC 2+ specimens were excluded from the analysis.38 The FISH assay had a higher failure rate (5 versus 0.08%), higher cost, and longer testing and interpretation times than the IHC assay.38

Because of limitations in the accuracy and precision of each of these types of assays, use of a single methodology for the evaluation of HER2 overexpression is not advised.1 Many experts currently recommend initial screening using an IHC assay followed by confirmation of positive results using a FISH assay, particularly for 2+ HER2-overexpressing tumors.36,37,38,39 The precision of HER2/neu evaluation may vary according to the type of assay and assay procedures used.1 Further study of these methods, particularly regarding their comparative efficacy in predicting disease prognosis and response to therapy, is needed to establish the optimum procedure for determining the HER2/neu status of breast cancer.1,9,18,19

The reliability of HER2 testing is improved when performed in large-volume central laboratories compared with local laboratories.40,41,43 Assessment of HER2 overexpression in breast tumors using IHC or FISH methodology should be performed by laboratories with demonstrated proficiency in the specific technology being used.1 Improper assay performance, including use of suboptimally fixed tissue, failure to use specified reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results.1 For full instructions on assay performance, refer to the prescribing information for each assay kit.1

Detection of HER2 Protein Overexpression

The IHC assay used to test breast tumors for HER2 overexpression in the pivotal trials of trastuzumab is a research assay known as the Clinical Trial Assay (CTA).1 The DAKO HercepTest^® is a commercially available immunohistochemical test that is used to measure HER2 protein in tumors and to help identify patients who may be candidates for treatment with trastuzumab.10,13 In the randomized trial involving patients with metastatic breast cancer (study 3), data suggest that benefit of combination therapy with trastuzumab and chemotherapy was largely limited to patients with disease testing 3+ for HER2 overexpression on the CTA.1

The HercepTest^® has been assessed for concordance with the CTA.1 The low specificity reported for the HercepTest^® when used according to manufacturer guidelines and the FDA-approved scoring system raises concerns about large numbers of false-positive specimens resulting in inappropriate use of trastuzumab.10,13,19 In one study using tissue specimens from 48 cases of invasive breast cancer, consideration of the level of staining of nonneoplastic epithelium in a specimen as an internal control helped compensate for variability in tissue fixation and processing and improved the specificity of the HercepTest^® from 42% to 93%.10

Detection of HER2 Gene Amplification

Measurement of the number of HER2 gene copies using the FISH assay to detect gene amplification may be used as a surrogate measurement of protein overexpression.1 PathVysion^® is a commercially available FISH assay that is used to identify patients who may be candidates for trastuzumab therapy.1

In a retrospective analysis of known CTA 2+ or 3+ tumor specimens from patients with metastatic breast cancer receiving trastuzumab and chemotherapy in a randomized trial (study 3), the data suggest that benefit of treatment was greater in patients with FISH-positive tumors than in those with FISH-negative tumors; however, time to progression of disease was prolonged in patients receiving combination therapy with trastuzumab and chemotherapy for CTA 2+ or 3+ tumors regardless of the FISH test status.1 This treatment effect was particularly strong among patients receiving trastuzumab and chemotherapy for CTA 3+ tumors even if the tumor was FISH-negative.1 There are insufficient data to determine whether the FISH assay can be used to identify a subgroup of patients with CTA 2+ tumors who would be unlikely to benefit from trastuzumab therapy.1

Adjuvant Therapy for Early-stage Breast Cancer

Trastuzumab is used in conjunction with standard adjuvant chemotherapy (doxorubicin and cyclophosphamide followed by paclitaxel) for the treatment of HER2-overexpressing, node-positive breast cancer.1,26

In several large randomized trials, the addition of trastuzumab to standard adjuvant chemotherapy in patients with operable HER2-positive breast cancer reduced the risk of death and/or prolonged disease-free survival.28,29

The current indication for trastuzumab as adjuvant therapy for HER2-overexpressing, node-positive breast cancer is based on 2 North American randomized clinical trials.1 In the National Surgical Adjuvant Breast and Bowel Project trial B-31 (study 1), 2043 women were randomly assigned to receive either doxorubicin and cyclophosphamide followed by paclitaxel or the same regimen with trastuzumab given concurrently with paclitaxel.28 In the North Central Cancer Treatment Group trial N9831 (study 2), 1633 of the 2766 patients enrolled were randomly assigned to receive either doxorubicin and cyclophosphamide followed by paclitaxel or the same regimen with trastuzumab given concurrently with paclitaxel.28

A total of 3752 patients were randomly assigned to treatment in the 2 trials prior to a planned interim analysis.1 In a combined analysis of data from patient groups from the 2 trials at a median follow-up of 2 years, disease-free survival at 3 years was prolonged (hazard ratio: 0.48, absolute disease-free survival rate: 87 versus 75%) and the risk of death at 3 years was decreased (hazard ratio: 0.67, absolute survival rate: 94 versus 92%) in patients receiving trastuzumab in combination with standard adjuvant chemotherapy compared with those receiving standard adjuvant chemotherapy alone.1,28 Subgroup analysis of the data from study 2 exploring efficacy according to HER2 overexpression showed a strong effect on disease-free survival (hazard ratio: 0.42) for the addition of trastuzumab to adjuvant chemotherapy in patients with disease that was 3+ HER2-overexpressing and FISH-positive.1 Because of the small number of events in the other subgroups, it is not known whether adjuvant therapy including trastuzumab would benefit patients with breast tumors that are FISH-positive but lack 3+ HER2 overexpression.1

Trastuzumab also was used as adjuvant therapy for operable HER2-positive breast cancer in an international multicenter randomized trial.29 In the Herceptin Adjuvant (HERA) trial, 5081 women received trastuzumab (1 or 2 years) or underwent observation following neoadjuvant and/or adjuvant chemotherapy for operable HER2-positive breast cancer.29 At a median follow-up of 1 year among 3387 patients receiving either 1 year of trastuzumab therapy or observation, the rate of disease-free survival was prolonged in patients receiving trastuzumab (hazard ratio for an event: 0.54, absolute difference in disease-free survival at 2 years of 8.4 percentage points).29 At a median follow-up of 2 years, prolonged survival has been observed in patients receiving 1 year of trastuzumab therapy compared with observation (hazard ratio for death: 0.66, absolute difference in death rate at 3 years of 2.7 percentage points).44

Patients were eligible for enrollment in the randomized trials if they had operable breast cancer that was identified as HER2-positive with either 3+ HER2 overexpression according to the IHC assay or positive results for amplification of the HER2 gene according to the FISH assay.1,28,29 HER2 testing was performed at a reference laboratory (study 1) or HER2 test results were confirmed by a central laboratory prior to randomization (study 2).1 For 1153 tumor specimens in study 2 which tested as IHC 3+ using HercepTest^® at a local laboratory, 85% were concordant and 15% were discordant when testing was confirmed by a central laboratory.1 For 414 tumor specimens in study 2 which tested as FISH-positive using PathVysion^® at a local laboratory, 94% were concordant and 6% were discordant when testing was confirmed by a central laboratory.1

In the 2 North American trials, most patients (91%) had node-positive disease.1,28 The median age of the patients was 49 years (range: 22-80 years), and most were Caucasian (84%).1 Most patients had intermediate-grade (27%) or high-grade (66%) breast tumors, and 53% had hormone receptor-positive disease.1 The benefit of trastuzumab appeared to be similar among patients with hormone receptor-positive or hormone receptor-negative breast tumors.28 Because of the lack of data in these trials, it is unknown whether the addition of trastuzumab to standard adjuvant chemotherapy would benefit patients with node-negative breast cancer.28 In the international trial, the median age of the patients was 49 years; about one-third of the patients had node-negative breast cancer, and 48% had hormone receptor-negative tumors.29 In this trial, the benefit of 1 year of trastuzumab therapy did not appear to differ according to nodal or estrogen receptor status.29

In both North American trials, for the comparison groups receiving trastuzumab given concurrently with paclitaxel, an initial dose of trastuzumab 4 mg/kg was administered with the first dose of paclitaxel followed by trastuzumab 2 mg/kg once weekly for 51 weeks.1,28 The same regimen of adjuvant chemotherapy with doxorubicin and cyclophosphamide was used in both trials (four 21-day cycles of doxorubicin 60 mg/m² and cyclophosphamide 600 mg/m²), but the regimens for paclitaxel differed: 80 mg/m² once weekly or 175 mg/m² once every 3 weeks for a total of 12 weeks in trial B-31 (study 1) and 80 mg/m² once weekly in trial N9831 (study 2).1,28 When administered, radiation therapy was initiated following the completion of chemotherapy.1 Patients with estrogen receptor-positive and/or progesterone receptor-positive tumors also received hormonal therapy.1

