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    Monoclonal Antibodies that Target HER2/neu

    BOXED WARNING

    Angioedema, hypotension, infusion-related reactions, respiratory distress syndrome

    Administration of trastuzumab products can result in infusion-related reactions characterized by fever and chills, nausea, vomiting, pain (in some cases at tumor sites), headache, dizziness, dyspnea, hypotension, rash, and asthenia. In postmarketing experience, serious and fatal infusion reactions have also been reported, including bronchospasm, anaphylaxis, angioedema, hypoxia, and severe hypotension. Infusion reactions were usually reported during or immediately following the initial infusion, but the onset and clinical course may vary, including progressive worsening, initial improvement followed by clinical deterioration, or delayed post-infusion events with rapid deterioration. For fatal events, death occurred within hours to days following a serious infusion reaction. Decrease the infusion rate for mild to moderate infusion reactions. Hold the infusion of trastuzumab product in all patients experiencing dyspnea or clinically significant hypotension, or if medical intervention (e.g., epinephrine, corticosteroids, diphenhydramine, bronchodilators, and oxygen) is required. Monitor patients until complete resolution of signs and symptoms. Discontinue trastuzumab product for anaphylaxis, angioedema, or acute respiratory distress syndrome; strongly consider discontinuation of therapy in patients with other severe reactions, as no data exist regarding the most appropriate method of identification of patients who may safely be retreated with trastuzumab. Most patients who experienced a severe infusion reaction were premedicated with antihistamines and/or corticosteroids before resumption of trastuzumab infusion. Some patients tolerated trastuzumab, but some patients had recurrent severe infusion reactions despite premedications.[28061] [62658] [63839] [63887] [64521] [64524]

    Asthma, chronic lung disease (CLD), chronic obstructive pulmonary disease (COPD), pneumonitis, pulmonary disease, pulmonary fibrosis, pulmonary toxicity

    Use trastuzumab products with caution in patients with preexisting chronic lung disease (CLD) such as chronic obstructive pulmonary disease (COPD), asthma, or pulmonary fibrosis. Trastuzumab products can cause serious and fatal pulmonary toxicity, including dyspnea, interstitial pneumonitis, pulmonary infiltrates, pleural effusions, non-cardiogenic pulmonary edema, pulmonary insufficiency and hypoxia, acute respiratory distress syndrome, and pulmonary fibrosis, which may be more severe in patients with symptomatic intrinsic lung disease or with more extensive tumor involvement of the lungs that results in dyspnea at rest. These reactions can also occur as sequelae of infusion reactions. Discontinue trastuzumab product for interstitial pneumonitis.

    Cardiac arrhythmias, cardiac disease, cardiomyopathy, geriatric, heart failure, hypertension, ventricular dysfunction

    Use trastuzumab products with caution in patients with a history of cardiac disease, heart failure, cardiomyopathy, ventricular dysfunction, hypertension, or cardiac arrhythmias, as trastuzumab products can cause these issues as well as cardiac death; an asymptomatic decline in the left ventricular ejection fraction (LVEF) is also possible. The risk of cardiac dysfunction was increased in geriatric patients compared to younger patients in clinical trials. Obtain a baseline measurement of LVEF by echocardiogram or MUGA immediately prior to initiation of trastuzumab products, every 3 months during treatment, upon completion of therapy, and every 6 months for at least 2 years after treatment for adjuvant therapy. An interruption or discontinuation of therapy may be necessary for a decline in LVEF; the safety of continuing or resuming trastuzumab product in patients with treatment-induced left ventricular cardiac dysfunction has not been adequately studied. However, 22 of 25 patients who developed left ventricular dysfunction during adjuvant trastuzumab therapy (after anthracycline treatment) had stable LVEF measurements and no CHF recurrence after rechallenge once symptoms were stable and patients were on maximum tolerated doses of ACE inhibitors and beta-blockers.[33927] In another study, 16 of 26 patients with metastatic breast cancer who developed trastuzumab-related cardiotoxicity and fully recovered did not experience additional cardiotoxicity upon rechallenge; 10 patients had a subsequent cardiac event, with varying degrees of resolution after trastuzumab discontinuation.[33928] Trastuzumab was continued in 17 of 34 metastatic breast cancer patients with asymptomatic cardiac dysfunction in an additional retrospective study; 13 of these patients had complete recovery without specific cardiac treatment, 2 had complete recovery with treatment, and 2 were not assessed.[33928] Monitoring of the LVEF should occur more frequently, at 4-week intervals, if treatment is held for significant left ventricular cardiac dysfunction.[28061] [62658] [63839] [63887] [64521] [64524] Elevated troponin I immediately before or after trastuzumab administration may also be a predictor of cardiotoxicity.[41906] Patients who receive anthracycline therapy after stopping a trastuzumab product may be at increased risk of cardiac dysfunction; among patients receiving trastuzumab products as a single agent or in combination therapy, the highest absolute incidence of symptomatic cardiac dysfunction occurs when trastuzumab product is administered with an anthracycline.[28061] [62658] [63839] [63887] [64521] [64524]

    Pregnancy

    Serious fetal harm can occur if trastuzumab product is administered during pregnancy or within 7 months prior to conception.[28061] [62658] [63839] [63887] Counsel women to avoid pregnancy during trastuzumab therapy and for 7 months after the last dose. If a woman becomes pregnant while receiving or within 7 months of receiving trastuzumab, inform her of the fetal risks, monitor for oligohydramnios, and immediately report to the pregnancy pharmacovigilance program at Genentech (1-888-835-2555).[28061] If oligohydramnios occurs, perform fetal testing that is appropriate for gestational age and is consistent with community standards of care. Oligohydramnios and oligohydramnios sequence (manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death) have occurred in pregnant women who received trastuzumab alone or in combination with chemotherapy. In some women, the amniotic fluid index increased after trastuzumab cessation. In one case, treatment was resumed with trastuzumab after the amniotic fluid index improved, resulting in a recurrence of oligohydramnios.[28061] [62658] [63839] [63887]

    Contraception requirements, pregnancy testing, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during and after treatment with trastuzumab product. Trastuzumab can be teratogenic if taken by the mother during pregnancy or within 7 months prior to conception. Females should avoid pregnancy and use effective contraception during and for at least 7 months after treatment with trastuzumab product. Females of reproductive potential should undergo pregnancy testing prior to treatment initiation.   Women who become pregnant while receiving trastuzumab or within 7 months of the last dose should be apprised of the potential hazard to the fetus; healthcare providers and patients should immediately report trastuzumab exposure to Genentech (1-888-835-2555).[28061]

    DEA CLASS

    Rx

    DESCRIPTION

    Recombinant DNA-derived humanized IgG1 kappa monoclonal antibody against the HER2 protein
    Used for breast and gastric cancers that overexpress HER2
    Monitor left ventricular ejection fraction in all patients before, during, and after treatment; also watch for infusion-related reactions

    COMMON BRAND NAMES

    Herceptin, KANJINTI, Ogivri

    HOW SUPPLIED

    Herceptin/KANJINTI/Ogivri Intravenous Inj Pwd F/Sol: 150mg, 420mg

    DOSAGE & INDICATIONS

    For the treatment of patients with HER2-positive breast cancer.
    NOTE: Patients should be selected based on the presence of HER2 protein overexpression or HER2 gene amplification in tumor specimens. Information on FDA-approved tests for the detection of HER2 protein overexpression and HER2 gene amplification is available at http://www.fda.gov/CompanionDiagnostics. Tests should be specific for breast cancers due to differences in breast vs. gastric histopathology, including incomplete membrane staining and more frequent heterogeneous expression of HER2 seen in gastric cancers.[28061] [62658] [63839] [63887]
    For the treatment of HER2-positive metastatic breast cancer in patients who have failed one or more chemotherapy regimens for metastatic disease as monotherapy.
    Intravenous dosage
    Adults

    4 mg/kg IV over 90 minutes on day 1 (first week only), then 2 mg/kg IV over 30 minutes once weekly until disease progression. Do not substitute trastuzumab for or with ado-trastuzumab emtansine, fam-trastuzumab deruxtecan, or trastuzumab; hyaluronidase. Monotherapy with trastuzumab resulted in an overall response rate of 14% (complete response, 2%; partial response, 12%) in a multicenter, open-label, single-arm clinical trial in patients with relapse after 1 or more prior chemotherapy regimens for metastatic disease. Complete responses only occurred in patients with disease limited to the skin and lymph nodes. The response rate for patients with tumors that tested as CTA 3+ was 18%, while the response rate was 6% for tumors that tested as CTA 2+.

