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    Monoclonal Antibodies that Target HER2/neu

    BOXED WARNING

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

    Subclinical and clinical heart failure can occur as a result of treatment with trastuzumab; hyaluronidase. There is a 4- to 6-fold increase in the incidence of symptomatic cardiac dysfunction in patients receiving trastuzumab (monotherapy or in combination with chemotherapy) compared with those not receiving trastuzumab. The incidence and severity were highest in patients receiving concomitant anthracycline-containing chemotherapy regimens; patients who receive anthracycline after stopping trastuzumab; hyaluronidase may also be at increased risk of cardiac dysfunction. The incidence of symptomatic cardiac dysfunction was similar for subcutaneous trastuzumab; hyaluronidase and intravenous trastuzumab. Use trastuzumab; hyaluronidase with caution in patients with a history of cardiac disease, heart failure, cardiomyopathy, ventricular dysfunction, hypertension, or cardiac arrhythmias, as trastuzumab; hyaluronidase 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; hyaluronidase, every 3 months during treatment, upon completion of therapy, and every 6 months for at least 2 years after adjuvant therapy. An interruption or discontinuation of therapy may be necessary for a decline in LVEF; the safety of continuing or resuming trastuzumab; hyaluronidase in patients with treatment-induced left ventricular cardiac dysfunction has not been adequately studied.[63988]

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

    Use trastuzumab; hyaluronidase with caution in patients with preexisting chronic lung disease (CLD) such as chronic obstructive pulmonary disease (COPD), asthma, or pulmonary fibrosis. Treatment with trastuzumab; hyaluronidase can result in 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. Symptoms usually occur during or within 24 hours of trastuzumab; hyaluronidase administration. Discontinue trastuzumab; hyaluronidase for interstitial pneumonitis or acute respiratory distress syndrome; monitor patients until symptoms completely resolve.

    DEA CLASS

    Rx

    DESCRIPTION

    Trastuzumab is a HER2/neu receptor antagonist; hyaluronidase is an endoglycosidase
    Used for the treatment of HER2-overexpressing breast cancer
    Do not substitute trastuzumab; hyaluronidase with other trastuzumab-based products; both administration and dosing recommendations are different

    COMMON BRAND NAMES

    HERCEPTIN HYLECTA

    HOW SUPPLIED

    HERCEPTIN HYLECTA Subcutaneous Inj Sol: 1mL, 120-2000U

    DOSAGE & INDICATIONS

    For the treatment of HER2-positive breast cancer.
    NOTE: Patients should be selected based on an FDA-approved companion diagnostic for trastuzumab showing 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.
    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.
    Subcutaneous dosage
    Adults

    600 mg trastuzumab and 10,000 units hyaluronidase (5 mL) subcutaneously over approximately 2 to 5 minutes once every 3 weeks for 52 weeks or until disease recurrence, whichever occurs first; extending treatment beyond 1 year is not recommended. No loading dose is required. Do not substitute trastuzumab; hyaluronidase with ado-trastuzumab emtansine or trastuzumab.[63988] 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] [63988] Treatment with subcutaneous trastuzumab; hyaluronidase with chemotherapy was noninferior to intravenous trastuzumab based on pharmacokinetic and efficacy outcomes in a randomized clinical trial.[63988]

    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).
    Subcutaneous dosage
    Adults

    600 mg trastuzumab and 10,000 units hyaluronidase (5 mL) subcutaneously over approximately 2 to 5 minutes, 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, continue 600 mg trastuzumab and 10,000 units hyaluronidase (5 mL) subcutaneously for a total of 52 weeks of trastuzumab therapy or until disease recurrence, whichever occurs first; extending treatment beyond 1 year is not recommended. No loading dose of trastuzumab; hyaluronidase is required. Do not substitute trastuzumab; hyaluronidase for or with other trastuzumab-based products. 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. Treatment with subcutaneous trastuzumab; hyaluronidase with chemotherapy was noninferior to intravenous trastuzumab based on pharmacokinetic and efficacy outcomes in a randomized clinical trial.[28061] [63988] Treatment with subcutaneous trastuzumab; hyaluronidase with chemotherapy was noninferior to intravenous trastuzumab based on pharmacokinetic and efficacy outcomes in a randomized clinical trial.[63988]

    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).
    Subcutaneous dosage
    Adults

    600 mg trastuzumab and 10,000 units hyaluronidase (5 mL) subcutaneously over approximately 2 to 5 minutes, in combination with docetaxel (100 mg/m2 IV) beginning on day 1 for a total of 4 cycles (12 weeks). Continue 600 mg trastuzumab and 10,000 units hyaluronidase (5 mL) subcutaneously for a total of 52 weeks of trastuzumab therapy or until disease recurrence, whichever occurs first; extending treatment beyond 1 year is not recommended. No loading dose of trastuzumab; hyaluronidase is required. Do not substitute trastuzumab; hyaluronidase for or with other trastuzumab-based products. Begin docetaxel plus trastuzumab; hyaluronidase after the completion of 4 cycles of AC chemotherapy (doxorubicin 60 mg/m2 IV and cyclophosphamide 600 mg/m2 IV every 21 days); do NOT administer trastuzumab; hyaluronidase concurrently with doxorubicin and cyclophosphamide. 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] [63988] Treatment with subcutaneous trastuzumab; hyaluronidase with chemotherapy was noninferior to intravenous trastuzumab based on pharmacokinetic and efficacy outcomes in a randomized clinical trial.[63988]