In trial N9831 (study 2), a third group of patients received adjuvant chemotherapy with doxorubicin and cyclophosphamide, followed by paclitaxel therapy, and then trastuzumab therapy.28 Further follow-up is needed before the comparative efficacy of concurrent versus sequential paclitaxel and trastuzumab therapy can be assessed, but an interim analysis of the data from this trial suggests that concurrent therapy may be more effective.28

In the international trial, differing regimens of neoadjuvant and/or adjuvant chemotherapy (including both anthracyclines and taxanes in about 26% of patients) were followed by an initial dose of trastuzumab 8 mg/kg and then trastuzumab 6 mg/kg once every 3 weeks.29

Increased risk of cardiac toxicity was associated with trastuzumab therapy.1,28,29,46 Among patients receiving adjuvant therapy for breast cancer, those receiving trastuzumab and paclitaxel following completion of doxorubicin and cyclophosphamide therapy experienced a higher incidence of symptomatic, laboratory-confirmed cardiomyopathy compared with those receiving paclitaxel alone (2 versus 0.4%).1 The cumulative incidence of class III or IV congestive heart failure or death from cardiac causes at 3 years in patients receiving trastuzumab was 4.1% in trial B-31 (study 1) and 2.9% in trial N9831 (study 2).28,46 The incidence of class III or IV congestive heart failure in patients receiving trastuzumab was 0.5% at 1 year in the international trial.29

Patients were eligible for enrollment in the North American randomized trials if they did not have previous or currently active cardiac disease based on symptoms or test findings (ECG, radiographs, and left ventricular ejection fraction [LVEF]) or uncontrolled hypertension (diastolic blood pressure exceeding 100 mm Hg or systolic blood pressure exceeding 200 mm Hg).1,28 Cardiac function was monitored at regular intervals, and trastuzumab therapy was not initiated or was discontinued if clinical manifestations or decline in LVEF indicated cardiac toxicity.28 Trastuzumab therapy was permanently discontinued in patients who developed congestive heart failure or persistent/recurrent LVEF decline.1 Similar eligibility criteria, cardiac monitoring, and stopping rules for cardiotoxicity were applied in the international trial.29 Further follow-up is needed to fully assess the risk of cardiotoxicity associated with trastuzumab as adjuvant therapy for operable HER2-positive breast cancer.28,29,30,31

Increased risk of pulmonary toxicity also was associated with trastuzumab therapy.1 Among patients receiving adjuvant therapy for breast cancer in the 2 North American trials (studies 1 and 2), those receiving trastuzumab and paclitaxel following completion of doxorubicin and cyclophosphamide therapy experienced a higher incidence of dyspnea, the most common pulmonary toxicity, compared with those receiving paclitaxel alone (study 1: 12 versus 4%, study 2: 2.5 versus 0.1%).1 Pneumonitis/pulmonary infiltrates (0.7 versus 0.3%) and deaths from respiratory failure (3 deaths versus 1 death) also occurred more frequently in patients receiving trastuzumab compared with chemotherapy alone.1

For patients with node-positive, HER2-positive operable breast cancer, trastuzumab should be added to standard adjuvant chemotherapy unless contraindicated.28,29,30 For patients with node-negative, HER2-positive operable breast cancer†, the use of trastuzumab in conjunction with standard adjuvant chemotherapy should be considered with careful weighing of possible benefit versus the risk of cardiac toxicity.28,29,30 Careful patient selection and monitoring of cardiac function is required in all patients receiving trastuzumab as adjuvant therapy.30 Further follow-up of these clinical trials and additional studies are needed to answer other questions, such as the optimal dosing schedule, timing of administration (concurrent versus sequential), and duration of therapy for trastuzumab, and to fully evaluate the nature and risk of cardiotoxicity associated with trastuzumab in this patient population.30

A randomized trial is under way comparing the addition of trastuzumab to anthracycline-containing versus non-anthracycline-containing adjuvant chemotherapy to determine whether similar efficacy can be achieved with less cardiac toxicity for HER2-positive operable breast cancer.30 Other regimens and schedules for adjuvant trastuzumab therapy are being investigated.45 For a small subgroup of 232 patients with HER2-positive tumors among 1010 women receiving adjuvant chemotherapy for node-positive or high-risk node-negative early breast cancer in a randomized trial, the addition of trastuzumab to chemotherapy with either docetaxel or vinorelbine compared with chemotherapy alone (prior to treatment with an anthracycline-containing regimen) prolonged recurrence-free survival.45 This shortened schedule for trastuzumab (9 weekly infusions) preceding the use of an anthracycline was not associated with decreased left ventricular ejection fraction or cardiac failure.45

First-line Therapy for Advanced Breast Cancer

The current indication for use of trastuzumab in combination with paclitaxel for the initial treatment of metastatic breast cancer is based on data from a randomized, controlled, multicenter clinical trial involving 469 patients with 2+ or 3+ HER2 -overexpressing metastatic breast cancer.1,3 Patients were randomized to receive combination therapy with trastuzumab (4-mg/kg IV initial dose followed by once-weekly doses of 2 mg/kg IV) and chemotherapy or chemotherapy alone.1,3 For patients who had received prior adjuvant therapy with an anthracycline, chemotherapy consisted of paclitaxel 175 mg/m² IV over 3 hours every 21 days for at least 6 cycles; for all other patients, chemotherapy consisted of an anthracycline (doxorubicin hydrochloride 60 mg/m² or epirubicin hydrochloride 75 mg/m² every 21 days) and cyclophosphamide (600 mg/m² every 21 days) for 6 cycles.1 Trastuzumab therapy was continued until disease progression or intolerable toxicity was observed.6 The median age of the patients was 52 years (range: 25-77 years) and most (89%) were Caucasian.1

Longer time to disease progression (7.2 versus 4.5 months), higher overall response rate (45 versus 29%), longer median duration of response (8.3 versus 5.8 months), and longer median survival (25.1 versus 20.3 months) were reported in patients receiving trastuzumab in combination with chemotherapy compared with those receiving chemotherapy alone.1 With the exception of overall survival, the magnitude of benefit was greater with the addition of trastuzumab to paclitaxel versus an anthracycline and cyclophosphamide despite the poorer prognosis of patients in the paclitaxel subgroup; in addition, the incidence and severity of cardiac toxicity were greater in patients receiving trastuzumab combined with an anthracycline and cyclophosphamide.1,18,19

The benefit of adding trastuzumab to conventional chemotherapy was greater in patients with 3+ -HER2 -overexpressing breast tumors than in those with 2+ -HER2 -overexpressing breast tumors.3,27 Although the study was not designed to include stratification by degree of HER2 overexpression, and the small number of patients with 2+-overexpressing tumors limits interpretation of the data,18,19 retrospective analysis suggests that response to trastuzumab is limited to the patients with the highest level of HER2 overexpression (3+).1,6 The relative risk for disease progression in patients receiving trastuzumab in combination with chemotherapy versus those receiving chemotherapy alone was lower among patients with 3+ versus 2+ HER2 -overexpressing disease (relative risk 0.42 versus 0.76) using the CTA methodology; lower relative risk for disease progression represents longer time to disease progression.1

Compared with patients receiving paclitaxel alone, those receiving trastuzumab and paclitaxel experienced a longer median time to disease progression (6.7 versus 2.5 months) and a higher overall response rate (38 versus 15%); median duration of response was 8 versus 4 months and median survival was 22 versus 18 months.1 Because of the difference in patient characteristics between the groups (i.e., poorer prognosis for patients in the paclitaxel subgroup), the results of this clinical trial cannot be used to compare the efficacy and safety of combination therapy with trastuzumab and paclitaxel versus standard first-line therapy of an anthracycline and cyclophosphamide for metastatic breast cancer.6,18,19

Combination therapy with trastuzumab, paclitaxel, and carboplatin† is used in the treatment of HER2-overexpressing metastatic breast cancer.26,49 In a phase 3 randomized trial, the addition of carboplatin to trastuzumab and paclitaxel increased response rate and prolonged progression-free survival in patients with HER2-overexpressing metastatic breast cancer.49 Combination therapy with vinorelbine and trastuzumab† is being investigated as an active regimen for the treatment of HER2-overexpressing metastatic breast cancer.25,26 (See Uses: Breast Cancer in Vinorelbine 10:00.) Another ongoing study will compare the efficacy of trastuzumab in combination with paclitaxel for tumors with overexpression versus normal expression of HER2 in patients with recurrent or metastatic breast cancer.18,19