    For the treatment of HER2-positive metastatic breast cancer, in combination with docetaxel†.
    Intravenous dosage
    Adults

    4 mg/kg IV over 90 minutes on day 1 (of first cycle only), then 2 mg/kg IV over 30 minutes once weekly until disease progression or unacceptable toxicity, in combination with docetaxel (100 mg/m2 IV on day 1) every 21 days for 6 to 8 cycles. Do not substitute trastuzumab for or with ado-trastuzumab emtansine, fam-trastuzumab deruxtecan, or trastuzumab; hyaluronidase. In a phase 2 trial of 186 patients with previously untreated HER2-positive metastatic breast cancer, docetaxel/trastuzumab significantly improved overall response rate (ORR) compared to docetaxel alone (61% vs 34%); time-to-progression (TTP) (11.7 vs. 6.1 months) and overall survival (OS) (31.2 vs. 22.7 months) were also significantly improved in the docetaxel/trastuzumab arm. This benefit has been confirmed in other clinical trials, including a phase 3 trial of 263 patients where it was shown to produce a similar TTP and OS to docetaxel/carboplatin/trastuzumab, a regimen with known activity against breast cancer in the adjuvant setting. In a phase 2 trial of 30 women with HER2-overexpressed metastatic breast cancer, docetaxel 35 mg/m2 IV on days 1, 8, and 15 was studied in combination with trastuzumab 2 mg/kg IV (4 mg/kg IV on day 0 of first cycle only) on days 1, 8, and 15, repeated every 28 days until disease progression or unacceptable toxicity; the ORR was 63%.

    For the treatment of HER2-positive metastatic breast cancer, in combination with vinorelbine†.
    Intravenous dosage, EVERY-3-WEEK VINORELBINE
    Adults

    8 mg/kg IV over 90 minutes on day 1 (of the first cycle only), followed 3 weeks later by 6 mg/kg IV over 30 minutes on day 1 every 3 weeks, in combination with vinorelbine (30 mg/m2 or 35 mg/m2 IV bolus on days 1 and 8) every 3 weeks, until disease progression or unacceptable toxicity. Administer vinorelbine after trastuzumab. Do not substitute trastuzumab for or with ado-trastuzumab emtansine, fam-trastuzumab deruxtecan, or trastuzumab; hyaluronidase. In a phase 3 trial, patients with previously untreated locally advanced or metastatic breast cancer randomized to receive trastuzumab plus vinorelbine (n = 141) had a nonsignificant improvement in median time to progression (15.3 vs. 12.4 months) and overall survival (38.8 vs. 35.7 months) compared with trastuzumab plus docetaxel (n = 143). Grade 3 or 4 febrile neutropenia, leukopenia, infection, fever, neuropathy, and edema were significantly worse in the docetaxel arm.

    Intravenous dosage, WEEKLY VINORELBINE
    Adults

    4 mg/kg IV over 90 minutes on day 1 (of the first cycle only), then 2 mg/kg IV over 30 minutes once weekly, in combination with vinorelbine (25 mg/m2 IV once weekly) beginning on day 1, until disease progression or unacceptable toxicity. Administer vinorelbine after trastuzumab. Do not substitute trastuzumab for or with ado-trastuzumab emtansine, fam-trastuzumab deruxtecan, or trastuzumab; hyaluronidase. Trastuzumab plus vinorelbine had a response rate of 51% to 58% in two small clinical trials.[41153] [44678]

    For adjuvant treatment of HER2-positive, node-positive or node-negative (ER/PR negative or with one high-risk feature) breast cancer in combination with paclitaxel, following completion of doxorubicin and cyclophosphamide chemotherapy (AC-TH).
    Intravenous dosage
    Adults

    4 mg/kg IV over 90 minutes on day 1 (of first cycle only), then 2 mg/kg IV over 30 minutes once weekly for a total of 12 weeks, in combination with paclitaxel (either 80 mg/m2 IV weekly or 175 mg/m2 IV every 3 weeks) beginning on day 1 for a total of 12 weeks. On week 13, begin trastuzumab 6 mg/kg IV over 30 to 90 minutes every 3 weeks as monotherapy for a total of 52 weeks of trastuzumab therapy. Begin paclitaxel plus trastuzumab after the completion of 4 cycles of AC chemotherapy (doxorubicin 60 mg/m2 IV and cyclophosphamide 600 mg/m2 IV every 21 days); trastuzumab should NOT be administered concurrently with doxorubicin and cyclophosphamide. Do not substitute trastuzumab for or with ado-trastuzumab emtansine, fam-trastuzumab deruxtecan, or trastuzumab; hyaluronidase. Extending treatment beyond 1 year is not recommended as it increased the risk of asymptomatic cardiac dysfunction (2 years, 8.1%; 1 year, 4.6%) and grade 3 or higher adverse reactions (2 years, 20.4%; 1 year, 16.3%) without improving efficacy. In an efficacy analysis of two randomized clinical trials of patients with HER2-positive breast cancer (n = 3,752), the adjuvant combination of paclitaxel plus trastuzumab after the completion of AC chemotherapy significantly improved both disease-free survival and overall survival compared with paclitaxel alone.

    For adjuvant treatment of HER2-positive, node-positive or node-negative (ER/PR negative or with one high-risk feature) breast cancer in combination with docetaxel, after completion of doxorubicin and cyclophosphamide chemotherapy (AC-TH).
    Intravenous dosage
    Adults

    4 mg/kg IV over 90 minutes on day 1 (of first cycle only), then 2 mg/kg IV over 30 minutes once weekly for a total of 12 weeks, in combination with docetaxel (100 mg/m2 IV every 21 days) beginning on day 1 for a total of 4 cycles (12 weeks). On week 13, begin trastuzumab 6 mg/kg IV over 30 to 90 minutes every 3 weeks as monotherapy for a total of 52 weeks of trastuzumab therapy. Begin docetaxel plus trastuzumab after the completion of 4 cycles of AC chemotherapy (doxorubicin 60 mg/m2 IV and cyclophosphamide 600 mg/m2 IV every 21 days); trastuzumab should NOT be administered concurrently with doxorubicin and cyclophosphamide. Do not substitute trastuzumab for or with ado-trastuzumab emtansine, fam-trastuzumab deruxtecan, or trastuzumab; hyaluronidase. Extending treatment beyond 1 year is not recommended as it increased the risk of asymptomatic cardiac dysfunction (2 years, 8.1%; 1 year, 4.6%) and grade 3 or higher adverse reactions (2 years, 20.4%; 1 year, 16.3%) without improving efficacy. In a randomized clinical trial of patients with HER2-positive breast cancer, adjuvant treatment with docetaxel plus trastuzumab after completion of AC chemotherapy significantly improved disease-free survival compared with docetaxel alone.[28061] [62658] [63839] [63887]

    For adjuvant treatment of HER2-positive, node-positive or node-negative (ER/PR negative or with one high-risk feature) breast cancer as monotherapy, following multimodality anthracycline-based chemotherapy.
    Intravenous dosage
    Adults