    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, after completion of doxorubicin and cyclophosphamide chemotherapy (AC-TH).
    Subcutaneous dosage
    Adults

    600 mg trastuzumab and 10,000 units hyaluronidase (5 mL) subcutaneously over approximately 2 to 5 minutes, 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. Continue 600 mg trastuzumab and 10,000 units hyaluronidase (5 mL) subcutaneously for a total of 52 weeks of trastuzumab therapy or until disease recurrence, whichever occurs first; extending treatment beyond 1 year is not recommended. No loading dose of trastuzumab; hyaluronidase is required. Do not substitute trastuzumab; hyaluronidase for or with other trastuzumab-based products. Begin paclitaxel plus trastuzumab; hyaluronidase after the completion of 4 cycles of AC chemotherapy (doxorubicin 60 mg/m2 IV and cyclophosphamide 600 mg/m2 IV every 21 days); do NOT administer trastuzumab; hyaluronidase concurrently with doxorubicin and cyclophosphamide. 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.[28061] [63988] Treatment with subcutaneous trastuzumab; hyaluronidase with chemotherapy was noninferior to intravenous trastuzumab based on pharmacokinetic and efficacy outcomes in a randomized clinical trial.[63988]

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

    600 mg trastuzumab and 10,000 units hyaluronidase (5 mL) subcutaneously over approximately 2 to 5 minutes, in combination with paclitaxel (175 mg/m2 IV over 3 hours) on day 1, every 3 weeks for at least 6 cycles or until disease progression. No loading dose of trastuzumab; hyaluronidase-oysk is required. Do not substitute trastuzumab; hyaluronidase for or with other trastuzumab-based products. 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. Treatment with subcutaneous trastuzumab; hyaluronidase with chemotherapy was noninferior to intravenous trastuzumab based on pharmacokinetic and efficacy outcomes in a randomized clinical trial.[63988]

    For the treatment of HER2-positive metastatic breast cancer in patients who have failed one or more chemotherapy regimens for metastatic disease, as monotherapy.
    Subcutaneous dosage
    Adults

    600 mg trastuzumab and 10,000 units hyaluronidase (5 mL) subcutaneously over approximately 2 to 5 minutes on day 1, every 3 weeks until disease progression. No loading dose of trastuzumab; hyaluronidase is required. Do not substitute trastuzumab; hyaluronidase for or with other trastuzumab-based products. Monotherapy with trastuzumab resulted in an overall response rate of 14% (complete response (CR), 2%; partial response, 12%) in a multicenter, noncomparative study in patients with metastatic breast cancer and relapse after 1 or more prior chemotherapy regimens; CR 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+.[28061] [63988] Treatment with subcutaneous trastuzumab; hyaluronidase with chemotherapy was noninferior to intravenous trastuzumab based on pharmacokinetic and efficacy outcomes in a randomized clinical trial.[63988]

    For the neoadjuvant treatment of HER2-positive, locally advanced, inflammatory, or early-stage breast cancer (greater than 2 cm diameter or node-positive) in combination with pertuzumab and chemotherapy†.
    NOTE: Pertuzumab is FDA-approved in combination with trastuzumab; hyaluronidase and chemotherapy for this indication.
    Subcutaneous dosage
    Adults

    600 mg trastuzumab and 10,000 units hyaluronidase (5 mL) subcutaneously over approximately 2 to 5 minutes on day 1, every 3 weeks, in combination with pertuzumab (840 mg IV over 60 minutes [of cycle 1 only], followed 3 weeks later by 420 mg IV over 30 to 60 minutes repeated every 3 weeks), for a total of 3 to 6 cycles as part of one of the following treatment regimens: Four preoperative cycles of pertuzumab in combination with trastuzumab; hyaluronidase and docetaxel with 3 postoperative cycles of fluorouracil, epirubicin, and cyclophosphamide (FEC); Three or four preopoerative cycles of FEC alone followed by 3 or 4 preoperative cycles of pertuzumab in combination with docetaxel and trastuzumab; hyaluronidase; Six preoperative cycles of pertuzumab in combination with docetaxel, carboplatin, and trastuzumab; hyaluronidase (TCH); Four preoperative cycles of dose-dense doxorubicin and cyclophosphamide (ddAC) alone followed by 4 preoperative doses of pertuzumab in combination with paclitaxel and trastuzumab; hyaluronidase. After surgery, give IV pertuzumab and trastuzumab; hyaluronidase every 3 weeks to complete 1 year of therapy (up to 18 cycles). Pertuzumab and trastuzumab; hyaluronidase can be given in any order; however, both agents should be given PRIOR to the taxane infusion in patients receiving a taxane-containing regimen. In patients receiving an anthracycline-containing regimen, pertuzumab and trastuzumab; hyaluronidase should be given following completion of the anthracycline. Observe closely for infusion-related reactions for 60 minutes after the first pertuzumab infusion and for 30 minutes after subsequent infusions; do not start other infusions until after this observation period. Do not administer pertuzumab without trastuzumab; hyaluronidase; withhold or discontinue pertuzumab therapy if trastuzumab; hyaluronidase is withheld or discontinued.