Second-line or Salvage Therapy for Advanced Breast Cancer

The current indication for use of trastuzumab as monotherapy for metastatic breast cancer is based on data from a single-arm, open-label, multicenter clinical trial in 222 patients with 2+ or 3+ HER2 -overexpressing metastatic breast cancer that relapsed following 1 or 2 previous chemotherapy regimens.1,4 Among patients enrolled in the study, 66% had received prior adjuvant chemotherapy, 68% had received 2 prior chemotherapy regimens for metastatic disease, and 25% had received prior myeloablative therapy with hematopoietic rescue.1 About 72% of the patients had visceral disease (i.e., lung or liver metastases), and patients with only bone metastases, a characteristic that generally is associated with an indolent course of disease, were ineligible for enrollment in the trial.4

Patients received an initial dose of trastuzumab 4 mg/kg IV followed by once weekly doses of 2 mg/kg IV; the overall response rate was 14% (2% complete responses, 12% partial responses), the median duration of response was 9 months, and the median survival was 13 months.1,4 Trastuzumab therapy was continued until disease progression or intolerable toxicity was observed.6 Complete responses to trastuzumab were observed only in patients with metastatic breast disease limited to the skin and the lymph nodes.1

Retrospective analysis suggests that response to trastuzumab is related to the degree of HER2 overexpression with an overall response rate of 18% in patients with 3+ overexpressing tumors versus 6% in those with 2+ overexpressing tumors.1,4,6 According to retrospective analysis of the tumor specimens, the overall response rate was 20% in patients with FISH-positive tumors compared with no responses in those with FISH-negative tumors.1

Among 352 patients (including 213 patients in the multicenter clinical trial) receiving trastuzumab as monotherapy for metastatic breast cancer, the median age of the patients was 50 years (range: 28-86 years), and most were Caucasian (86%).1

Reconstitution and Administration

Trastuzumab is administered by IV infusion.1 The initial dose of trastuzumab should be administered as an IV infusion over 90 minutes; if the first infusion is well tolerated, subsequent doses may be administered by IV infusion over 30 minutes.1 Trastuzumab solutions should not be administered by rapid IV injection, such as IV push or bolus.1 The usual precautions for handling and preparing cytotoxic drugs should be observed when reconstituting or administering trastuzumab.1

Commercially available trastuzumab powder for injection must be reconstituted prior to administration.1 Trastuzumab is supplied with a diluent of bacteriostatic water for injection, which contains 1.1% benzyl alcohol; reconstitution using the 20 mL of supplied diluent results in a solution containing 21 mg/mL of trastuzumab.1 Alternatively, for patients sensitive to benzyl alcohol, 20 mL of sterile water for injection may be used for reconstitution.1

Trastuzumab must be handled carefully during reconstitution; shaking the reconstituted solution of trastuzumab or causing excessive foaming during the addition of diluent may cause problems with dissolution and the amount of the drug that can be withdrawn from the vial.1,22 Using a sterile syringe, the 20 mL of supplied diluent should be injected slowly into the vial with the stream of diluent directed into the lyophilized cake of trastuzumab.1,22 The vial should be swirled gently to aid reconstitution; because trastuzumab may be sensitive to shear-induced stress (e.g., agitation, rapid expulsion from a syringe), the reconstituted solution of the drug should not be shaken.1,22 Slight foaming of the reconstituted trastuzumab solution is not unusual, and the vial should be allowed to stand undisturbed for 5 minutes following reconstitution.1,22 The reconstituted solution of trastuzumab should be clear to slightly opalescent, colorless to pale yellow, and free of visible particulate matter.1,22

Immediately upon reconstitution with bacteriostatic water for injection, the vial containing trastuzumab solution must be labeled to indicate the date by which the contents should be used (i.e., 28 days from the date of reconstitution); unused portions should be discarded after 28 days.1,42 For administration in patients with known hypersensitivity to benzyl alcohol, trastuzumab should be reconstituted using sterile water for injection; the resulting solution must be used immediately , and any unused solution should be discarded.1

Reconstituted solutions of trastuzumab should be further diluted prior to administration by adding an appropriate volume of trastuzumab 21 mg/mL solution to a polyvinyl chloride or polyethylene infusion bag containing 250 mL of 0.9% sodium chloride injection; the bag should be inverted gently to mix the solution.1 Trastuzumab solutions for infusion should not be diluted in or administered through an IV line containing 5% dextrose injection, and trastuzumab should not be mixed or diluted with other drugs.1 Prior to administration, trastuzumab solutions should be inspected visually for particulate matter and discoloration.1

Dispensing and Administration Precautions

Trastuzumab (Herceptin^®) should not be confused with ado-trastuzumab emtansine (Kadcyla^®).1001,1005,1006 Because of the similarity between the original generic name of Kadcyla^® (trastuzumab emtansine) and the generic name for Herceptin^® (trastuzumab), the US Food and Drug Administration (FDA) approved the addition of the prefix “ado” to the generic name for Kadcyla^® (i.e., ado-trastuzumab emtansine).1004,1005 However, the potential exists for dispensing or prescribing errors involving these drugs.1001,1004,1005,1006 Extra care should be exercised to ensure the accuracy of prescriptions for trastuzumab (Herceptin^®) or ado-trastuzumab emtansine (Kadcyla^®).1001,1002,1005,1006 To avoid medication errors, the Institute for Safe Medication Practices (ISMP), the FDA, and the manufacturer of ado-trastuzumab emtansine (Kadcyla^®) recommend that prescribers communicate both the brand and generic names for ado-trastuzumab emtansine (Kadcyla^®) on the prescription order form.1001,1002,1005,1006 (See Special Alerts.)

Dosage

Adjuvant Therapy for Early-stage Breast Cancer

For the adjuvant treatment of HER2-overexpressing, node-positive breast cancer, trastuzumab is given concurrently with paclitaxel following adjuvant chemotherapy with doxorubicin and cyclophosphamide; an initial dose of trastuzumab 4 mg/kg is administered (given with the first dose of paclitaxel), followed by trastuzumab 2 mg/kg once weekly for 51 weeks.1,28 Trastuzumab should not be administered concurrently with doxorubicin and cyclophosphamide.1 Following the completion of therapy with doxorubicin and cyclophosphamide, trastuzumab is administered weekly for 52 weeks, concurrently with paclitaxel for the first 12 weeks, then as monotherapy.1

Therapy for Advanced Breast Cancer

When used for the treatment of metastatic breast cancer that overexpresses the HER2 protein, either as monotherapy for treatment of disease that has relapsed following prior chemotherapy or in combination therapy with paclitaxel for initial treatment, the manufacturer recommends an initial trastuzumab dose of 4 mg/kg administered by IV infusion over 90 minutes, followed by once-weekly doses of 2 mg/kg IV.1,4

Patients should be observed for fever and chills or other infusion-associated symptoms during trastuzumab infusion.1 (See Cautions: Infusion-related Effects.) If prior infusions were well tolerated, subsequent weekly doses of trastuzumab 2 mg/kg IV may be administered over 30 minutes.1,4 Trastuzumab therapy is administered until disease progression occurs.1 In clinical trials, once-weekly administration of trastuzumab was continued until disease progression or intolerable toxicity was observed.6

Among patients receiving trastuzumab and chemotherapy as first-line therapy for metastatic breast cancer, 58% of patients received trastuzumab for at least 6 months and 9% received trastuzumab for at least 12 months.1 Among patients receiving trastuzumab monotherapy as second-line or salvage therapy for metastatic breast cancer, 31% of patients received trastuzumab for at least 6 months and 16% received trastuzumab for at least 12 months.1

Dosage Modification for Toxicity and Contraindications for Continued Therapy

Respiratory Toxicity

Infusion of trastuzumab should be interrupted in patients experiencing dyspnea, and discontinuance of trastuzumab therapy should be considered strongly in patients who develop pneumonitis or acute respiratory distress syndrome.1 (Also see Infusion-related Toxicity under Dosage: Dosage Modification for Toxicity and Contraindications for Continued Therapy, in Dosage and Administration.)