    8 mg/kg IV over 90 minutes on day 1 (of the first cycle only), followed 3 weeks later by 6 mg/kg IV over 30 to 90 minutes, repeated every 21 days for a total of 52 weeks. Do not substitute trastuzumab for or with ado-trastuzumab emtansine, fam-trastuzumab deruxtecan, or trastuzumab; hyaluronidase. Trastuzumab therapy should begin within 3 weeks after completion of multi-modality, anthracycline-based chemotherapy. Extending treatment beyond 1 year is not recommended as it increased the risk of asymptomatic cardiac dysfunction (2 years, 8.1%; 1 year, 4.6%) and grade 3 or higher adverse reactions (2 years, 20.4%; 1 year, 16.3%) without improving efficacy. In a randomized clinical trial of patients with HER2-positive breast cancer, one year of adjuvant trastuzumab after the completion chemotherapy and radiation (if applicable) resulted in significantly improved disease-free survival compared with observation; overall survival was not significantly improved.[28061] [62658] [63887] [64521] [63839] [64524]

    For adjuvant treatment of HER2-positive, node-positive or node negative (ER/PR negative or with one high-risk feature) breast cancer, in combination with carboplatin and docetaxel (TCH).
    Intravenous dosage
    Adults

    4 mg/kg IV over 90 minutes on day 1 (of first cycle only), then 2 mg/kg IV over 30 minutes once weekly for a total of 18 weeks, in combination with docetaxel (75 mg/m2 IV) followed by carboplatin (AUC 6 IV over 30 to 60 minutes) every 3 weeks beginning on day 1 for a total of 6 cycles (18 weeks). On week 19, begin trastuzumab 6 mg/kg IV over 30 to 90 minutes every 3 weeks as monotherapy for a total of 52 weeks of trastuzumab therapy. Do not substitute trastuzumab for or with ado-trastuzumab emtansine, fam-trastuzumab deruxtecan, or trastuzumab; hyaluronidase. Extending treatment beyond 1 year is not recommended as it increased the risk of asymptomatic cardiac dysfunction (2 years, 8.1%; 1 year, 4.6%) and grade 3 or higher adverse reactions (2 years, 20.4%; 1 year, 16.3%) without improving efficacy. In a randomized clinical trial, adjuvant treatment with trastuzumab in combination with docetaxel and carboplatin significantly improved disease-free survival compared with doxorubicin plus cyclophosphamide (AC) followed by docetaxel.[28061] [44516] [62658] [63839] [63887]

    For the front-line treatment of HER2-overexpressing metastatic breast cancer, in combination with carboplatin and paclitaxel†.
    Intravenous dosage, EVERY-3-WEEK CARBOPLATIN/PACLITAXEL
    Adults

    4 mg/kg IV over 90 minutes on day 1 (of first cycle only), then 2 mg/kg IV over 30 minutes once weekly, in combination with paclitaxel (175 mg/m2 IV) followed by carboplatin (AUC 6 IV) administered on day 2 every 3 weeks, for at least 6 cycles. After chemotherapy is complete, continue trastuzumab 2 mg/kg IV over 30 minutes once weekly until disease progression or unacceptable toxicity. Do not substitute trastuzumab for or with ado-trastuzumab emtansine, fam-trastuzumab deruxtecan, or trastuzumab; hyaluronidase. The primary endpoint of overall response rate was significantly increased with the addition of carboplatin to trastuzumab/paclitaxel compared with paclitaxel alone in a phase 3 clinical trial (52% vs. 36%). Progression-free survival was also superior in the carboplatin arm (10.7 vs. 7.1 months). Grade 4 neutropenia (36% vs. 12%) and grade 3 thrombocytopenia (9% vs. 1%) occurred more frequently in the carboplatin arm.[34295]

    Intravenous dosage, WEEKLY CARBOPLATIN/PACLITAXEL
    Adults

    4 mg/kg IV over 90 minutes on day 1 (of first cycle only), then 2 mg/kg IV over 30 minutes once weekly, in combination with paclitaxel (80 mg/m2 IV over 1 hour) followed by carboplatin (AUC 2 IV over 15 minutes) on days 1, 8, and 15, repeated every 28 days for a maximum of 6 cycles. On days 1, 8, and 15 in the clinical trial, trastuzumab was administered immediately after paclitaxel and carboplatin infusions. After chemotherapy is complete, continue trastuzumab (2 mg/kg IV over 30 minutes once weekly, or 6 mg/kg IV every 3 weeks) until disease progression or unacceptable toxicity. Do not substitute trastuzumab for or with ado-trastuzumab emtansine, fam-trastuzumab deruxtecan, or trastuzumab; hyaluronidase. In a parallel, multicenter phase 2 trial, weekly administration of paclitaxel/carboplatin/trastuzumab had an overall response rate of 81% compared to 65% with every-3-week therapy; median time to progression and median overall survival were also improved.[34296]

    For the treatment of HER2-positive, trastuzumab-refractory metastatic breast cancer, in combination with lapatinib†.
    Intravenous dosage
    Adults

    4 mg/kg IV over 90 minutes on week 1 (of the first cycle only), then 2 mg/kg IV over 30 minutes once weekly, in combination with lapatinib (1,000 mg PO once daily) beginning on day 1. Continue until disease progression or unacceptable toxicity. Do not substitute trastuzumab for or with ado-trastuzumab emtansine, fam-trastuzumab deruxtecan, or trastuzumab; hyaluronidase. Progression-free survival was significantly improved in patients with HER2-positive, trastuzumab-refractory metastatic breast cancer treated with lapatinib plus trastuzumab compared with lapatinib alone in a phase 3 clinical trial (12 weeks vs. 8.1 weeks); the overall response rate was not significantly different between the two arms. Diarrhea occurred significantly more often in the combination therapy arm (60% vs. 48%); the incidence of symptomatic (2% vs. 0.7%) and asymptomatic (3.4% vs. 1.4%) cardiac events were also higher in the combination therapy arm.[40357]

    For the treatment of HER2-positive, hormone receptor-positive metastatic breast cancer, in combination with anastrozole†.
    Intravenous dosage
    Adults

    4 mg/kg IV over 90 minutes on day 1 (of the first cycle only), then 2 mg/kg IV over 30 minutes once weekly, in combination with anastrozole (1 mg PO once daily) until disease progression or unacceptable toxicity. Do not substitute trastuzumab for or with ado-trastuzumab emtansine, fam-trastuzumab deruxtecan, or trastuzumab; hyaluronidase. Progression-free survival was significantly improved with the addition of trastuzumab to anastrozole therapy compared with anastrozole alone in a phase 3 clinical trial (4.8 months vs. 2.4 months); overall survival was not significantly different between the treatment groups. Of note, 70% of patients in the anastrozole alone arm received a trastuzumab-containing regimen after developing progressive disease on anastrozole. Cardiac events occurred more frequently in the trastuzumab arm (14 events vs. 2 events); however, the incidence of grade 3 of 4 events was similar between the groups (2 events each).[43323]

    For the neoadjuvant treatment of HER2-positive breast cancer sequential to and in combination with doxorubicin, paclitaxel, and CMF chemotherapy†.
    Intravenous dosage
    Adults