    For the adjuvant treatment of early breast cancer in patients at high risk of recurrence, in combination with pertuzumab and standard anthracycline- and/or taxane-based chemotherapy†.
    NOTE: Pertuzumab is FDA-approved in combination with trastuzumab; hyaluronidase and standard anthracycline- and/or taxane-based chemotherapy for this indication.
    Subcutaneous dosage
    Adults

    600 mg trastuzumab and 10,000 units hyaluronidase (5 mL) subcutaneously over approximately 2 to 5 minutes on day 1 every 3 weeks, in combination with pertuzumab (840 mg IV over 60 minutes [of cycle 1 only], followed 3 weeks later by 420 mg IV over 30 to 60 minutes repeated every 3 weeks), for for a total of 1 year (up to 18 cycles) or until disease recurrence or unmanageable toxicity. Give with standard anthracycline- and/or taxane-based chemotherapy for early breast cancer. Pertuzumab and trastuzumab; hyaluronidase can be given in any order; however, both agents should be given before the taxane in taxane-containing regimens. Give pertuzumab and trastuzumab; hyaluronidase after the completion of the anthracycline dose in anthracycline-containing regimens. Observe closely for infusion-related reactions after the first pertuzumab infusion for 60 minutes and for 30 minutes after subsequent infusions; do not start other therapy until after this observation period. Do not administer pertuzumab without trastuzumab; hyaluronidase; withhold or discontinue pertuzumab therapy if trastuzumab; hyaluronidase is withheld or discontinued.

    For the treatment of HER2-positive metastatic breast cancer in patients who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease, in combination with pertuzumab and docetaxel†.
    NOTE: Pertuzumab is FDA-approved in combination with trastuzumab; hyaluronidase and docetaxel for this indication.
    Subcutaneous dosage
    Adults

    600 mg trastuzumab and 10,000 units hyaluronidase (5 mL) subcutaneously over approximately 2 to 5 minutes in combination with pertuzumab (840 mg IV over 60 minutes [of cycle 1 only], followed 3 weeks later by 420 mg IV over 30 to 60 minutes repeated every 3 weeks) and docetaxel (75 mg/m2 IV) on day 1; in the clinical trial, docetaxel was continued for at least a total of 6 cycles and pertuzumab/trastuzumab were administered until disease progression or unacceptable toxicity. Pertuzumab and trastuzumab; hyaluronidase can be given in any order; however, both agents should be given PRIOR TO the docetaxel infusion. Observe closely for infusion-related reactions for 60 minutes after the first pertuzumab infusion and for 30 minutes after subsequent infusions; do not start other infusions until after this observation period. Do not administer pertuzumab without trastuzumab; hyaluronidase; withhold or discontinue pertuzumab therapy if trastuzumab; hyaluronidase is withheld or discontinued. In a multicenter, double-blind, placebo-controlled trial of patients with HER2-positive metastatic breast cancer (CLEOPATRA), treatment with pertuzumab, trastuzumab, and docetaxel significantly improved progression-free survival (18.5 months vs. 12.4 months) compared with trastuzumab and docetaxel alone. Overall survival was also significantly improved in the pertuzumab arm (56.5 months vs. 40.8 months).

    MAXIMUM DOSAGE

    Adults

    600 mg trastuzumab and 10,000 units of hyaluronidase (5 mL) subcutaneously once every 3 weeks.

    Geriatric

    600 mg trastuzumab and 10,000 units of hyaluronidase (5 mL) subcutaneously once every 3 weeks.

    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

    Trastuzumab; hyaluronidase is for subcutaneous administration only; do not administer intravenously. Trastuzumab; hyaluronidase has different dosing and administration instructions than intravenous trastuzumab products.
    Do not substitute trastuzumab; hyaluronidase for or with other trastuzumab-based products.
    No dose adjustments for patient body weight or for different concomitant chemotherapy regimens are required.
    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Do not use vial if particulates or discoloration is present.
    If a dose is delayed or missed, administer as soon as possible; do not wait until the next planned cycle. Adjust the schedule of administration to maintain a 3-week interval between doses.

