Class: Antineoplastic Agents
- HER2 Dimerization Inhibitors
VA Class: AN900
CAS Number: 180288-69-1
Medically reviewed by Drugs.com. Last updated on Aug 17, 2020.
Do not confuse trastuzumab (Herceptin) with ado-trastuzumab emtansine (Kadcyla). Latter agent is an anti-human epidermal growth factor receptor type 2 (anti-HER2) antibody-drug conjugate; the anti-HER2 antibody trastuzumab, a humanized immunoglobulin (IgG1), is conjugated with the microtubule inhibitor DM1 (derivative of maytansine) via the linker MCC (4-[N-maleimidomethyl] cyclohexane-1-carboxylate).
Original generic name for Kadcyla was trastuzumab emtansine (established by the US Adopted Name [USAN] Council). Because of similarity between the original generic name for Kadcyla (trastuzumab emtansine) and the generic name for Herceptin (trastuzumab), FDA approved the prefix addition “ado” to the generic name for Kadcyla (i.e., ado-trastuzumab emtansine). However, potential exists for dispensing or prescribing errors involving these drugs.
Exercise extra care to ensure accuracy of prescriptions. Institute for Safe Medication Practices (ISMP), FDA, and the manufacturer of ado-trastuzumab emtansine (Kadcyla) recommend that prescribers communicate both brand and generic names for ado-trastuzumab emtansine (Kadcyla) on prescription order forms. (See Possible Prescribing and Dispensing Errors under General Precautions, in Cautions.)
Risk of cardiotoxicity (e.g., ventricular dysfunction, CHF).
Evaluate left ventricular function prior to and during therapy.
Discontinuance of trastuzumab should be strongly considered in patients who develop a clinically important decrease in left ventricular function.
- Anthracyclines and Cyclophosphamide
Increased frequency and severity of cardiac toxicity when used in combination with an anthracycline and cyclophosphamide.
- Hypersensitivity, Infusion, and Pulmonary Reactions
Risk of severe (rarely fatal) hypersensitivity reactions, (e.g., anaphylaxis), infusion reactions, or severe pulmonary effects.
Onset of symptoms generally occurs during or within 24 hours of initiation of the infusion.
Interrupt infusion in patients who develop dyspnea or clinically important hypotension.
Patients should be monitored until signs and symptoms of these effects completely resolve.
Discontinuance of trastuzumab should be strongly considered in patients who develop anaphylaxis, angioedema, or acute respiratory distress syndrome (ARDS).
Antineoplastic agent; a recombinant DNA-derived humanized anti-HER2 monoclonal antibody.
Uses for Trastuzumab
Use as monotherapy for treatment of metastatic breast cancer that has relapsed following prior chemotherapy for metastatic disease in patients with tumors that overexpress the HER2 protein.
Initial treatment of metastatic breast cancer, in combination with paclitaxel, in patients with tumors that overexpress the HER2 protein.
Adjuvant treatment in conjunction with chemotherapy in patients with operable HER2-positive breast cancer†.
Evaluation of HER2 status is required prior to initiating therapy. (See Evaluation of HER2 under Cautions.) Use only in patients whose tumors overexpress HER2 protein. Not indicated for use in patients with tumors that do not overexpress the HER2 protein.
Although the use of trastuzumab in combination with an anthracycline and cyclophosphamide for initial treatment of HER2-overexpressing metastatic breast cancer has been investigated in a large, randomized clinical trial, the clinical benefit did not outweigh the increased risk of serious cardiac toxicity and use of this combination regimen did not receive approval from FDA.
Trastuzumab Dosage and Administration
Observe patients for fever and chills or other infusion-associated symptoms during infusion. (See Infusion-related Effects under Cautions.)
Infusion should be interrupted in patients experiencing dyspnea or clinically important hypotension. Discontinuance of therapy should be considered strongly in patients who develop ARDS, anaphylaxis, or angioedema. Immediately discontinue infusion and initiate appropriate medical treatment if severe trastuzumab-induced reactions occur. Patients should be monitored carefully until signs and symptoms have resolved completely.
Administer by IV infusion.
Do not administer by rapid IV injection (e.g., IV push or bolus).
Reconstitute prior to administration.
Reconstitute vial containing 440 mg of lyophilized drug with 20 mL of the supplied bacteriostatic water for injection, containing 1.1% benzyl alcohol to provide a solution containing 21 mg of trastuzumab per mL.
Alternatively, for patients sensitive to benzyl alcohol, reconstitute using 20 mL of sterile water for injection.
Handle with care during reconstitution; shaking the reconstituted solution or causing excessive foaming during the addition of diluent may cause problems with dissolution and the amount of the drug that can be withdrawn from the vial.
Slowly inject 20 mL of diluent into the vial with the stream of diluent directed into the lyophilized cake of trastuzumab. Swirl vial gently to aid reconstitution; do not shake reconstituted solution because trastuzumab may be sensitive to shear-induced stress (e.g., agitation, rapid expulsion from a syringe).