    8 mg/kg IV over 90 minutes on day 1 (of cycle 1 only), followed 3 weeks later by 6 mg/kg IV over 30 minutes repeated every 3 weeks for 10 cycles, in combination with the following chemotherapy regimens. Doxorubicin (60 mg/m2 IV), followed by paclitaxel (150 mg/m2 IV over 3 hours) every 3 weeks for 3 cycles beginning on day 1 of trastuzumab therapy; then give paclitaxel (175 mg/m2 IV) alone every 3 weeks for an additional 4 cycles. After completion of doxorubicin/paclitaxel, administer cyclophosphamide (600 mg/m2 IV), methotrexate (40 mg/m2 IV), and fluorouracil (600 mg/m2 IV) on days 1 and 8, every 4 weeks for 3 cycles (CMF); trastuzumab may be administered every 4 weeks during CMF chemotherapy. Do not substitute trastuzumab for or with ado-trastuzumab emtansine, fam-trastuzumab deruxtecan, or trastuzumab; hyaluronidase. Patients with ER-/PR-positive breast cancer should receive an antiestrogen agent per guidelines. Surgery followed by radiation therapy should be scheduled after the completion of chemotherapy. In the clinical trial, additional cycles of trastuzumab were administered after surgery, beginning before or during radiotherapy, until the completion of one year total of trastuzumab therapy. In a phase 3 clinical trial, event-free survival was significantly improved at 3 years with the addition of trastuzumab to neoadjuvant doxorubicin/paclitaxel followed by CMF (71% vs. 56%) in patients with locally advanced HER2-positive breast cancer. In addition, the addition of trastuzumab significantly improved pathologic complete response rates compared to patients who did not receive trastuzumab (38% vs. 19%). Adverse events were similar between the treatment groups.[40610]

    For the neoadjuvant treatment of HER2-positive breast cancer in combination with paclitaxel, after completion of 4 cycles of fluorouracil and cyclophosphamide (FEC-75)†.
    Intravenous dosage
    Adults

    4 mg/kg IV over 90 minutes on week 1, then 2 mg/kg IV over 30 minutes once weekly, in combination with paclitaxel 80 mg/m2 IV once weekly, every 21 days for 4 cycles (12 weeks). Administer after completion of 4 cycles of cyclophosphamide (500 mg/m2 IV), epirubicin (75 mg/m2 IV), and fluorouracil (500 mg/m2 IV) on day 1, every 21 days for 4 cycles (FEC-75).[63560] [63561] Epirubicin dose adjustments for subsequent cycles are recommended by the manufacturer based on nadir ANC and platelet counts.[41751] Surgery should be performed after completion of paclitaxel plus trastuzumab therapy, followed by trastuzumab 6 mg/kg IV every 3 weeks for a total of 52 weeks from the first preoperative dose. Do not substitute trastuzumab for or with ado-trastuzumab emtansine, fam-trastuzumab deruxtecan, or trastuzumab; hyaluronidase. In a randomized, phase 3 clinical trial, neoadjuvant treatment with FEC-75 followed by paclitaxel plus trastuzumab (sequential therapy) resulted in similar rates of pathologic complete response (pCR), disease-free survival (DFS), and overall survival (OS) compared with paclitaxel plus trastuzumab followed by FEC-75 plus trastuzumab (concurrent therapy). Sequential therapy was better tolerated and had a lower incidence of cardiac adverse reactions.[63560] [63561]

    For first-line treatment of HER2-positive metastatic breast cancer in combination with pertuzumab and docetaxel†.
    NOTE: Pertuzumab is FDA approved in combination with trastuzumab and docetaxel for the first-line treatment of HER2-positive metastatic breast cancer.
    Intravenous dosage
    Adults

    8 mg/kg IV over 90 minutes on day 1 (of first cycle only), followed 3 weeks later by trastuzumab 6 mg/kg IV over 30 to 90 minutes, repeated every 3 weeks until disease progression or unacceptable toxicity, in combination with pertuzumab (840 mg IV over 60 minutes initially, followed 3 weeks later by pertuzumab 420 mg IV over 30 to 60 minutes, repeated every 3 weeks until disease progression or unacceptable toxicity) and docetaxel (75 mg/m2 IV every 3 weeks for at least 6 cycles; dose may be escalated to 100 mg/m2 if the initial dose is well-tolerated). Pertuzumab and trastuzumab can be given in any order; however, both agents should precede docetaxel. If trastuzumab is given after pertuzumab, delay the infusion 30 to 60 minutes to observe for pertuzumab-related infusion reactions.[50557] Do not substitute trastuzumab for or with ado-trastuzumab emtansine, fam-trastuzumab deruxtecan, or trastuzumab; hyaluronidase. Progression-free survival time was significantly improved in patients with HER2-positive metastatic breast cancer (CLEOPATRA study) treated with pertuzumab plus trastuzumab and docetaxel arm compared with those who received placebo plus trastuzumab and docetaxel (18.5 vs. 12.4 months) in a multicenter, double-blind, placebo-controlled trial.[50559] In a second interim analysis, median overall survival (OS) was also significantly improved in the pertuzumab-containing arm (not reached vs. 37.6 months).[50557]

    For the first-line treatment of HER2-positive metastatic breast cancer, in combination with paclitaxel.
    Intravenous dosage
    Adults

    4 mg/kg IV over 90 minutes on day 1 (of the first cycle only), then 2 mg/kg IV over 30 minutes once weekly until disease progression, in combination with paclitaxel (175 mg/m2 IV over 3 hours on day 1) every 21 days for at least 6 cycles. Do not substitute trastuzumab for or with ado-trastuzumab emtansine, fam-trastuzumab deruxtecan, or trastuzumab; hyaluronidase. In a multicenter, randomized, open-label clinical trial of patients with previously untreated metastatic breast cancer, treatment with trastuzumab plus paclitaxel significantly improved the median time to progression (6.7 vs. 2.5 months), overall response rate (38% vs. 15%), and duration of response (8.3 vs. 4.3 months) compared with paclitaxel alone; overall survival was not significantly improved.[28061] [62658] [63839] [63887] [64524] [64521]

    For the treatment of HER2-positive, trastuzumab-resistant, advanced breast cancer in patients previously treated with a taxane, in combination with vinorelbine and everolimus†.
    Intravenous dosage
    Adults

    4 mg/kg IV over 90 minutes on day 1 (of the first cycle only), then 2 mg/kg IV over 30 minutes once weekly, in combination with vinorelbine (25 mg/m2 IV once weekly) and everolimus (5 mg PO once daily) until disease progression or unacceptable toxicity.[62221] Coadministration of certain drugs may need to be avoided with everolimus or everolimus dosage adjustments may be necessary; review drug interactions.[49823] Do not substitute trastuzumab for or with ado-trastuzumab emtansine, fam-trastuzumab deruxtecan, or trastuzumab; hyaluronidase. Everolimus plus vinorelbine and trastuzumab significantly improved progression-free survival compared with placebo plus vinorelbine and trastuzumab in patients with HER2-positive, trastuzumab-resistant advanced breast cancer in patients who had received prior taxane therapy; objective response rate and overall survival were not significantly improved.[62221] [62222]

    For the treatment of advanced unresectable or metastatic HER2-positive breast cancer in patients who have received at least one prior anti-HER2-based regimen in the metastatic setting, in combination with tucatinib and capecitabine†.
    Intravenous dosage
    Adults

    8 mg/kg IV over 90 minutes on day 1 (of cycle 1 only), followed 3 weeks later by 6 mg/kg IV over 30 minutes repeated every 21 days. This is given in combination with tucatinib and capecitabine until disease progression or unacceptable toxicity; tucatinib and capecitabine can be taken at the same time. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. The addition of tucatinib to trastuzumab and capecitabine significantly improved median progression-free survival (PFS) (7.8 months vs. 5.6 months) and overall survival (21.9 months vs. 17.4 months) compared with placebo plus trastuzumab and capecitabine in patients with HER2-positive, unresectable locally advanced or metastatic breast cancer after prior HER2 treatment in a randomized, double-blind clinical trial (HER2CLIMB); all patients had received prior trastuzumab and ado-trastuzumab emtansine and all but 2 patients had prior pertuzumab. The confirmed objective response rate was also significantly improved with the addition of tucatinib (40.6% vs. 22.8%; complete response, 3% vs. 2%) for a median duration of 8.3 months versus 6.3 months, respectively. Patients with brain metastases were eligible for inclusion in the HER2CLIMB study as long as they were neurologically stable and did not require immediate radiation or surgery; patients with leptomeningeal disease were excluded. The median PFS in patients with brain metastases was similar to the overall population (7.6 months vs. 5.4 months).