    Subcutaneous Administration

    Trastuzumab; hyaluronidase should be administered by a health care professional.
    Trastuzumab; hyaluronidase is a ready-to-use solution and does not need to be diluted.
    To prepare the dosing syringe, withdraw the solution of trastuzumab; hyaluronidase from the vial into the syringe. Replace the transfer needle with a syringe closing cap and label the syringe with the peel-off sticker.
    Discard any unused portion remaining in the vial.
    To avoid needle clogging, attach the injection needle to the syringe immediately prior to administration followed by volume adjustment to 5 mL. Trastuzumab; hyaluronidase is compatible with polypropylene and polycarbonate syringe material as well as stainless steel transfer and injection needles.
    Alternate injection sites between the left and right thigh. Administer over 2 to 5 minutes.
    New injections should be at least 2.5 cm from the previous site on healthy skin. Do not inject into areas where the skin is red, bruised, tender or hard, or areas where there are moles or scars.
    Inject other medicinal products for subcutaneous administration at different sites if possible.
     
    Storage
    If a syringe containing trastuzumab; hyaluronidase is not used immediately, it may be stored in the refrigerator for up to 24 hours and subsequently at room temperature for up to 4 hours. Protect from light. Do not shake or freeze.

    STORAGE

    HERCEPTIN HYLECTA:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Do not freeze
    - Protect from light
    - See package insert for detailed storage information
    - Store between 36 to 46 degrees F
    - Store in original package until time of use

    CONTRAINDICATIONS / PRECAUTIONS

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

    Subclinical and clinical heart failure can occur as a result of treatment with trastuzumab; hyaluronidase. There is a 4- to 6-fold increase in the incidence of symptomatic cardiac dysfunction in patients receiving trastuzumab (monotherapy or in combination with chemotherapy) compared with those not receiving trastuzumab. The incidence and severity were highest in patients receiving concomitant anthracycline-containing chemotherapy regimens; patients who receive anthracycline after stopping trastuzumab; hyaluronidase may also be at increased risk of cardiac dysfunction. The incidence of symptomatic cardiac dysfunction was similar for subcutaneous trastuzumab; hyaluronidase and intravenous trastuzumab. Use trastuzumab; hyaluronidase with caution in patients with a history of cardiac disease, heart failure, cardiomyopathy, ventricular dysfunction, hypertension, or cardiac arrhythmias, as trastuzumab; hyaluronidase 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; hyaluronidase, every 3 months during treatment, upon completion of therapy, and every 6 months for at least 2 years after adjuvant therapy. An interruption or discontinuation of therapy may be necessary for a decline in LVEF; the safety of continuing or resuming trastuzumab; hyaluronidase in patients with treatment-induced left ventricular cardiac dysfunction has not been adequately studied.[63988]

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

    Use trastuzumab; hyaluronidase with caution in patients with preexisting chronic lung disease (CLD) such as chronic obstructive pulmonary disease (COPD), asthma, or pulmonary fibrosis. Treatment with trastuzumab; hyaluronidase can result in 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. Symptoms usually occur during or within 24 hours of trastuzumab; hyaluronidase administration. Discontinue trastuzumab; hyaluronidase for interstitial pneumonitis or acute respiratory distress syndrome; monitor patients until symptoms completely resolve.

    Serious hypersensitivity reactions or anaphylaxis

    Serious hypersensitivity reactions or anaphylaxis have been reported with trastuzumab; hyaluronidase treatment. Patients who have dyspnea at rest due to complications of advanced malignancy and comorbidities may be at increased risk of a severe or fatal reaction. Closely monitor patients for systemic hypersensitivity reactions, especially during the first administration. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use. Consider premedication with an analgesic, antipyretic, or antihistamine prior to readministration of trastuzumab; hyaluronidase for patients experiencing reversible grade 1 or 2 hypersensitivity reactions. Discontinue trastuzumab; hyaluronidase for angioedema or acute respiratory distress syndrome (ARDS); monitor patients until symptoms completely resolve. Permanently discontinue trastuzumab; hyaluronidase in patients who experience anaphylaxis or severe hypersensitivity reactions.[63988]

    Chemotherapy, neutropenia

    Chemotherapy-induced neutropenia and febrile neutropenia may be exacerbated by the addition of subcutaneous trastuzumab; hyaluronidase. The incidence of grade 3 or 4 neutropenia and febrile neutropenia were higher in patients receiving intravenous trastuzumab plus myelosuppressive chemotherapy compared to those receiving chemotherapy alone in randomized, controlled clinical trials; the incidence of septic death was similar.