Infusion-related Toxicity

Discontinuance of trastuzumab should be strongly considered for infusion reactions manifesting as anaphylaxis, angioedema, pneumonitis, or acute respiratory distress syndrome.1

Infusion of trastuzumab should be interrupted in all patients experiencing dyspnea or clinically important hypotension and appropriate medical therapy, which may include epinephrine, corticosteroids, diphenhydramine, bronchodilators, and oxygen, should be instituted.1,24 Patients should be evaluated and monitored carefully until signs and symptoms have resolved completely.1 Permanent discontinuance of trastuzumab therapy should be strongly considered in all patients experiencing severe or life-threatening infusion reactions.1 For mild or moderate infusion reactions, the rate of infusion of trastuzumab may be slowed.1

According to the manufacturer, the most appropriate method for identifying patients who may safely receive additional infusions of trastuzumab following a severe infusion-related reaction to the drug has not been determined.1 Following complete recovery from a severe infusion-related reaction, some patients have tolerated subsequent infusions of the drug, typically accompanied by prophylactic treatment including antihistamines and/or corticosteroids, but others have experienced severe reactions to additional infusions of trastuzumab despite the use of premedication.1

Mild to moderate infusion-related symptoms, such as chills or fever, have been treated with acetaminophen, diphenhydramine, and/or meperidine, and, in some patients, the rate of infusion of trastuzumab was reduced.1,4 Permanent discontinuance of the drug because of such infusion-related symptoms was required in less than 1% of patients.1

Sensitivity Reactions

Discontinuance of trastuzumab should be strongly considered for infusion reactions manifesting as anaphylaxis or angioedema.1

Infusion of trastuzumab should be interrupted in all patients experiencing dyspnea or clinically important hypotension and appropriate medical therapy should be instituted.1 See Infusion-related Toxicity under Dosage: Dosage Modification for Toxicity and Contraindications for Continued Therapy, in Dosage and Administration.

Cardiovascular Toxicity

Careful assessment of cardiac function and monitoring of clinical condition are required in patients receiving trastuzumab.1,28,31 For cardiac monitoring requirements, see Cardiovascular Effects under Cautions: Precautions and Contraindications. Trastuzumab-induced decline in left ventricular ejection fraction (LVEF) may be asymptomatic.1 If clinical manifestations of cardiotoxicity or a clinically important decrease in LVEF occurs, trastuzumab therapy should be interrupted or discontinued.1,28,31 Medical management of cardiac dysfunction may result in recovery of LVEF to at least 50% in some patients.1,47

For patients receiving adjuvant therapy, left ventricular function should be assessed before initiation of trastuzumab and frequently during therapy.1 If LVEF decreases by 16 percentage points or more from the baseline value, or if LVEF decreases by 10 or more percentage points from the baseline value to a value that is below the lower limit of normal, trastuzumab therapy should be discontinued for 4 weeks.1,28,31 After 4 weeks, cardiac function should be reassessed; if there are no clinical manifestations of cardiotoxicity, LVEF returns to normal limits, and the absolute decrease in LVEF from baseline is 15 percentage points or less, trastuzumab therapy can be resumed.1,28,31 If LVEF decline is persistent (greater than 8 weeks) and 2 consecutive holds are placed on therapy, or if therapy has been interrupted on more than 3 occasions for cardiomyopathy, therapy with trastuzumab should be discontinued permanently.1,31 Among patients receiving adjuvant trastuzumab in trial B-31 (study 1), 30.5% required at least one dose delay because of asymptomatic decrease in LVEF or cardiac symptoms.31,46 In 16% of patients, trastuzumab therapy was discontinued because of substantial decline in LVEF or clinical evidence of myocardial dysfunction.1,31

Patients receiving trastuzumab therapy for advanced or metastatic breast cancer, particularly those with preexisting cardiac dysfunction, should be monitored closely for signs of cardiotoxicity.1,17 Discontinuance of trastuzumab should be considered strongly in patients who develop a clinically important decrease in left ventricular function or congestive heart failure.1,18,19

An independent committee reviewing cardiac data from clinical trials of trastuzumab used alone or in combination with chemotherapy for metastatic breast cancer found that, in most cases, cardiac dysfunction in patients receiving trastuzumab was similar to anthracycline-induced cardiomyopathy.21 Others report a lack of anthracycline-like ultrastructural changes and suggest a different mechanism for trastuzumab-induced cardiac toxicity.47 In clinical trials for metastatic breast cancer, cardiac dysfunction associated with trastuzumab typically responded to appropriate medical therapy, often including discontinuance of the drug.21 For the treatment of cardiac dysfunction, single-agent therapy with a diuretic or an angiotensin-converting enzyme (ACE) inhibitor often was used in patients receiving trastuzumab and paclitaxel whereas combination therapy with digoxin, a diuretic, and an ACE inhibitor typically was used in patients receiving trastuzumab with an anthracycline and cyclophosphamide.6,18,19

Among patients for whom trastuzumab therapy is discontinued because of left ventricular dysfunction, close monitoring for evidence of clinical deterioration and further decline in left ventricular function is required.1 The safety of continuing or restarting treatment with the drug in patients who have developed trastuzumab-induced left ventricular cardiac dysfunction has not been fully evaluated.1 Some clinicians report reinitiation of therapy in patients with metastatic breast cancer following recovery from trastuzumab-induced cardiac dysfunction.47,48

Serious adverse effects, sometimes fatal, have occurred in patients receiving trastuzumab.1,24 Serious adverse effects associated with trastuzumab include cardiomyopathy; pulmonary toxicity such as respiratory failure, pneumonitis, and pulmonary infiltrates; infusion reactions such as anaphylaxis or angioedema; febrile neutropenia; and exacerbation of chemotherapy-induced neutropenia.1 Deaths associated with pulmonary reactions (including acute respiratory distress syndrome), infusion-related reactions, and hypersensitivity reactions (including fatal anaphylaxis) have been reported in patients receiving trastuzumab.1,24 Deaths caused by sepsis in patients with severe neutropenia have been reported when trastuzumab is used in combination with myelosuppressive chemotherapy.1 Another serious adverse effect associated with trastuzumab is cardiotoxicity, including ventricular dysfunction and congestive heart failure, which may be severe and occasionally disabling;1 the risk of cardiotoxicity increases substantially when the drug is combined with an anthracycline,1,3 and such combination therapy for use in metastatic breast cancer is not recommended by most experts.6,17,19

Adverse effects are common with trastuzumab therapy, with the incidence of most effects generally increasing with combination versus monotherapy.1 The most common adverse effects associated with trastuzumab include fever, nausea, vomiting, infusion reactions, diarrhea, infections, increased cough, headache, fatigue, dyspnea, rash, neutropenia, anemia, and myalgia.1

Data regarding serious adverse effects are based on experience in a total of 958 patients receiving trastuzumab alone or in combination with chemotherapy for metastatic breast cancer or other cancers in clinical trials.1 The incidence of adverse effects that occurred in at least 5% of patients receiving the drug or that occurred at increased incidence among patients receiving trastuzumab and chemotherapy versus chemotherapy alone is derived from data for a total of 586 patients with metastatic breast cancer (352 patients receiving trastuzumab as a single agent and 234 patients receiving trastuzumab in combination with chemotherapy).1

Of 213 patients receiving trastuzumab as a single agent, about 3% discontinued the drug because of adverse effects.4,6 Of 91 patients receiving trastuzumab and paclitaxel, 6 patients (6.6%) discontinued trastuzumab because of an adverse effect, 3 of which were cardiac in origin.6 A higher percentage of patients (20/143 or 14%) receiving the drug in combination with an anthracycline and cyclophosphamide discontinued trastuzumab because of adverse effects, mostly cardiovascular in nature.6

Limited data were collected for adverse effects in clinical trials of adjuvant trastuzumab for early breast cancer (studies 1 and 2).1 Unless otherwise noted, the incidence data for noncardiac adverse effects occurring in at least 2% of patients refer to grade 2-5 toxicities for study 1.1

Respiratory Effects

Trastuzumab can cause serious, sometimes fatal, pulmonary toxicity.1 Severe adverse respiratory effects, including acute respiratory distress syndrome, have been reported in patients receiving trastuzumab and, in some cases, have been fatal.1,24 Interstitial pneumonitis, sometimes fatal, was reported rarely in patients receiving adjuvant trastuzumab.28 Manifestations of severe adverse pulmonary reactions, which may occur as sequelae of infusion-related reactions (see Cautions: Infusion-related Effects), include dyspnea, wheezing, pneumonitis, pulmonary infiltrates, pleural effusions, noncardiogenic pulmonary edema, pulmonary insufficiency and hypoxia requiring supplemental oxygen or ventilatory support, acute respiratory distress syndrome, and pulmonary fibrosis.1,24 Patients with symptomatic intrinsic lung disease or extensive tumor involvement of the lungs, resulting in dyspnea at rest, experience more severe pulmonary toxicity associated with trastuzumab.1 (See Precautions and Contraindications.)