    For the treatment of gastric cancer.
    For the treatment of patients with previously untreated HER2-positive metastatic gastric cancer or gastroesophageal junction adenocarcinoma, in combination with cisplatin and fluorouracil or capecitabine.
    NOTE: Patients should be selected based on the presence of HER2 protein overexpression or HER2 gene amplification in tumor specimens. Information on FDA-approved tests for the detection of HER2 protein overexpression and HER2 gene amplification is available at www.fda.gov/CompanionDiagnostics. Tests should be specific for gastric cancers due to differences in breast vs. gastric histopathology, including incomplete membrane staining and more frequent heterogeneous expression of HER2 seen in gastric cancers.
    Intravenous dosage
    Adults

    8 mg/kg IV over on day 1 (of first cycle only), followed 3 weeks later by 6 mg/kg IV over every 21 days until disease progression or unacceptable toxicity, in combination with cisplatin (80 mg/m2 IV on day 1) plus either fluorouracil (800 mg/m2 per day by continuous IV infusion on days 1 to 5) or capecitabine (1,000 mg/m2 PO twice daily on days 1 through 14), every 21 days for 6 cycles. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Do not substitute trastuzumab for or with ado-trastuzumab emtansine, fam-trastuzumab deruxtecan, or trastuzumab; hyaluronidase. The primary endpoint of median overall survival was significantly improved in previously untreated patients with metastatic gastric cancer who received trastuzumab plus cisplatin and fluorouracil or capecitabine (n = 298) compared with chemotherapy alone (n = 296) (13.1 months vs. 11.7 months) in open-label clinical trial.[28061] [62658] [63887]

    For the first-line treatment of HER2-positive locally advanced unresectable or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma, in combination with pembrolizumab, cisplatin, and fluorouracil†.
    NOTE: Pembrolizumab is FDA-approved for this indication in combination with trastuzumab, cisplatin, and fluorouracil.
    Intravenous dosage
    Adults

    8 mg/kg IV on day 1 of cycle 1, followed 3 weeks later by 6 mg/kg IV every 3 weeks in subsequent cycles. Administer in combination with pembrolizumab (200 mg IV every 3 weeks OR 400 mg IV every 6 weeks until disease progression, unacceptable toxicity, or for up to 24 months in patients without disease progression), followed by cisplatin (80 mg/m2 IV every 3 weeks for up to 6 cycles) and fluorouracil (800 mg/m2 per day by continuous IV infusion on days 1 to 5 every 3 weeks). In the clinical trial, treatment with fluorouracil could continue after completion of 6 cycles of cisplatin, per protocol. Administer pembrolizumab prior to trastuzumab and chemotherapy when given on the same day. Treatment with pembrolizumab plus trastuzumab and investigator's choice of chemotherapy (cisplatin plus fluorouracil, or capecitabine plus oxaliplatin) significantly improved objective response rate (74% vs. 52%; complete response, 11% vs. 3.1%) compared with placebo plus trastuzumab and chemotherapy in patients with previously untreated HER2-positive advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma at an interim analysis of a multicenter, randomized phase 3 trial (KEYNOTE-811). The median duration of response was 10.6 months in the pembrolizumab arm compared with 9.5 months in the placebo arm; 65% versus 53% of patients, respectively, had a duration of response of at least 6 months. 

    For the first-line treatment of HER2-positive locally advanced unresectable or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma, in combination with pembrolizumab, oxaliplatin, and capecitabine (XELOX; CapeOx)†.
    NOTE: Pembrolizumab is FDA-approved for this indication in combination with trastuzumab, oxaliplatin, and capecitabine.
    Intravenous dosage
    Adults

    8 mg/kg IV on day 1 of cycle 1, followed 3 weeks later by 6 mg/kg IV every 3 weeks in subsequent cycles. Administer in combination with pembrolizumab (200 mg IV every 3 weeks OR 400 mg IV every 6 weeks until disease progression, unacceptable toxicity, or for up to 24 months in patients without disease progression), followed by oxaliplatin (130 mg/m2 IV every 3 weeks for up to 6 to 8 cycles) and capecitabine (1,000 mg/m2 PO twice daily on days 1 to 14 every 3 weeks). Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Administer pembrolizumab prior to trastuzumab and chemotherapy when given on the same day. Treatment with pembrolizumab plus trastuzumab and investigator's choice of chemotherapy (cisplatin plus fluorouracil, or capecitabine plus oxaliplatin) significantly improved objective response rate (74% vs. 52%; complete response, 11% vs. 3.1%) compared with placebo plus trastuzumab and chemotherapy in patients with previously untreated HER2-positive advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma at an interim analysis of a multicenter, randomized phase 3 trial (KEYNOTE-811). The median duration of response was 10.6 months in the pembrolizumab arm compared with 9.5 months in the placebo arm; 65% versus 53% of patients, respectively, had a duration of response of at least 6 months. 

    MAXIMUM DOSAGE

    Adults

    Every-3-week dosing: 8 mg/kg IV initially, then 6 mg/kg IV every 3 weeks.
    Weekly dosing: 4 mg/kg IV initially, then 2 mg/kg IV every 2 weeks.

    Geriatric

    Every-3-week dosing: 8 mg/kg IV initially, then 6 mg/kg IV every 3 weeks.
    Weekly dosing: 4 mg/kg IV initially, then 2 mg/kg IV every 2 weeks.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
     
    NOTE: Patients should be selected based on the presence of HER2 protein overexpression or HER2 gene amplification in tumor specimens. Information on FDA-approved tests for the detection of HER2 protein overexpression and HER2 gene amplification is available at http://www.fda.gov/CompanionDiagnostics. Tests should be specific for breast cancers due to differences in breast vs. gastric histopathology, including incomplete membrane staining and more frequent heterogeneous expression of HER2 seen in gastric cancers.[28061] [62658] [63839] [63887]

    Intravenous Administration

    Administer as an intravenous infusion; do not administer IV push or as a bolus.
    Do not substitute trastuzumab for or with ado-trastuzumab emtansine, fam-trastuzumab deruxtecan, or trastuzumab; hyaluronidase.
    If a patient misses a dose by 1 week or less, administer the usual maintenance dose (weekly schedule, 2 mg/kg; every-3-week schedule, 6 mg/kg) as soon as possible; do not wait until the next planned cycle. Administer subsequent maintenance doses 7 days or 21 days later, according to the weekly or 3-weekly schedules, respectively.
    If a patient misses a dose by more than 1 week, administer a reloading dose (weekly schedule, 4 mg/kg; every-3-week schedule, 8 mg/kg) over approximately 90 minutes as soon as possible. Administer subsequent maintenance doses 7 days or 21 days later, according to the weekly or 3-weekly schedules, respectively.
    Observe patients for infusion-related reactions such as fever or chills, or more severe reactions including respiratory distress or severe hypersensitivity reactions. Interrupt the infusion for patients experiencing dyspnea (e.g., acute bronchospasm) or clinically significant hypotension. Decrease the rate of infusion for mild or moderate infusion reactions. Monitor patients until signs and symptoms completely resolve. Discontinue trastuzumab for severe or life-threatening infusion reactions and strongly consider permanent discontinuation of therapy.
    Do NOT mix or dilute with other drugs or dextrose solutions.[28061] [62658] [63839] [63887]
    Reconstitution:
    420 mg multiple-dose vial: Inject 20 mL of Bacteriostatic Water for Injection (containing 0.9% to 1.1% benzyl alcohol) into the vial to result in a 21 mg/mL solution that delivers 20 mL. May also be reconstituted with 20 mL of Sterile Water for Injection USP (without a preservative) for patients with benzyl alcohol hypersensitivity, for single-use.[62658] [63839]
    150 mg single-dose vial: Inject 7.4 mL of Sterile Water for Injection into the vial, to result in a 21 mg/mL solution that delivers 7.15 mL.
    The stream of diluent should be directed into the lyophilized powder, which has a cake-like appearance. Swirl gently to aid dissolution; do not shake.
    Slight foaming of the product upon reconstitution is not unusual. Allow the vial to stand undisturbed for approximately 5 minutes. The solution should be free of visible particles, clear to slightly opalescent and colorless to pale yellow.
    Storage after reconstitution: Solutions reconstituted with Bacteriostatic Water for Injection are stable for 28 days under refrigeration (36 to 46 degrees F; 2 to 8 degrees C); do NOT freeze. If reconstituted with Sterile Water for Injection (no preservative), the vial should be used immediately for only 1 dose. If not used immediately, store reconstituted trastuzumab without preservative refrigerated for up to 24 hours (2 to 8 degrees Celsius or 36 to 46 degrees Fahrenheit); do NOT freeze. Discard any unused trastuzumab after 24 hours.[28061] [62658] [63839] [63887]
    Dilution:
    Withdraw the appropriate amount of solution and add to 250 mL of 0.9% Sodium Chloride Injection in polyvinylchloride or polyethylene bags. Do not use 5% Dextrose Injection. Gently invert the bag to mix the solution.
    Storage after dilution:
    Diluted solutions are stable for up to 24 hours under refrigeration (36 to 46 degrees F; 2 to 8 degrees C) in addition to any time allowed for the reconstituted vials; do NOT freeze.[28061] [62658] [63839] [63887]