    Ensure correct formulation selection

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

    Pregnancy

    Serious fetal harm can occur if trastuzumab; hyaluronidase is administered during pregnancy or within 7 months prior to conception. Counsel women to avoid pregnancy during trastuzumab; hyaluronidase therapy and for 7 months after the last dose. If a woman becomes pregnant while receiving or within 7 months of receiving trastuzumab; hyaluronidase, inform her of the fetal risks, monitor for oligohydramnios, and immediately report to the pregnancy pharmacovigilance program at Genentech (1-888-835-2555). 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. Based on animals studies with hyaluronidase, there is no evidence of teratogenicity or other adverse effects on sexual maturation, learning and memory, or fertility of the offspring.[63988]

    Contraception requirements, pregnancy testing, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during and after treatment with trastuzumab; hyaluronidase. 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; hyaluronidase. Females of reproductive potential should undergo pregnancy testing prior to treatment initiation. Women who become pregnant while receiving trastuzumab; hyaluronidase 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).

    Breast-feeding

    It is not known whether trastuzumab is 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; hyaluronidase and for 7 months after the last dose.[63988]

    ADVERSE REACTIONS

    Severe

    neutropenia / Delayed / 4.0-30.0
    heart failure / Delayed / 0.8-28.0
    arrhythmia exacerbation / Early / 0-5.0
    leukopenia / Delayed / 1.0-5.0
    diarrhea / Early / 1.0-2.7
    hypertension / Early / 2.0-2.4
    oligomenorrhea / Delayed / 0-2.0
    alopecia / Delayed / 0-1.3
    nausea / Early / 0-1.3
    edema / Delayed / 0-1.0
    flushing / Rapid / 0-1.0
    cough / Delayed / 0-1.0
    dyspnea / Early / 0-1.0
    serious hypersensitivity reactions or anaphylaxis / Rapid / 0-1.0
    injection site reaction / Rapid / 0-1.0
    rash / Early / 0-1.0
    erythema / Early / 0-1.0
    anemia / Delayed / 0-1.0
    abdominal pain / Early / 0-1.0
    constipation / Delayed / 0-1.0
    vomiting / Early / 0-1.0
    anorexia / Delayed / 0-1.0
    back pain / Delayed / 0-1.0
    myalgia / Early / 0-1.0
    bone pain / Delayed / 0-1.0
    arthralgia / Delayed / 0-1.0
    infection / Delayed / 0-1.0
    fever / Early / 0-1.0
    peripheral neuropathy / Delayed / 0-1.0
    paresthesias / Delayed / 0-1.0
    fatigue / Early / 0-1.0
    dizziness / Early / 0-1.0
    headache / Early / 0-1.0
    insomnia / Early / 0-1.0
    amenorrhea / Delayed / 0-1.0
    acute respiratory distress syndrome (ARDS) / Early / Incidence not known
    pulmonary toxicity / Early / Incidence not known
    pleural effusion / Delayed / Incidence not known
    pulmonary edema / Early / Incidence not known
    pulmonary fibrosis / Delayed / Incidence not known
    teratogenesis / Delayed / Incidence not known
    glomerulonephritis / Delayed / Incidence not known
    tumor lysis syndrome (TLS) / Delayed / Incidence not known

    Moderate

    antibody formation / Delayed / 16.0-16.0
    hot flashes / Early / 10.0-10.0
    peripheral edema / Delayed / Incidence not known
    sinus tachycardia / Rapid / Incidence not known
    pneumonitis / Delayed / Incidence not known
    hypoxia / Early / Incidence not known
    bleeding / Early / Incidence not known
    hematoma / Early / Incidence not known
    thrombocytopenia / Delayed / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known