Among patients receiving trastuzumab and paclitaxel as adjuvant therapy for breast cancer, the most common pulmonary toxicity was dyspnea (study 1: 12%, study 2: 2.5%).1 Pneumonitis/pulmonary infiltrates and respiratory failure, sometimes fatal, also occurred in patients receiving trastuzumab and chemotherapy.1

Among patients with metastatic breast cancer, increased cough occurred in 26 or 41% of patients receiving trastuzumab as a single agent or in combination with paclitaxel, respectively.1 Dyspnea and pharyngitis have been reported in 22 and 12%, respectively, of patients receiving trastuzumab monotherapy for metastatic breast cancer.1 Rhinitis and sinusitis have been reported in 14 and 9%, respectively, of patients receiving trastuzumab as a single agent and in 22 and 21%, respectively, of patients receiving trastuzumab and paclitaxel for metastatic breast cancer.1 Other adverse respiratory effects, including apnea, asthma, hypoxia, laryngitis, and pneumothorax, have been reported in patients receiving trastuzumab.42

Infusion-related Effects

Serious infusion-related reactions, sometimes fatal, have been reported infrequently in patients receiving trastuzumab.1,24 Severe infusion-related reactions include bronchospasm, hypoxia, and severe hypotension.1 In most patients experiencing such reactions, manifestations typically occurred with the first dose of trastuzumab, with onset generally occurring during or immediately following the infusion; however, the onset and clinical course were variable.1,24 In some patients, symptoms progressively worsened.1 In some patients, initial improvement was followed by marked clinical deterioration.1 Delayed adverse events with rapid clinical deterioration occurring following completion of trastuzumab infusion also has been reported.1 Fatal infusion-related reactions resulted in death within hours or days of the infusion.1 (See Infusion-related Toxicity under Dosage: Dosage Modification for Toxicity and Contraindications for Continued Therapy, in Dosage and Administration. Also see Infusion-related Effects under Cautions: Precautions and Contraindications.)

Other infusion-related symptoms, typically consisting of chills1,2 and/or fever,1,2 occurred in approximately 40% of patients with metastatic breast cancer in clinical trials during the first infusion of trastuzumab.1,4 Other manifestations of infusion reactions include nausea, vomiting, pain (including pain at tumor sites), rigors, headache, dizziness, dyspnea, hypotension, elevated blood pressure, rash, and asthenia.1 On second (or subsequent) infusions of trastuzumab administered as monotherapy or in combination with chemotherapy, infusion-related reactions occurred in 21 or 35% of patients, respectively, and were severe in 1.4% or 9% of patients, respectively.1

Sensitivity Reactions

Serious infusion-related reactions may manifest as hypersensitivity reactions, including anaphylaxis, angioedema, bronchospasm, and/or hypotension, in patients receiving trastuzumab.1,24 See Cautions: Infusion-related Effects.

Allergic reactions have occurred in 3% of patients receiving trastuzumab monotherapy and 8% of patients receiving trastuzumab and paclitaxel for metastatic breast cancer.1 Anaphylactoid reactions have been reported in patients receiving trastuzumab.42

Hematologic Effects

Hematologic toxicity occurs infrequently in patients receiving trastuzumab as a single agent.1 Grade 3 adverse hematologic effects, including leukopenia, anemia, and thrombocytopenia, each occurred in less than 1% of patients receiving trastuzumab monotherapy in clinical trials, and grade 4 hematologic toxicity was not reported.1

Deaths caused by sepsis in patients with severe neutropenia have been reported when trastuzumab is used in combination with myelosuppressive chemotherapy for metastatic breast cancer.1 In controlled clinical trials, the incidence of septic death was not increased in patients receiving trastuzumab in combination with chemotherapy.1 Although the mechanism is not known, trastuzumab is thought to exacerbate chemotherapy-induced neutropenia.1 In randomized clinical trials in women with metastatic breast cancer, the incidences of moderate or severe neutropenia and of febrile neutropenia were higher in patients receiving trastuzumab in combination with myelosuppressive chemotherapy than in those receiving chemotherapy alone.1 In a randomized trial, moderate or severe neutropenia occurred more frequently in patients receiving trastuzumab in combination with myelosuppressive chemotherapy for metastatic breast cancer than in those receiving chemotherapy alone (32 versus 22%).1 The incidence of febrile neutropenia also was higher in patients receiving trastuzumab in combination with myelosuppressive chemotherapy for metastatic breast cancer than in those receiving chemotherapy alone (23 versus 17%).1 Among patients receiving adjuvant therapy for breast cancer, neutropenia occurred more frequently in patients receiving trastuzumab and chemotherapy than in those receiving chemotherapy alone (study 1: 7.1 versus 4.5%, grade 4-5 neutropenia in study 2: 2 versus 0.7%).1

Leukopenia and anemia occurred in 24 and 14%, respectively, of patients receiving trastuzumab in combination with paclitaxel for metastatic breast cancer in a randomized trial.1 The incidence of leukopenia was increased in patients receiving trastuzumab combined with chemotherapy compared with those receiving chemotherapy alone (53 versus 37%) for metastatic breast cancer.42 The incidence of anemia was higher in patients receiving trastuzumab combined with chemotherapy compared with those receiving chemotherapy alone for metastatic breast cancer (30 versus 21%) or as adjuvant therapy for breast cancer (study 1: 13 versus 7%).1

Other adverse hematologic effects reported in patients receiving trastuzumab in clinical trials include pancytopenia, acute leukemia (see Mutagenicity and Carcinogenicity), and coagulation disorder.42

Cardiovascular Effects

Deaths from cardiomyopathy have occurred in patients receiving trastuzumab.1 Trastuzumab can cause left ventricular myocardial dysfunction characterized by a decline in ejection fraction and manifestations of congestive heart failure.1 Cardiotoxicity manifested by dyspnea, increased cough, paroxysmal nocturnal dyspnea, peripheral edema, S₃ gallop, cardiomyopathy, congestive heart failure, and/or reduced ejection fraction (decrease of greater than 10%) has been observed in patients receiving trastuzumab.4 Cardiac dysfunction associated with trastuzumab may be severe and in some cases has resulted in disabling heart failure, mural thrombosis and stroke, and/or death.1 Trastuzumab also can cause asymptomatic decline in left ventricular ejection fraction.1 Volume overload and congestive heart failure have been reported as complications of nephrotic syndrome in patients receiving trastuzumab.1 (See Cautions: Renal and Genitourinary Effects.)

In patients receiving trastuzumab monotherapy for metastatic breast cancer in an open-label, phase 2 study, cardiac dysfunction including congestive heart failure occurred in 7% of patients, and class III or IV cardiac dysfunction (according to the New York Heart Association [NYHA] classification system with class IV being the most severe level of cardiac failure) was reported in 5% of patients.1 Among patients receiving a combination of trastuzumab and paclitaxel for metastatic breast cancer in a randomized, phase 3 trial, cardiac dysfunction including congestive heart failure was reported in 11% of patients, and 4% of patients experienced NYHA class III or IV cardiac dysfunction.1

Among patients receiving adjuvant trastuzumab in 2 North American randomized trials, the cumulative incidence of class III or IV congestive heart failure or death from cardiac causes at 3 years was 4.1% in trial B-31 (study 1) and 2.9% in trial N9831 (study 2).28,31,46 The incidence of new-onset left ventricular dysfunction was approximately twofold higher in patients receiving trastuzumab and paclitaxel versus paclitaxel alone following adjuvant chemotherapy with doxorubicin and cyclophosphamide.1,28 About 50% of the adverse cardiac events among patients receiving trastuzumab were identified by the completion of paclitaxel therapy and about 90% were identified within 1 year of the completion of paclitaxel therapy.1 In an international randomized trial, the incidence of class III or IV congestive heart failure in patients receiving adjuvant trastuzumab was 0.5% at 1 year.29

In a randomized trial, patients who received trastuzumab in combination with an anthracycline (rather than paclitaxel) for advanced or metastatic breast cancer had the highest incidence of cardiotoxicity; cardiac dysfunction including congestive heart failure occurred in 28% of patients, and 19% of patients developed NYHA class III or IV cardiac dysfunction.1 Because of the increased frequency and severity of cardiac toxicity, most experts believe that the clinical benefit obtained from the concomitant use of trastuzumab with an anthracycline and cyclophosphamide regimen does not outweigh the increased risk of toxicity, and combined therapy with an anthracycline is not recommended for the treatment of advanced or metastatic breast cancer.6,17,19

For discussion of risks of cardiotoxicity, precautions and contraindications, and monitoring requirements in patients receiving trastuzumab therapy, see Cardiovascular Effects under Cautions: Precautions and Contraindications.