Allow vial to stand undisturbed for 5 minutes following reconstitution; slight foaming of the reconstituted solution is not unusual. Reconstituted solution should be clear to slightly opalescent, colorless to pale yellow, and free of visible particulate matter.
Vials reconstituted with bacteriostatic water for injection should be immediately labeled in the area marked “Do not use after:” with the future date that is 28 days from the date of reconstitution; discard unused portions after 28 days.
Vials reconstituted with sterile water for injection should be used immediately; discard any unused solution.
Dilute reconstituted solutions prior to administration by adding an appropriate volume of trastuzumab 21 mg/mL solution to a polyvinyl chloride or polyethylene infusion bag containing 250 mL of 0.9% sodium chloride injection; gently invert bag to mix the solution.
Do not dilute infusion solutions in or administer with 5% dextrose injection; do not mix or dilute trastuzumab with other drugs.
Rate of Administration
Administer initial loading dose over 90 minutes; if initial dose is well tolerated, administer maintenance doses over 30 minutes.
Metastatic Breast CancerIV
Initially, 4 mg/kg as a loading dose followed by once-weekly maintenance doses of 2 mg/kg. Continue once-weekly administration until disease progression or intolerable toxicity is observed.
Adjuvant Treatment of Early Breast Cancer†IV
Loading dose of 4 mg/kg followed by maintenance doses of 2 mg/kg once weekly for 51 weeks has been used in clinical studies. Trastuzumab was initiated concurrently with paclitaxel after doxorubicin and cyclophosphamide in these studies. Other regimens also have been investigated.
Cautions for Trastuzumab
Risk of cardiotoxicity (e.g., dyspnea [including paroxysmal nocturnal], increased cough, peripheral edema, S3 gallop, cardiomyopathy, CHF, and reduced ejection fraction [decrease of >10%]). CHF may be severe and may result in disabling heart failure, mural thrombosis and stroke, and/or death.
Discontinue therapy if a clinically important decrease in left ventricular function or CHF occurs. If trastuzumab is used in early breast cancer, therapy interruption may be needed in patients experiencing asymptomatic decreases in left ventricular function. Institute appropriate medical therapy if cardiac dysfunction occurs.
Monitor patients closely for signs of cardiotoxicity. Perform baseline cardiac evaluation including history, physical examination, and cardiac function tests (i.e., ECG, echocardiogram and/or MUGA scan) prior to initiating therapy. Monitor cardiac function frequently. Closely monitor patients who develop asymptomatic decreases in ejection fraction for signs and symptoms of heart failure.
Increased risk of cardiac dysfunction in geriatric patients, patients with preexisting cardiac disease, and patients who have had prior cardiotoxic therapy (e.g., anthracycline therapy or radiation therapy to the chest area).
Extreme caution is advised during trastuzumab therapy for metastatic breast cancer in patients with preexisting cardiac dysfunction.
Risk of severe and rarely fatal infusion-related reactions (e.g., bronchospasm, dyspnea, hypoxia, severe hypotension) generally with the first dose (possibly during or immediately following the infusion).
Risk of symptoms worsening progressively and leading to further pulmonary complications.
Risk of marked clinical deterioration following initial improvement in those with acute signs and symptoms.
Risk of delayed adverse events with rapid clinical deterioration occurring following completion of trastuzumab infusion.
Severe infusion-related reactions may result in death within hours of the infusion or up to 1 week after the infusion.
Interrupt infusion and administer supportive therapy (e.g., oxygen, IV fluids, β-adrenergic agonists, corticosteroids) if severe infusion-related reactions occur.
Subsequent infusions may be tolerated following complete recovery, typically accompanied by prophylactic treatment (e.g., antihistamines and/or corticosteroids); severe reactions may recur despite the use of premedication.
Preexisting pulmonary compromise may increase risk of serious infusion-related adverse effects.
Risk of mild to moderate infusion-related symptoms (e.g., chills, fever, nausea, vomiting, pain [including at tumor sites], rigors, headache, dizziness, dyspnea, hypotension, rash, asthenia) occurring during the first infusion or possibly with subsequent infusions. Administer acetaminophen, diphenhydramine, and/or meperidine, and reduce infusion rate if such infusion-related symptoms occur. Discontinuance of therapy is required infrequently.
Risk of severe and rarely fatal adverse respiratory effects (e.g., dyspnea, wheezing, pulmonary infiltrates, pleural effusions, noncardiogenic pulmonary edema, pulmonary insufficiency, hypoxia); may require supplemental oxygen or ventilatory support. ARDS also may occur. (See Boxed Warning.)
Possible increased risk of serious or fatal adverse pulmonary reactions in patients with clinically important preexisting pulmonary compromise secondary to intrinsic lung disease (e.g., asthma, COPD) and/or malignant pulmonary involvement (e.g., lymphangitic spread of tumor, pleural effusions, parenchymal masses) resulting in dyspnea at rest. Administer with extreme caution in such patients; carefully weigh the risks and benefits of therapy.