    Mild

    dyspepsia / Early / 0-11.0
    dysgeusia / Early / 0-10.0
    skin discoloration / Delayed / 9.0-9.0
    nasal irritation / Early / 5.0-6.0
    epistaxis / Delayed / 6.0-6.0
    pruritus / Rapid / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen; Aspirin, ASA; Caffeine: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Amide local anesthetics: (Moderate) Hyaluronidase, when used in combination with local anesthetics, hastens the onset of analgesia and reduces the swelling caused by local infiltration; this interaction is beneficial and is the reason hyaluronidase is used adjunctively in local infiltrative anesthesia techniques. However, the wider spread of the local anesthetic solution may increase the systemic absorption of the local anesthetic, which shortens the duration of anesthetic action and tends to increase the potential risk for systemic side effects.
    Aminosalicylate sodium, Aminosalicylic acid: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    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.
    Articaine; Epinephrine: (Moderate) Hyaluronidase, when used in combination with local anesthetics, hastens the onset of analgesia and reduces the swelling caused by local infiltration; this interaction is beneficial and is the reason hyaluronidase is used adjunctively in local infiltrative anesthesia techniques. However, the wider spread of the local anesthetic solution may increase the systemic absorption of the local anesthetic, which shortens the duration of anesthetic action and tends to increase the potential risk for systemic side effects.
    Aspirin, ASA: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Aspirin, ASA; Butalbital; Caffeine: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Aspirin, ASA; Caffeine: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Aspirin, ASA; Caffeine; Orphenadrine: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Aspirin, ASA; Carisoprodol: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Aspirin, ASA; Carisoprodol; Codeine: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Aspirin, ASA; Dipyridamole: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Aspirin, ASA; Omeprazole: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Aspirin, ASA; Oxycodone: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Aspirin, ASA; Pravastatin: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Bismuth Subsalicylate: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Bupivacaine Liposomal: (Moderate) Hyaluronidase, when used in combination with local anesthetics, hastens the onset of analgesia and reduces the swelling caused by local infiltration; this interaction is beneficial and is the reason hyaluronidase is used adjunctively in local infiltrative anesthesia techniques. However, the wider spread of the local anesthetic solution may increase the systemic absorption of the local anesthetic, which shortens the duration of anesthetic action and tends to increase the potential risk for systemic side effects.
    Bupivacaine: (Moderate) Hyaluronidase, when used in combination with local anesthetics, hastens the onset of analgesia and reduces the swelling caused by local infiltration; this interaction is beneficial and is the reason hyaluronidase is used adjunctively in local infiltrative anesthesia techniques. However, the wider spread of the local anesthetic solution may increase the systemic absorption of the local anesthetic, which shortens the duration of anesthetic action and tends to increase the potential risk for systemic side effects.
    Bupivacaine; Lidocaine: (Moderate) Hyaluronidase, when used in combination with local anesthetics, hastens the onset of analgesia and reduces the swelling caused by local infiltration; this interaction is beneficial and is the reason hyaluronidase is used adjunctively in local infiltrative anesthesia techniques. However, the wider spread of the local anesthetic solution may increase the systemic absorption of the local anesthetic, which shortens the duration of anesthetic action and tends to increase the potential risk for systemic side effects.
    Bupivacaine; Meloxicam: (Moderate) Hyaluronidase, when used in combination with local anesthetics, hastens the onset of analgesia and reduces the swelling caused by local infiltration; this interaction is beneficial and is the reason hyaluronidase is used adjunctively in local infiltrative anesthesia techniques. However, the wider spread of the local anesthetic solution may increase the systemic absorption of the local anesthetic, which shortens the duration of anesthetic action and tends to increase the potential risk for systemic side effects.
    Chloroprocaine: (Moderate) Hyaluronidase, when used in combination with local anesthetics, hastens the onset of analgesia and reduces the swelling caused by local infiltration; this interaction is beneficial and is the reason hyaluronidase is used adjunctively in local infiltrative anesthesia techniques. However, the wider spread of the local anesthetic solution may increase the systemic absorption of the local anesthetic, which shortens the duration of anesthetic action and tends to increase the potential risk for systemic side effects.
    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.
    Choline Salicylate; Magnesium Salicylate: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Cocaine: (Moderate) Hyaluronidase, when used in combination with local anesthetics, hastens the onset of analgesia and reduces the swelling caused by local infiltration; this interaction is beneficial and is the reason hyaluronidase is used adjunctively in local infiltrative anesthesia techniques. However, the wider spread of the local anesthetic solution may increase the systemic absorption of the local anesthetic, which shortens the duration of anesthetic action and tends to increase the potential risk for systemic side effects.
    Conjugated Estrogens: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Conjugated Estrogens; Bazedoxifene: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Conjugated Estrogens; Medroxyprogesterone: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Corticotropin, ACTH: (Minor) Corticosteroids (e.g., cortisone, corticotropin, ACTH), when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Cortisone: (Minor) Corticosteroids (e.g., cortisone, corticotropin, ACTH), when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    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.
    Desogestrel; Ethinyl Estradiol: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Dienogest; Estradiol valerate: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Diethylstilbestrol, DES: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    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.
    Drospirenone; Estetrol: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Drospirenone; Estradiol: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Drospirenone; Ethinyl Estradiol: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Elagolix; Estradiol; Norethindrone acetate: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    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.
    Ester local anesthetics: (Moderate) Hyaluronidase, when used in combination with local anesthetics, hastens the onset of analgesia and reduces the swelling caused by local infiltration; this interaction is beneficial and is the reason hyaluronidase is used adjunctively in local infiltrative anesthesia techniques. However, the wider spread of the local anesthetic solution may increase the systemic absorption of the local anesthetic, which shortens the duration of anesthetic action and tends to increase the potential risk for systemic side effects.