Among patients receiving trastuzumab and paclitaxel as adjuvant therapy for breast cancer, hot flushes (flashes) (study 1: 17%) have been reported.1 Among patients with metastatic breast cancer, tachycardia has been reported in 5% of patients receiving trastuzumab as a single agent and in 12% of patients receiving trastuzumab in combination with paclitaxel.1 Peripheral edema and edema occurred in 10 and 8%, respectively, of patients receiving trastuzumab alone for metastatic breast cancer.1 The incidence of thrombosis/embolism was higher in patients receiving trastuzumab and chemotherapy versus chemotherapy alone for metastatic breast cancer (study 3: 2 versus 0%) or as adjuvant therapy for breast cancer (study 1: 3 versus 1%).1 Other adverse cardiovascular effects reported in patients receiving trastuzumab in clinical trials include pericardial effusion, cardiac arrest, syncope, hemorrhage, shock, and arrhythmia.42

GI Effects

Diarrhea, typically mild to moderate in severity, occurred in 25 or 45% of patients receiving trastuzumab as a single agent or in combination with paclitaxel, respectively, for metastatic breast cancer.1 An increased incidence of diarrhea was observed in patients receiving trastuzumab in combination with chemotherapy compared with those receiving trastuzumab alone.1 Among patients with metastatic breast cancer, nausea and vomiting have been reported in 33 and 23%, respectively, of patients receiving trastuzumab as a single agent and in 51 and 37%, respectively, of patients receiving trastuzumab and paclitaxel; nausea in combination with vomiting1 occurred in 8% of patients receiving trastuzumab as a single agent in clinical trials.1 Some patients experiencing adverse GI effects of trastuzumab consequently had metabolic complications, such as dehydration and hypokalemia.6 Anorexia occurred in 14% of patients receiving trastuzumab alone and in 24% of patients receiving trastuzumab and paclitaxel for metastatic breast cancer.1

Other adverse GI effects, including gastroenteritis, hematemesis, ileus, intestinal obstruction, colitis, esophageal ulcer, stomatitis, and pancreatitis, have been reported in patients receiving trastuzumab.42

Infectious Complications

Febrile neutropenia and infection with neutropenia resulting in death have been reported in patients receiving trastuzumab in combination with myelosuppressive chemotherapy.1 (See Cautions: Hematologic Effects.)

Among patients with metastatic breast cancer, infection has been reported in 20 or 47% of patients receiving trastuzumab as a single agent or in combination with paclitaxel, respectively.1 Among patients receiving trastuzumab and paclitaxel as adjuvant therapy for breast cancer, infection/febrile neutropenia (study 1: 22%, grade 3-5 infection/febrile neutropenia in study 2: 3%) has been reported.1 Compared with patients receiving chemotherapy alone, patients receiving trastuzumab combined with chemotherapy for metastatic breast cancer or as adjuvant therapy for early breast cancer experienced an increased incidence of infections (study 3: 46 versus 30%, study 1: 22 versus 14%).1 Upper respiratory tract infections, typically mild, and infections of indwelling catheters were the most commonly reported infectious complications in patients receiving trastuzumab for metastatic breast cancer.42 Infections of the upper respiratory tract, skin, and urinary tract were the most commonly reported infectious complications in patients receiving trastuzumab as adjuvant therapy for breast cancer.1 Urinary tract infection occurred in 5% of patients receiving trastuzumab monotherapy for metastatic breast cancer in clinical trials.1 Lymphangitis and cellulitis also have been reported in patients receiving the drug.42

Musculoskeletal Effects

Back pain has been reported in 22% of patients receiving trastuzumab monotherapy for metastatic breast cancer in clinical trials.1 Among patients with metastatic breast cancer, bone pain and arthralgia have occurred in 7 and 6%, respectively, of patients receiving trastuzumab as a single agent and in 24 and 37%, respectively, of patients receiving trastuzumab and paclitaxel.1 Among patients receiving trastuzumab and paclitaxel as adjuvant therapy for breast cancer, arthralgia (study 1: 31%, study 2: 11%) and myalgia (study 2: 10%) have been reported.1 Bone necrosis, pathologic fractures, and myopathy also have been reported in patients receiving trastuzumab.42

Dermatologic and Immunologic Reactions

Among patients receiving trastuzumab and paclitaxel as adjuvant therapy for breast cancer, rash/desquamation (study 1: 11%) and nail changes (study 2: 9%) have been reported.1 Among patients with metastatic breast cancer, rash has been reported in 18 or 38% of patients receiving trastuzumab as a single agent or in combination with paclitaxel, respectively.1 Acne and herpes simplex occurred in 11 and 12%, respectively, of patients receiving trastuzumab and paclitaxel, and each has been reported in 2% of patients receiving trastuzumab alone for metastatic breast cancer.1 Other adverse dermatologic effects, including herpes zoster and skin ulceration, have been reported in patients receiving trastuzumab.42

Of 903 women receiving trastuzumab for metastatic breast cancer, human anti-human antibody (HAHA) to the drug has been detected in one patient, who had no allergic reactions.1

Flu-like Syndrome

Flu-like syndrome has occurred in about 10% of patients receiving trastuzumab alone or in combination with chemotherapy for metastatic breast cancer.1 Pain, asthenia, and abdominal pain have been reported in 47, 42, and 22%, respectively, of patients receiving trastuzumab monotherapy for metastatic breast cancer.1

Nervous System Effects

Among patients with metastatic breast cancer, paresthesia, which occurred in 48% of patients receiving trastuzumab and paclitaxel, occurred in 9% of patients receiving trastuzumab alone and 39% of those receiving paclitaxel alone.1 Peripheral neuritis and neuropathy have been reported in 2 and 1%, respectively, of patients receiving trastuzumab as a single agent and in 23 and 13%, respectively, of patients receiving trastuzumab and paclitaxel for metastatic breast cancer.1 A larger cumulative dose of paclitaxel given in conjunction with trastuzumab (approximately 20% greater than the cumulative dose in patients receiving paclitaxel alone) may have contributed to the increased incidence of paresthesia, peripheral neuritis, and neuropathy in these patients compared with those receiving paclitaxel alone.6,18,19

Among patients with metastatic breast cancer, headache, insomnia, and dizziness have occurred in 26, 14, and 13%, respectively, of patients receiving trastuzumab monotherapy.1 Depression has been reported in 6% of patients receiving trastuzumab as a single agent and in 12% of patients receiving trastuzumab and paclitaxel for metastatic breast cancer.1 Among patients receiving trastuzumab and paclitaxel as adjuvant therapy for breast cancer, headache (study 1: 6%) and insomnia (study 1: 4%) have been reported.1 Other adverse neurologic effects, including ataxia, confusion, seizures, hydrocephalus, and manic reaction, have been reported in patients receiving trastuzumab.42

Endocrine and Metabolic Effects

Adverse endocrine and metabolic effects, including hypothyroidism, hypercalcemia, hypomagnesemia, hyponatremia, and hypoglycemia, have been reported in patients receiving trastuzumab.42 Growth retardation and weight loss also occurred in patients receiving the drug.42

Hepatic Effects

Ascites, hepatitis, and hepatic failure have been reported in patients receiving trastuzumab.42

Ocular Effects

Amblyopia has been reported in patients receiving trastuzumab.42

Renal and Genitourinary Effects

Nephrotic syndrome with pathologic evidence of glomerulopathy has been reported rarely in patients receiving trastuzumab.1 Onset has ranged from 4 to approximately 18 months following initiation of trastuzumab therapy.1 Pathologic findings have included membranous glomerulonephritis, focal glomerulosclerosis, and fibrillary glomerulonephritis, and complications have included volume overload and congestive heart failure.1 Renal failure has been reported in patients receiving trastuzumab.42

Other adverse genitourinary effects reported in patients receiving trastuzumab include hematuria, hemorrhagic cystitis, hydronephrosis, and pyelonephritis.42

Other Adverse Effects

Among patients with metastatic breast cancer, accidental injury has been reported in 6% of patients receiving trastuzumab as a single agent and in 13% of patients receiving trastuzumab and paclitaxel.1 Among patients receiving trastuzumab and paclitaxel as adjuvant therapy for breast cancer, fatigue (study 1: 28%) has been reported.1 Other adverse effects occurring in patients receiving trastuzumab in clinical trials include radiation injury and deafness.42

Precautions and Contraindications

Serious adverse events, rarely fatal, including severe respiratory effects, such as acute respiratory distress syndrome (see Cautions: Respiratory Effects), severe infusion-related reactions (see Cautions: Infusion-related Effects), and severe hypersensitivity reactions, such as anaphylaxis (see Cautions: Sensitivity Reactions), have occurred in patients receiving trastuzumab.1,24 In most patients experiencing severe adverse reactions, manifestations typically occurred during or within 24 hours of the infusion of trastuzumab.1 In some cases, initial improvement in symptoms was followed by marked and delayed clinical deterioration, and a small number of patients died at home.24 Patients should be informed of the possibility of delayed severe reactions associated with trastuzumab therapy.24

Trastuzumab should be administered with extreme caution in patients with preexisting pulmonary compromise, and the risks and benefits of therapy should be weighed carefully. 24 Most patients experiencing fatal adverse reactions associated with trastuzumab had clinically important preexisting pulmonary compromise secondary to intrinsic lung disease and/or malignant pulmonary involvement.24

Interruption or discontinuance of trastuzumab therapy is required in patients experiencing severe or life-threatening adverse reactions. (See Dosage Modification for Toxicity and Contraindications for Continued Therapy under Dosage and Administration: Dosage.)