    STORAGE

    Herceptin:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Do not freeze
    - Product reconstituted with SWFI should be used immediately and any used portion discarded
    - Reconstituted product may be stored under refrigeration (36 to 46 degrees F) for up to 28 days
    - Refrigerate (between 36 and 46 degrees F)
    KANJINTI:
    - Discard unused portion. Do not store for later use.
    - Do not freeze reconstituted product
    - Protect from light
    - Store in original container
    - Store reconstituted product in refrigerator (36 to 46 degrees F) and administer within 24 hours
    - Store unreconstituted product in refrigerator (36 to 46 degrees F)
    Ogivri:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused product 28 days after opening the bottle
    - Do not freeze
    - Product reconstituted with SWFI should be used immediately and any used portion discarded
    - Reconstituted product may be stored under refrigeration (36 to 46 degrees F) for up to 28 days
    - Store unreconstituted product in refrigerator (36 to 46 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    Angioedema, hypotension, infusion-related reactions, respiratory distress syndrome

    Administration of trastuzumab products can result in infusion-related reactions characterized by fever and chills, nausea, vomiting, pain (in some cases at tumor sites), headache, dizziness, dyspnea, hypotension, rash, and asthenia. In postmarketing experience, serious and fatal infusion reactions have also been reported, including bronchospasm, anaphylaxis, angioedema, hypoxia, and severe hypotension. Infusion reactions were usually reported during or immediately following the initial infusion, but the onset and clinical course may vary, including progressive worsening, initial improvement followed by clinical deterioration, or delayed post-infusion events with rapid deterioration. For fatal events, death occurred within hours to days following a serious infusion reaction. Decrease the infusion rate for mild to moderate infusion reactions. Hold the infusion of trastuzumab product in all patients experiencing dyspnea or clinically significant hypotension, or if medical intervention (e.g., epinephrine, corticosteroids, diphenhydramine, bronchodilators, and oxygen) is required. Monitor patients until complete resolution of signs and symptoms. Discontinue trastuzumab product for anaphylaxis, angioedema, or acute respiratory distress syndrome; strongly consider discontinuation of therapy in patients with other severe reactions, as no data exist regarding the most appropriate method of identification of patients who may safely be retreated with trastuzumab. Most patients who experienced a severe infusion reaction were premedicated with antihistamines and/or corticosteroids before resumption of trastuzumab infusion. Some patients tolerated trastuzumab, but some patients had recurrent severe infusion reactions despite premedications.[28061] [62658] [63839] [63887] [64521] [64524]

    Asthma, chronic lung disease (CLD), chronic obstructive pulmonary disease (COPD), pneumonitis, pulmonary disease, pulmonary fibrosis, pulmonary toxicity

    Use trastuzumab products with caution in patients with preexisting chronic lung disease (CLD) such as chronic obstructive pulmonary disease (COPD), asthma, or pulmonary fibrosis. Trastuzumab products can cause serious and fatal pulmonary toxicity, including dyspnea, interstitial pneumonitis, pulmonary infiltrates, pleural effusions, non-cardiogenic pulmonary edema, pulmonary insufficiency and hypoxia, acute respiratory distress syndrome, and pulmonary fibrosis, which may be more severe in patients with symptomatic intrinsic lung disease or with more extensive tumor involvement of the lungs that results in dyspnea at rest. These reactions can also occur as sequelae of infusion reactions. Discontinue trastuzumab product for interstitial pneumonitis.

    Cardiac arrhythmias, cardiac disease, cardiomyopathy, geriatric, heart failure, hypertension, ventricular dysfunction

    Use trastuzumab products with caution in patients with a history of cardiac disease, heart failure, cardiomyopathy, ventricular dysfunction, hypertension, or cardiac arrhythmias, as trastuzumab products can cause these issues as well as cardiac death; an asymptomatic decline in the left ventricular ejection fraction (LVEF) is also possible. The risk of cardiac dysfunction was increased in geriatric patients compared to younger patients in clinical trials. Obtain a baseline measurement of LVEF by echocardiogram or MUGA immediately prior to initiation of trastuzumab products, every 3 months during treatment, upon completion of therapy, and every 6 months for at least 2 years after treatment for adjuvant therapy. An interruption or discontinuation of therapy may be necessary for a decline in LVEF; the safety of continuing or resuming trastuzumab product in patients with treatment-induced left ventricular cardiac dysfunction has not been adequately studied. However, 22 of 25 patients who developed left ventricular dysfunction during adjuvant trastuzumab therapy (after anthracycline treatment) had stable LVEF measurements and no CHF recurrence after rechallenge once symptoms were stable and patients were on maximum tolerated doses of ACE inhibitors and beta-blockers.[33927] In another study, 16 of 26 patients with metastatic breast cancer who developed trastuzumab-related cardiotoxicity and fully recovered did not experience additional cardiotoxicity upon rechallenge; 10 patients had a subsequent cardiac event, with varying degrees of resolution after trastuzumab discontinuation.[33928] Trastuzumab was continued in 17 of 34 metastatic breast cancer patients with asymptomatic cardiac dysfunction in an additional retrospective study; 13 of these patients had complete recovery without specific cardiac treatment, 2 had complete recovery with treatment, and 2 were not assessed.[33928] Monitoring of the LVEF should occur more frequently, at 4-week intervals, if treatment is held for significant left ventricular cardiac dysfunction.[28061] [62658] [63839] [63887] [64521] [64524] Elevated troponin I immediately before or after trastuzumab administration may also be a predictor of cardiotoxicity.[41906] Patients who receive anthracycline therapy after stopping a trastuzumab product may be at increased risk of cardiac dysfunction; among patients receiving trastuzumab products as a single agent or in combination therapy, the highest absolute incidence of symptomatic cardiac dysfunction occurs when trastuzumab product is administered with an anthracycline.[28061] [62658] [63839] [63887] [64521] [64524]

    Benzyl alcohol hypersensitivity

    Multidose vials of trastuzumab product are supplied in a carton with a vial of bacteriostatic water for injection as diluent, containing 1.1% benzyl alcohol as a preservative. For patients with known benzyl alcohol hypersensitivity, do not use the supplied diluent but reconstitute trastuzumab product with sterile water for injection.[28061] [62658] [63839]

    Human anti-human antibody (HAHA)

    Initial studies indicate a low level of immunogenicity of trastuzumab. Of 903 patients evaluated, human anti-human antibody (HAHA) was only detected in one patient who did not experience any allergic manifestations. Immunogenicity data are highly dependent on the sensitivity and specificity of the test methods used. Results may be influenced by several factors, including sample handling, timing of sample collection, drug interference, concomitant medication, and the underlying disease. Comparison of the incidence of antibodies to trastuzumab with the incidence of antibodies to other products may be misleading.[28061] [62658] [63839] [63887]

    Chemotherapy, neutropenia

    Trastuzumab product may exacerbate chemotherapy-induced neutropenia; monitor patients closely. The incidence of grade 3 or 4 neutropenia and febrile neutropenia was higher in patients treated with trastuzumab in combination with myelosuppressive chemotherapy compared to chemotherapy alone in randomized clinical trials; however, the rate of septic death was similar among these two groups.[28061] [62658] [63839] [63887]

    Tumor lysis syndrome (TLS)

    Cases of tumor lysis syndrome (TLS) have been reported in patients treated with trastuzumab. Patients with significant tumor burden (e.g., bulky metastases) may be at higher risk. Patients could present with hyperuricemia, hyperphosphatemia, and acute renal failure (unspecified); consider additional monitoring and/or treatment as clinically indicated.