    Esterified Estrogens: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Esterified Estrogens; Methyltestosterone: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Estradiol Cypionate; Medroxyprogesterone: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Estradiol: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Estradiol; Levonorgestrel: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Estradiol; Norethindrone: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Estradiol; Norgestimate: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Estradiol; Progesterone: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Estrogens: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Estropipate: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Ethinyl Estradiol: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Ethinyl Estradiol; Norelgestromin: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Ethinyl Estradiol; Norethindrone Acetate: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Ethinyl Estradiol; Norgestrel: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Ethynodiol Diacetate; Ethinyl Estradiol: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Etonogestrel; Ethinyl Estradiol: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    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.
    Levobupivacaine: (Moderate) Hyaluronidase, when used in combination with local anesthetics, hastens the onset of analgesia and reduces the swelling caused by local infiltration; this interaction is beneficial and is the reason hyaluronidase is used adjunctively in local infiltrative anesthesia techniques. However, the wider spread of the local anesthetic solution may increase the systemic absorption of the local anesthetic, which shortens the duration of anesthetic action and tends to increase the potential risk for systemic side effects.
    Levonorgestrel; Ethinyl Estradiol: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Lidocaine: (Moderate) Hyaluronidase, when used in combination with local anesthetics, hastens the onset of analgesia and reduces the swelling caused by local infiltration; this interaction is beneficial and is the reason hyaluronidase is used adjunctively in local infiltrative anesthesia techniques. However, the wider spread of the local anesthetic solution may increase the systemic absorption of the local anesthetic, which shortens the duration of anesthetic action and tends to increase the potential risk for systemic side effects.
    Lidocaine; Prilocaine: (Moderate) Hyaluronidase, when used in combination with local anesthetics, hastens the onset of analgesia and reduces the swelling caused by local infiltration; this interaction is beneficial and is the reason hyaluronidase is used adjunctively in local infiltrative anesthesia techniques. However, the wider spread of the local anesthetic solution may increase the systemic absorption of the local anesthetic, which shortens the duration of anesthetic action and tends to increase the potential risk for systemic side effects.
    Magnesium Salicylate: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Mepivacaine: (Moderate) Hyaluronidase, when used in combination with local anesthetics, hastens the onset of analgesia and reduces the swelling caused by local infiltration; this interaction is beneficial and is the reason hyaluronidase is used adjunctively in local infiltrative anesthesia techniques. However, the wider spread of the local anesthetic solution may increase the systemic absorption of the local anesthetic, which shortens the duration of anesthetic action and tends to increase the potential risk for systemic side effects.
    Mepivacaine; Levonordefrin: (Moderate) Hyaluronidase, when used in combination with local anesthetics, hastens the onset of analgesia and reduces the swelling caused by local infiltration; this interaction is beneficial and is the reason hyaluronidase is used adjunctively in local infiltrative anesthesia techniques. However, the wider spread of the local anesthetic solution may increase the systemic absorption of the local anesthetic, which shortens the duration of anesthetic action and tends to increase the potential risk for systemic side effects.
    Mestranol; Norethindrone: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Norethindrone; Ethinyl Estradiol: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Norgestimate; Ethinyl Estradiol: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    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.
    Prilocaine: (Moderate) Hyaluronidase, when used in combination with local anesthetics, hastens the onset of analgesia and reduces the swelling caused by local infiltration; this interaction is beneficial and is the reason hyaluronidase is used adjunctively in local infiltrative anesthesia techniques. However, the wider spread of the local anesthetic solution may increase the systemic absorption of the local anesthetic, which shortens the duration of anesthetic action and tends to increase the potential risk for systemic side effects.
    Prilocaine; Epinephrine: (Moderate) Hyaluronidase, when used in combination with local anesthetics, hastens the onset of analgesia and reduces the swelling caused by local infiltration; this interaction is beneficial and is the reason hyaluronidase is used adjunctively in local infiltrative anesthesia techniques. However, the wider spread of the local anesthetic solution may increase the systemic absorption of the local anesthetic, which shortens the duration of anesthetic action and tends to increase the potential risk for systemic side effects.
    Procaine: (Moderate) Hyaluronidase, when used in combination with local anesthetics, hastens the onset of analgesia and reduces the swelling caused by local infiltration; this interaction is beneficial and is the reason hyaluronidase is used adjunctively in local infiltrative anesthesia techniques. However, the wider spread of the local anesthetic solution may increase the systemic absorption of the local anesthetic, which shortens the duration of anesthetic action and tends to increase the potential risk for systemic side effects.
    Relugolix; Estradiol; Norethindrone acetate: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Ropivacaine: (Moderate) Hyaluronidase, when used in combination with local anesthetics, hastens the onset of analgesia and reduces the swelling caused by local infiltration; this interaction is beneficial and is the reason hyaluronidase is used adjunctively in local infiltrative anesthesia techniques. However, the wider spread of the local anesthetic solution may increase the systemic absorption of the local anesthetic, which shortens the duration of anesthetic action and tends to increase the potential risk for systemic side effects.
    Salicylates: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Salsalate: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    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.
    Sedating H1-blockers: (Minor) H1-blockers (antihistamines), when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Segesterone Acetate; Ethinyl Estradiol: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Tetracaine: (Moderate) Hyaluronidase, when used in combination with local anesthetics, hastens the onset of analgesia and reduces the swelling caused by local infiltration; this interaction is beneficial and is the reason hyaluronidase is used adjunctively in local infiltrative anesthesia techniques. However, the wider spread of the local anesthetic solution may increase the systemic absorption of the local anesthetic, which shortens the duration of anesthetic action and tends to increase the potential risk for systemic side effects.
    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; hyaluronidase is administered during pregnancy or within 7 months prior to conception. Counsel women to avoid pregnancy during trastuzumab; hyaluronidase therapy and for 7 months after the last dose. If a woman becomes pregnant while receiving or within 7 months of receiving trastuzumab; hyaluronidase, inform her of the fetal risks, monitor for oligohydramnios, and immediately report to the pregnancy pharmacovigilance program at Genentech (1-888-835-2555). 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. Based on animals studies with hyaluronidase, there is no evidence of teratogenicity or other adverse effects on sexual maturation, learning and memory, or fertility of the offspring.[63988]