Respiratory Effects

Patients with either symptomatic intrinsic pulmonary disease (e.g., asthma, COPD) or extensive tumor involvement of the lungs (e.g., lymphangitic spread of tumor, pleural effusions, parenchymal masses) resulting in dyspnea at rest may be at increased risk of serious adverse pulmonary events associated with trastuzumab, and the manufacturer recommends extreme caution in such patients.1,24

Infusion-related Effects

Patients with preexisting pulmonary compromise may be at increased risk of serious infusion-related adverse effects associated with trastuzumab.24

Sensitivity Reactions

For administration in patients with known hypersensitivity to benzyl alcohol, the preservative in bacteriostatic water for injection (the diluent supplied by the manufacturer), trastuzumab should be reconstituted using sterile water for injection.1 (See Dosage and Administration: Reconstitution and Administration.)

Trastuzumab should be administered with caution in patients with known hypersensitivity to trastuzumab, Chinese Hamster Ovary (CHO) cell proteins, or any component of the formulation.42

Cardiovascular Effects

Because trastuzumab may cause serious adverse cardiovascular effects, including ventricular dysfunction and congestive heart failure, a thorough baseline cardiac evaluation including history, physical examination, and cardiac function tests (i.e., echocardiogram and/or MUGA scan) should be performed prior to initiating trastuzumab therapy.1,28,31

Among patients with metastatic breast cancer, the risk of cardiac dysfunction including congestive heart failure associated with trastuzumab therapy may be increased with increased age, preexisting cardiac disease, or prior cardiotoxic therapy (e.g., anthracycline therapy or radiation therapy to the chest area).1,17 Potential benefit versus the increased risk of cardiac toxicity should be weighed carefully when deciding whether the use of trastuzumab is advisable in patients with preexisting cardiac disease.17,18,19

Among patients receiving adjuvant therapy for breast cancer, the risk of symptomatic cardiomyopathy associated with trastuzumab may be increased in patients experiencing decline in left ventricular ejection fraction (LVEF) to below the lower limit of normal (following completion of treatment with doxorubicin and cyclophosphamide or during treatment with trastuzumab), patients with previous or concurrent use of antihypertensive medications, and geriatric patients.1,46 According to the exclusion criteria applied in the North American randomized trials, use of adjuvant trastuzumab therapy is not recommended in patients with angina pectoris requiring medication; arrhythmia requiring medication; a severe conduction abnormality; clinically important valvular disease; cardiomegaly on chest radiography; left ventricular hypertrophy on echocardiography; poorly controlled hypertension; clinically important pericardial effusion; or a history of myocardial infarction, congestive heart failure, or cardiomyopathy.28,31 Adjuvant trastuzumab therapy should be initiated only if the measurement of LVEF at baseline is within normal limits (at least 50%) and the decrease from the baseline value is less than 15 points following completion of adjuvant chemotherapy with doxorubicin and cyclophosphamide.1,28,31 Patients who develop clinical manifestations of cardiac toxicity during adjuvant chemotherapy with doxorubicin and cyclophosphamide should not receive trastuzumab.28 In clinical trials of adjuvant therapy for breast cancer, 6% of patients were unable to receive trastuzumab following completion of doxorubicin and cyclophosphamide therapy because of cardiac dysfunction.1

Left ventricular function should be monitored frequently in patients receiving trastuzumab.1 For patients with preexisting cardiac dysfunction, more frequent monitoring is required.1 Monitoring will not identify all patients who will develop cardiac dysfunction.1

In patients receiving adjuvant trastuzumab, cardiac function must be assessed at regular intervals using MUGA scan or echocardiogram performed at baseline (prior to adjuvant therapy with doxorubicin and cyclophosphamide), at the completion of adjuvant chemotherapy with doxorubicin and cyclophosphamide (immediately prior to initiation of trastuzumab therapy), at 3 months following the initiation of concomitant therapy with paclitaxel and trastuzumab, at 3 months following the initiation of trastuzumab monotherapy (upon completion of concomitant therapy with paclitaxel and trastuzumab), and at 3 months following the completion of trastuzumab monotherapy.1,28,31 Age and LVEF following adjuvant chemotherapy with doxorubicin and cyclophosphamide may be risk factors for symptomatic cardiac dysfunction in patients being considered for adjuvant therapy with trastuzumab.31

A thorough cardiac assessment, including evaluation of left ventricular function, should be performed in candidates for trastuzumab therapy for advanced or metastatic breast cancer, and cardiac function should be monitored frequently in those receiving the drug.1,14 Following baseline echocardiogram or MUGA scan, clinicians recommend cardiac monitoring with either test as indicated by the presence of clinical manifestations of cardiac dysfunction or at regular intervals every 1-4 months according to the patient's age and risk of cardiac toxicity.19 Extreme caution is advised during trastuzumab therapy for metastatic disease in patients with preexisting cardiac dysfunction. 17,42

Because of the increased risk of cardiotoxicity, most experts generally do not recommend use of trastuzumab in combination with an anthracycline agent for the treatment of metastatic breast cancer.6,19

Dispensing and Administration Precautions

Trastuzumab (Herceptin^®) should not be confused with ado-trastuzumab emtansine (Kadcyla^®).1001,1005,1006 Because of the similarity between the original generic name of Kadcyla^® (trastuzumab emtansine) and the generic name for Herceptin^® (trastuzumab), the US Food and Drug Administration (FDA) approved the addition of the prefix “ado” to the generic name for Kadcyla^® (i.e., ado-trastuzumab emtansine).1004 However, the potential exists for dispensing or prescribing errors involving these drugs.1001,1004,1005,1006 Such medication errors may be associated with severe toxicity or lack of appropriate therapy in patients who did not receive the intended drug.1001,1004,1005 The manufacturer of ado-trastuzumab emtansine (Kadcyla^®) states that this drug should not be substituted for or used with trastuzumab (Herceptin^®).1002 Therefore, extra care should be exercised to ensure the accuracy of prescriptions for trastuzumab (Herceptin^®) and ado-trastuzumab emtansine (Kadcyla^®).1001,1002,1005,1006 (See Special Alerts.)

Pediatric Precautions

Safety and efficacy of trastuzumab in children younger than 18 years of age have not been established.1,18

Geriatric Precautions

Although safety and efficacy of trastuzumab in geriatric patients 65 years of age or older have not been established specifically, the manufacturer cautions that clinical data currently are insufficient to exclude the possibility of age-related differences during trastuzumab therapy.1 The risk of cardiotoxicity associated with trastuzumab is increased in geriatric patients compared with younger patients receiving either adjuvant therapy for early breast cancer or treatment for metastatic breast cancer.1,18,19

Mutagenicity and Carcinogenicity

Data from in vitro and in vivo tests of trastuzumab, including Ames tests, the micronucleus assay, and tests in human peripheral blood lymphocytes, have not shown any evidence of mutagenic activity.1

The carcinogenicity of trastuzumab has not been evaluated.1 Acute leukemia and cervical cancer have been reported in patients receiving trastuzumab.42 Several cases of secondary leukemia have occurred in patients receiving trastuzumab.18

Pregnancy, Fertility, and Lactation

Pregnancy

Oligohydramnios has been reported in women receiving trastuzumab during pregnancy.1 Placental transfer of trastuzumab has been observed in monkeys.1 Although reproduction studies in cynomolgus monkeys using trastuzumab dosages up to 25 times the weekly human maintenance dosage of 2 mg/kg have not revealed evidence of harm to the fetus,1 the important role of the HER2 receptor in embryonic development of the cardiac and central nervous systems raises concerns about possible teratogenic effects of trastuzumab.6,19,33 The HER2 receptor is expressed at high levels in many embryonic tissues, including cardiac and neural tissues, and death of embryos in early gestation has been observed in mice lacking the HER2 protein.1,6,33 Further study is needed to determine whether trastuzumab has teratogenic effects in humans.18,33 The possibility that trastuzumab may persist in maternal tissues for up to 5-6 months after the last dose should be considered.33 There are no adequate and controlled studies to date using trastuzumab in pregnant women, and the drug should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.1