    Ensure correct formulation selection

    Intravenous trastuzumab has different dosage and administration recommendations than trastuzumab; hyaluronidase, fam-trastuzumab deruxtecan, or ado-trastuzumab emtansine. Ensure correct formulation selection and dose before preparation and administration.

    Pregnancy

    Serious fetal harm can occur if trastuzumab product is administered during pregnancy or within 7 months prior to conception.[28061] [62658] [63839] [63887] Counsel women to avoid pregnancy during trastuzumab therapy and for 7 months after the last dose. If a woman becomes pregnant while receiving or within 7 months of receiving trastuzumab, inform her of the fetal risks, monitor for oligohydramnios, and immediately report to the pregnancy pharmacovigilance program at Genentech (1-888-835-2555).[28061] If oligohydramnios occurs, perform fetal testing that is appropriate for gestational age and is consistent with community standards of care. Oligohydramnios and oligohydramnios sequence (manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death) have occurred in pregnant women who received trastuzumab alone or in combination with chemotherapy. In some women, the amniotic fluid index increased after trastuzumab cessation. In one case, treatment was resumed with trastuzumab after the amniotic fluid index improved, resulting in a recurrence of oligohydramnios.[28061] [62658] [63839] [63887]

    Contraception requirements, pregnancy testing, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during and after treatment with trastuzumab product. Trastuzumab can be teratogenic if taken by the mother during pregnancy or within 7 months prior to conception. Females should avoid pregnancy and use effective contraception during and for at least 7 months after treatment with trastuzumab product. Females of reproductive potential should undergo pregnancy testing prior to treatment initiation.   Women who become pregnant while receiving trastuzumab or within 7 months of the last dose should be apprised of the potential hazard to the fetus; healthcare providers and patients should immediately report trastuzumab exposure to Genentech (1-888-835-2555).[28061]

    Breast-feeding

    It is not known whether trastuzumab products are excreted into human milk. Published data suggest human IgG is present in human milk but does not enter the neonatal and infant circulation in substantial amounts. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in a nursing infant, advise women to discontinue breast-feeding during treatment with trastuzumab product and for 7 months after the last dose.[28061] [62658] [63839] [63887]

    ADVERSE REACTIONS

    Severe

    neutropenia / Delayed / 1.7-34.0
    heart failure / Delayed / 0.4-28.0
    infection / Delayed / 0-25.0
    hypokalemia / Delayed / 10.0-10.0
    infusion-related reactions / Rapid / 1.4-9.0
    thrombocytopenia / Delayed / 0-5.0
    fatigue / Early / 0-4.0
    thrombosis / Delayed / 2.1-3.7
    renal failure (unspecified) / Delayed / 0-2.7
    chills / Rapid / 0-1.0
    fever / Early / 0-1.0
    myocardial infarction / Delayed / 0-0.3
    pulmonary hypertension / Delayed / 0-0.2
    anemia / Delayed / 0-0.1
    cardiomyopathy / Delayed / Incidence not known
    glomerulonephritis / Delayed / Incidence not known
    nephrotic syndrome / Delayed / Incidence not known
    anaphylactic shock / Rapid / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    acute respiratory distress syndrome (ARDS) / Early / Incidence not known
    angioedema / Rapid / Incidence not known
    pulmonary fibrosis / Delayed / Incidence not known
    pulmonary toxicity / Early / Incidence not known
    pleural effusion / Delayed / Incidence not known
    pulmonary edema / Early / Incidence not known
    teratogenesis / Delayed / Incidence not known
    tumor lysis syndrome (TLS) / Delayed / Incidence not known

    Moderate

    leukopenia / Delayed / 3.0-52.0
    dyspnea / Early / 2.4-42.0
    bone pain / Delayed / 3.0-24.0
    peripheral edema / Delayed / 5.0-22.0
    depression / Delayed / 6.0-20.0
    hot flashes / Early / 0-17.1
    sinus tachycardia / Rapid / 5.0-12.0
    edema / Delayed / 4.7-11.0
    hypertension / Early / 0-4.0
    palpitations / Early / 0-3.0
    neuritis / Delayed / 0-2.0
    constipation / Delayed / 0-2.0
    peripheral neuropathy / Delayed / 0-1.0
    pneumonitis / Delayed / 0.2-0.7
    antibody formation / Delayed / 0.1-0.1
    dysphagia / Delayed / Incidence not known
    stomatitis / Delayed / Incidence not known
    hypoxia / Early / Incidence not known
    hypotension / Rapid / Incidence not known
    hyperuricemia / Delayed / Incidence not known
    hyperphosphatemia / Delayed / Incidence not known

    Mild

    asthenia / Delayed / 4.5-62.0
    headache / Early / 6.2-44.0
    cough / Delayed / 5.0-43.0
    rash / Early / 4.0-38.0
    arthralgia / Delayed / 6.0-37.0
    back pain / Delayed / 5.0-34.0
    nausea / Early / 6.0-33.0
    pharyngitis / Delayed / 8.0-30.0
    insomnia / Early / 4.3-29.0
    diarrhea / Early / 2.2-25.0
    vomiting / Early / 3.5-23.0
    rhinitis / Early / 2.0-22.0
    abdominal pain / Early / 2.0-22.0
    sinusitis / Delayed / 2.0-21.0
    anorexia / Delayed / 0-14.0
    influenza / Delayed / 2.0-13.0
    dizziness / Early / 4.0-13.0
    acne vulgaris / Delayed / 2.0-11.0
    dysgeusia / Early / 0-10.0
    paresthesias / Delayed / 2.0-9.0
    myalgia / Early / 0-4.0
    pruritus / Rapid / 0-2.0
    epistaxis / Delayed / 0-2.0
    dyspepsia / Early / 0-2.0
    weight loss / Delayed / Incidence not known