    It is not known whether trastuzumab is 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; hyaluronidase and for 7 months after the last dose.[63988]

    MECHANISM OF ACTION

    Trastuzumab is a humanized IgG1 kappa monoclonal antibody that selectively binds with high affinity to the extracellular domain of HER2. The HER2 or 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. Trastuzumab-mediated antibody-dependent cellular cytotoxicity (ADCC) preferentially acts on cancer cells that overexpress HER2 compared with cancer cells that do not overexpress HER2.[63988] 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]
     
    Hyaluronidase is a endoglycosidase used to increase dispersion and absorption of coadministered drugs when administered subcutaneously. In the administered doses, hyaluronidase in trastuzumab; hyaluronidase acts transiently and locally. It increases permeability of the subcutaneous tissue by depolymerizing hyaluronan, which is a polysaccharide found in the extracellular matrix of the subcutaneous tissue. Unlike the stable structural components of the interstitial matrix, hyaluronan has a half-life of approximately 0.5 days; the effects of hyaluronidase are reversible and permeability of subcutaneous tissue is restored within 24 to 48 hours. Hyaluronidase has been shown to increase the absorption rate of a trastuzumab product into systemic circulation when given in the subcutis of Gottingen Minipigs.[63988]

    PHARMACOKINETICS

    Trastuzumab; hyaluronidase is administered subcutaneously. Based on a population pharmacokinetic model, the volume of distribution (Vd) of trastuzumab after subcutaneous administration of trastuzumab; hyaluronidase was 2.9 Liters. The linear elimination clearance was 0.11 Liters/day. The non-linear elimination Vmax was 11.9 mg/day and the non-linear elimination Km was 33.9 mg/Liter.
     
    Affected cytochrome P450 isoenzymes and drug transporters: None
    Formal drug interaction studies have not been performed with trastuzumab in humans. Clinically significant interactions between trastuzumab and concomitant medications have not been observed in clinical trials.

    Subcutaneous Route

    The absolute bioavailability of trastuzumab after subcutaneous administration of trastuzumab; hyaluronidase was 0.77. The first-order absorption rate of subcutaneous trastuzumab; hyaluronidase was 0.4 days, with a time to maximal concentration (Tmax) of 3 days. The Cmax after subcutaneous administration of trastuzumab; hyaluronidase was 79.3 mcg/mL after the first cycle and 149 mcg/mL after the 7th cycle, compared with 178 mcg/mL and 179 mcg/mL for intravenous trastuzumab, respectively. The AUC was 1,065 mcg/mL x day for trastuzumab; hyaluronidase in the first cycle and 2,337 mg/mL x day in the 7th cycle; the AUC for trastuzumab was 1,373 mcg/mL x day and 1,794 mcg/mL x day, respectively. In a multicenter, randomized, open-label clinical trial (the HannaH study; n = 596), treatment with subcutaneous trastuzumab; hyaluronidase with chemotherapy was noninferior to intravenous trastuzumab based on coprimary pharmacokinetic (trastuzumab Cmin) and efficacy (pCR rate at definitive surgery) outcomes. In this study, the Cmin pre-dose Cycle 8 was 78.7 mcg/mL for subcutaneous trastuzumab; hyaluronidase compared to 57.8 mcg/mL for intravenous trastuzumab; the geometric mean ratio was 1.3 (90% CI, 1.2 to 1.4). The mean Cmax was 32% lower, and the mean AUC following the Cycle 7 dose and the Cycle 12 dose was 10% and 20% higher, respectively, with subcutaneous trastuzumab; hyaluronidase compared to intravenous trastuzumab. Trastuzumab is estimated to reach concentrations that are less than 1 mcg/mL by 7 months in at least 95% of patients. The rate of pCR prior to surgery in the HannaH study was 45.4% in the subcutaneous trastuzumab and hyaluronidase arm compared with 40.7% in the intravenous trastuzumab arm (95% CI for difference in pCR, -4 to 13.4); there was no difference in event-free survival or overall survival after a median follow-up of over 70 months. No new safety signals were identified for trastuzumab and hyaluronidase in another nonrandomized, open-label clinical trial (the SafeHER study; n = 1,864).[63988]