Fertility

Reproduction studies in cynomolgus monkeys using trastuzumab dosages up to 25 times the weekly human maintenance dosage of 2 mg/kg have not revealed evidence of impaired fertility.1

Lactation

When trastuzumab was administered in lactating cynomolgus monkeys at dosages 25 times the usual human maintenance dosage of 2 mg/kg weekly, distribution of the drug in milk was demonstrated.1 No adverse effects on growth or development from birth to 3 months of age were observed in infant monkeys with measurable serum trastuzumab concentrations.1 It is not known whether trastuzumab is distributed into human milk.1 Because human IgG is distributed in milk, and because of the potential for absorption of trastuzumab and adverse reactions to the drug in nursing infants, women should be advised to discontinue nursing during trastuzumab therapy and for 6 months following the last dose of the drug.1

Formal drug interaction studies of trastuzumab have not been conducted.1 However, the incidence of most common adverse effects of the drug has been increased in patients receiving combination chemotherapy.1 (See Cautions.)

Anthracycline Antineoplastic Agents

The risk of trastuzumab-induced cardiotoxic effects is increased in patients receiving an anthracycline concomitantly.1,6,26 (See Cautions: Cardiovascular Effects.) Such combined therapy currently is not recommended by most experts for use in the treatment of metastatic breast cancer.6,17,19,26

Paclitaxel

In clinical studies, a 1.5-fold increase in mean trough serum concentrations of trastuzumab was reported when the drug was administered concomitantly with paclitaxel versus an anthracycline and cyclophosphamide.1 In primate studies, administration of trastuzumab in combination with paclitaxel resulted in a twofold decrease in trastuzumab clearance.1 The clinical importance of the interaction between trastuzumab and paclitaxel is not known.18,19

Acute Toxicity

Limited information is available on the acute toxicity of trastuzumab.1 The acute lethal dose of trastuzumab in humans is not known.18 Overdosage has not been reported in clinical trials with patients receiving single doses of trastuzumab of up to 500 mg.1

Pharmacology

Trastuzumab is an antineoplastic agent that inhibits proliferation of tumor cells that overexpress HER2 .1 The HER2 proto-oncogene (also known as c- erb B2 or neu ) encodes a 185-kd transmembrane tyrosine kinase receptor known as p185^HER2 or human epidermal growth factor receptor 2 ( HER2 ), which has partial homology with other members of the epidermal growth factor receptor family.1,4,19 Trastuzumab, a recombinant humanized murine monoclonal antibody, binds specifically to the extracellular domain of the HER2 receptor or HER2/neu 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 Results from in vitro assays and animal studies have shown that trastuzumab inhibits the proliferation of human tumor cells that overexpress HER2/neu protein.1,7 Trastuzumab-mediated antibody-dependent cellular cytotoxicity (ADCC) also has been demonstrated and, according to in vitro studies, occurs preferentially in cells that overexpress the HER2 protein compared with cells that do not.1

Amplification of the HER2 oncogene and/or overexpression of the HER2 protein occurs in 25-30% of node-positive or -negative primary breast cancers, and several studies have shown that HER2 amplification and/or overexpression is an independent predictor of poor prognosis, including more rapid disease progression and shorter overall survival, in patients with node-positive breast cancer.8,11,15 Overexpression of this growth factor receptor also has been shown to be associated with other adverse prognostic factors in breast cancer, including advanced pathologic stage, DNA ploidy, increased S-phase fraction, high nuclear grade, absence of estrogen and progesterone receptors, and number of metastatic axillary lymph nodes.2

Pharmacokinetics

Data from studies in patients with metastatic breast cancer receiving trastuzumab 10-500 mg once weekly by IV infusion over short periods indicate that the pharmacokinetics of the drug are dose dependent.1 Limited data suggest that the pharmacokinetics of trastuzumab are not affected by age or increased serum creatinine concentrations up to 2 mg/dL.1

Absorption

In patients with metastatic breast cancer receiving a loading dose of 4 mg/kg IV followed by a weekly maintenance dose of 2 mg/kg IV, peak and trough plasma concentrations of trastuzumab at steady state (between weeks 16 and 32) averaged approximately 123 and 79 mcg/mL, respectively.1 In patients with metastatic breast cancer receiving trastuzumab 500 mg once weekly by short-duration IV infusion, peak plasma concentrations of the drug averaged 377 mcg/mL.1

Measurable serum concentrations of circulating extracellular domain of the HER2 receptor (i.e., shed antigen) have been detected in some patients with tumors that overexpress HER2/neu .1 Shed antigen in concentrations of up to 1880 ng/mL (median: 11 ng/mL) was detected in baseline serum samples of 64% of patients (286/447) receiving a loading dose of trastuzumab 4 mg/kg IV followed by 2 mg/kg IV once weekly.1,18 Higher baseline concentrations of shed antigen were associated with lower trough serum concentrations of trastuzumab;1,16 however, with once-weekly dosing of trastuzumab, target serum concentrations of the drug were attained by week 6 in most patients with elevated serum concentrations of shed antigen.42 Concentration of shed antigen does not appear to affect tumor response to trastuzumab.4

Distribution

Following administration of trastuzumab by short-duration IV infusion, the mean apparent volume of distribution is about 44 mL/kg (approximately equal to serum volume).1,4 It is not known whether trastuzumab crosses the blood-brain barrier or distributes into the CSF.18,19 It also is not known whether trastuzumab crosses the placenta or distributes into milk in humans; however, placental transfer of trastuzumab and distribution of the drug into milk have been observed in monkeys.1

Elimination

The pharmacokinetics of trastuzumab are nonlinear; increased doses of the drug are associated with increased mean half-life and decreased clearance.1 In patients receiving a loading dose of trastuzumab 4 mg/kg IV followed by a weekly maintenance dose of 2 mg/kg IV, elimination half-life averaged 5.8 days (range: 1-32 days).1,16 Following IV infusion of 10 or 500 mg of trastuzumab, elimination half-life averaged 1.7 or 12 days, respectively.1 The metabolism of trastuzumab is not fully understood, but it appears that elimination of the drug would involve clearance of IgG through the reticuloendothelial system.2,5,18,19

Chemistry and Stability

Chemistry

Trastuzumab, a recombinant DNA-derived humanized anti- HER2 monoclonal antibody, is an antineoplastic agent.1,5

Trastuzumab is an IgG₁ kappa immunoglobulin containing human framework regions and the complementarity-determining regions of a murine antibody (4D5) that binds to HER2/neu , a transmembrane receptor protein that is overexpressed in selected cancer cells.1,2 The drug occurs as a sterile, lyophilized, white to pale yellow powder and is soluble in water;1,23 trastuzumab powder for injection also contains histidine monohydrochloride, histidine, α,α-trehalose dihydrate, and polysorbate (Tween^®) 20.1 Following reconstitution as recommended with bacteriostatic water for injection containing benzyl alcohol (see Dosage and Administration: Reconstitution and Administration), solutions containing trastuzumab 21 mg/mL are clear to slightly opalescent and colorless to pale yellow and have a pH of about 6.1,22

Stability

Vials of trastuzumab should be stored at 2-8°C; when stored under recommended conditions, commercially available trastuzumab powder for injection should be stable up to the date of expiration marked on the vial.1,18

Following reconstitution of the sterile powder with bacteriostatic water for injection containing benzyl alcohol (as supplied by the manufacturer), trastuzumab solutions are stable for 28 days when refrigerated at 2-8°C.1 If trastuzumab powder for injection is reconstituted with sterile water for injection (e.g., in patients with hypersensitivity to benzyl alcohol),1 the possibility of microbial contamination should be considered, and the manufacturer recommends that such solutions be used immediately and unused portions discarded.1 The manufacturer states that use of other diluents for the reconstitution of trastuzumab should be avoided.1 Trastuzumab solutions should not be frozen following reconstitution or dilution.1

Reconstituted solutions of trastuzumab diluted in 0.9% sodium chloride injection are stable for no more than 24 hours when prepared and stored in polyvinyl chloride or polyethylene bags at 2-8°C.1,18 The manufacturer states that 5% dextrose injection should not be used as a diluent for trastuzumab solutions;1 diluents other than those recommended by the manufacturer may not maintain the stability or sterility of the antibody solution.1,18,22

For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].

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