    DRUG INTERACTIONS

    Anthracyclines: (Major) Avoid coadministration of anthracyclines and trastuzumab products due to the risk of increased cardiac dysfunction; if possible, continue to avoid for up to 7 months after the last dose of trastuzumab. If concomitant use is unavoidable, carefully monitor cardiac function. Anthracycline treatment after therapy with trastuzumab product may increase the risk of cardiac dysfunction due to the long washout period of trastuzumab.
    Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
    Cyclophosphamide: (Moderate) Monitor for signs and symptoms of cardiac dysfunction if coadministration of cyclophosphamide with trastuzumab is necessary as there is an increased risk of cardiotoxicity.
    Daunorubicin Liposomal: (Major) Avoid coadministration of anthracyclines and trastuzumab products due to the risk of increased cardiac dysfunction; if possible, continue to avoid for up to 7 months after the last dose of trastuzumab. If concomitant use is unavoidable, carefully monitor cardiac function. Anthracycline treatment after therapy with trastuzumab product may increase the risk of cardiac dysfunction due to the long washout period of trastuzumab.
    Daunorubicin Liposomal; Cytarabine Liposomal: (Major) Avoid coadministration of anthracyclines and trastuzumab products due to the risk of increased cardiac dysfunction; if possible, continue to avoid for up to 7 months after the last dose of trastuzumab. If concomitant use is unavoidable, carefully monitor cardiac function. Anthracycline treatment after therapy with trastuzumab product may increase the risk of cardiac dysfunction due to the long washout period of trastuzumab.
    Daunorubicin: (Major) Avoid coadministration of anthracyclines and trastuzumab products due to the risk of increased cardiac dysfunction; if possible, continue to avoid for up to 7 months after the last dose of trastuzumab. If concomitant use is unavoidable, carefully monitor cardiac function. Anthracycline treatment after therapy with trastuzumab product may increase the risk of cardiac dysfunction due to the long washout period of trastuzumab.
    Doxorubicin Liposomal: (Major) Avoid coadministration of anthracyclines and trastuzumab products due to the risk of increased cardiac dysfunction; if possible, continue to avoid for up to 7 months after the last dose of trastuzumab. If concomitant use is unavoidable, carefully monitor cardiac function. Anthracycline treatment after therapy with trastuzumab product may increase the risk of cardiac dysfunction due to the long washout period of trastuzumab.
    Doxorubicin: (Major) Avoid coadministration of anthracyclines and trastuzumab products due to the risk of increased cardiac dysfunction; if possible, continue to avoid for up to 7 months after the last dose of trastuzumab. If concomitant use is unavoidable, carefully monitor cardiac function. Anthracycline treatment after therapy with trastuzumab product may increase the risk of cardiac dysfunction due to the long washout period of trastuzumab.
    Epirubicin: (Major) Avoid coadministration of anthracyclines and trastuzumab products due to the risk of increased cardiac dysfunction; if possible, continue to avoid for up to 7 months after the last dose of trastuzumab. If concomitant use is unavoidable, carefully monitor cardiac function. Anthracycline treatment after therapy with trastuzumab product may increase the risk of cardiac dysfunction due to the long washout period of trastuzumab.
    Idarubicin: (Major) Avoid coadministration of anthracyclines and trastuzumab products due to the risk of increased cardiac dysfunction; if possible, continue to avoid for up to 7 months after the last dose of trastuzumab. If concomitant use is unavoidable, carefully monitor cardiac function. Anthracycline treatment after therapy with trastuzumab product may increase the risk of cardiac dysfunction due to the long washout period of trastuzumab.
    Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
    Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.

    PREGNANCY AND LACTATION

    Pregnancy

    Serious fetal harm can occur if trastuzumab product is administered during pregnancy or within 7 months prior to conception.[28061] [62658] [63839] [63887] Counsel women to avoid pregnancy during trastuzumab therapy and for 7 months after the last dose. If a woman becomes pregnant while receiving or within 7 months of receiving trastuzumab, inform her of the fetal risks, monitor for oligohydramnios, and immediately report to the pregnancy pharmacovigilance program at Genentech (1-888-835-2555).[28061] If oligohydramnios occurs, perform fetal testing that is appropriate for gestational age and is consistent with community standards of care. Oligohydramnios and oligohydramnios sequence (manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death) have occurred in pregnant women who received trastuzumab alone or in combination with chemotherapy. In some women, the amniotic fluid index increased after trastuzumab cessation. In one case, treatment was resumed with trastuzumab after the amniotic fluid index improved, resulting in a recurrence of oligohydramnios.[28061] [62658] [63839] [63887]

    It is not known whether trastuzumab products are excreted into human milk. Published data suggest human IgG is present in human milk but does not enter the neonatal and infant circulation in substantial amounts. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in a nursing infant, advise women to discontinue breast-feeding during treatment with trastuzumab product and for 7 months after the last dose.[28061] [62658] [63839] [63887]

    MECHANISM OF ACTION

    Trastuzumab is a humanized IgG1 kappa monoclonal antibody that selectively binds with high affinity to the extracellular domain of HER2. Trastuzumab-mediated antibody-dependent cellular cytotoxicity (ADCC) preferentially acts on cancer cells that overexpress HER2 compared with cancer cells that do not overexpress HER2. The c-erbB2 gene is an oncogene that encodes for the HER2 transmembrane receptor protein (185 Kd) and is structurally related to the epidermal growth factor receptor.[28061] [62658] [63839] [63887] The overexpression of HER2 in tumor cells is closely associated with increased angiogenesis and expression of vascular epidermal growth factor (VEGF); when the VEGF pathway is inhibited, tumor growth is suppressed.[25663] In cells treated with trastuzumab, the HER2 receptor is downregulated, cyclin-dependent kinase inhibitor p27 accumulates, and cell cycle arrest occurs. Trastuzumab also inhibits the constitutive HER2 cleavage/shedding mediated by metalloproteases, which may correlate with the clinical activity of trastuzumab.[25176]

    PHARMACOKINETICS

    Trastuzumab products are administered intravenously. In a pooled pharmacokinetic analysis of patients with breast cancer and metastatic gastric cancer (n = 1,582), total clearance increased with decreasing concentrations due to parallel linear and nonlinear elimination pathways. The total clearance range at steady state was 0.173 to 0.283 L/day in patients with breast cancer who received a trastuzumab loading dose of 8 mg/kg IV followed by 6 mg/kg IV every 3 weeks; the total clearance range was 0.201 to 0.244 L/day after a loading dose of 4 mg/kg IV followed by 2 mg/kg IV weekly (n = 1,195). In patients with metastatic gastric cancer (n = 274), the total clearance range at steady state was 0.189 to 0.337 L/day.[28061] [62658] [63887]

    Intravenous Route

    Based on population parameters, patients treated with trastuzumab will experience approximately a 97% washout by 7 months after completion of therapy. The time to steady state is 9 weeks in patients with metastatic gastric cancer and 12 weeks in breast cancer patients.[28061] [62658] [63839] [63887] [64524] [64521]
     
    The average trastuzumab exposure after the first cycle in breast cancer patients was higher with 3-weekly dosing (8 mg/kg load followed by 6 mg/kg every 3 weeks) compared to weekly administration (4 mg/kg load followed by 2 mg/kg weekly), but the average steady-state exposure was essentially the same. The average trastuzumab exposure after the first cycle and at steady state, as well as the time to steady-state, was higher in breast cancer patients compared to metastatic gastric cancer patients at the same dose; the reason for this difference is unknown. The median Cmin after the first dose for trastuzumab with 3-weekly dosing was 29.4 mcg/mL in breast cancer patients and 23.1 mcg/mL in patients with gastric cancer; the median Cmax was 178 mcg/mL and 132 mcg/mL, while the median AUC was 1,373 mcg x day/mL and 1,109 mcg x day/mL, respectively. For weekly administration, the median Cmin after the first dose was 37.7 mcg/mL, median Cmax 88.3 mcg/mL, and median AUC 1,066 mcg x day/mL. At steady-state, the median Cmin for breast cancer and gastric cancer patients receiving 3-weekly dosing is 47.4 mcg/mL and 32.9 mcg/mL, respectively; the median Cmax at steady-state is 179 mcg/mL for breast cancer patients and 131 mcg/mL for gastric cancer patients, and the median AUC was 1,794 mcg x day/mL and 1,338 mcg x day/mL, respectively. With breast cancer patients receiving weekly administration of trastuzumab, the median Cmin was 66.1 mcg/mL, median Cmax 109 mcg/mL, and median AUC 1,765 mcg x day/mL. The time to steady-state for breast cancer patients, whether receiving 3-weekly or weekly dosing, was 12 weeks; the time to steady-state for patients with metastatic gastric cancer was 9 weeks.[28061] [62658] [63839] [63887] [64524] [64521]