Possible exacerbation of chemotherapy-induced neutropenia (including fatal sepsis associated with neutropenia) in patients receiving trastuzumab in combination with myelosuppressive chemotherapy.
Risk of leukopenia and anemia especially in those receiving trastuzumab in combination with paclitaxel. These reactions occur frequently with combination chemotherapy, but rarely in those receiving monotherapy; they are mild to moderate in severity, reversible, and do not require discontinuance of therapy.
Risk of severe hypersensitivity reactions (e.g., fatal anaphylaxis). Signs and symptoms of hypersensitivity reactions include anaphylaxis, urticaria, bronchospasm, angioedema, and/or hypotension. Onset usually during initial infusion, but may occur following completion of an infusion.
If a severe hypersensitivity reaction occurs, interrupt infusion and administer appropriate medical therapy (e.g., epinephrine, corticosteroids, diphenhydramine, bronchodilators, oxygen). Monitor patients carefully until signs and symptoms have resolved completely. Discontinuance of therapy should be considered strongly in patients who develop anaphylaxis or angioedema. Additional infusions may be tolerated following complete recovery, typically accompanied by prophylactic treatment (e.g., antihistamines, corticosteroids); severe reactions may occur despite the use of premedication.
Administer with caution in patients with known hypersensitivity to trastuzumab, Chinese Hamster Ovary (CHO) cell proteins, or any component of the formulation.
Evaluation of HER2
Assess breast tumors for HER2 overexpression prior to initiating therapy. Fluorescent in situ hybridization (FISH) (e.g., PathVysion), which measures amplification of the HER2 oncogene, and immunohistochemistry (IHC) assays (e.g., HercepTest), which measure overexpression of the HER2 protein are tests most commonly used.
Possible Prescribing and Dispensing Errors
Ensure accuracy of prescriptions; similarity in generic name of Herceptin (trastuzumab) and Kadcyla (ado-trastuzumab emtansine) may result in medication errors. Such errors may be associated with severe toxicity or lack of appropriate therapy. (See Special Alerts.)
Distributed into milk in monkeys; not known whether distributed into human milk. Discontinue nursing during trastuzumab therapy and for 6 months following the last dose of the drug because of potential risk to nursing infants.
Safety and efficacy not established in children <18 years of age.
Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults. Possible increased frequency of cardiotoxicity and cardiac dysfunction compared with younger adults. Pharmacokinetics not affected by age.
Pharmacokinetics are not affected by increased Scr concentrations up to 2 mg/dL.
Common Adverse Effects
Fever, diarrhea, infections, chills, increased cough, headache, rash, insomnia.
Interactions for Trastuzumab
Increased risk of trastuzumab-induced cardiotoxic effects (see Cardiovascular Toxicity under Cautions)
Metastatic Breast Cancer: Concomitant therapy not recommended
Possible increased mean trough serum concentrations of trastuzumab and decreased trastuzumab clearance
Clinical importance not known
Peak and trough plasma concentrations at steady state (between weeks 16 and 32) approximately 123 and 79 mcg/mL, respectively.
Target serum concentrations usually are attained by week 6 in patients with elevated serum concentrations of shed antigen (circulating extracellular domain of the HER2 receptor).
Not known whether trastuzumab crosses the blood-brain barrier or distributes into the CSF.
Not known whether trastuzumab crosses the placenta or distributes into milk in humans; however, placental transfer of trastuzumab and distribution of the drug into milk have been observed in monkeys.
Metabolism not fully understood.
Elimination may involve clearance of IgG through the reticuloendothelial system.
5.8 days (range: 1–32 days) following a loading dose of 4 mg/kg followed by a weekly maintenance dose of 2 mg/kg IV. Following IV infusion of 10 or 500 mg of trastuzumab, elimination half-life averaged 1.7 or 12 days, respectively.
Pharmacokinetics are nonlinear; increased doses are associated with increased mean half-life and decreased clearance.
Powder for Injection
Reconstituted solutions (in bacteriostatic water for injection containing benzyl alcohol) are stable for 28 days (when refrigerated at 2–8°C). Do not freeze.
Solutions reconstituted with sterile water for injection should be used immediately and unused portions discarded.
Reconstituted solutions diluted in 0.9% sodium chloride injection are stable for up to 24 hours when prepared and stored in PVC or polyethylene bags at 2–8°C.
5% dextrose injection should not be used as a diluent for trastuzumab solutions; diluents other than those recommended by the manufacturer may not maintain the stability or sterility of the antibody solution.
For information on systemic interactions resulting from concomitant use, see Interactions.
Trastuzumab should not be used with diluents containing dextrose.
Sodium chloride 0.9%
Inhibits proliferation of tumor cells that overexpress HER2. The HER2 proto-oncogene encodes a 185-kd transmembrane tyrosine kinase receptor known as p185HER2 or human epidermal growth factor receptor 2 (HER2).
Binds specifically to the extracellular domain of the HER2 receptor or HER2 protein.
The HER2 receptor participates in receptor-receptor interactions that regulate cell differentiation, growth, and proliferation. Overexpression of the HER2 receptor contributes to the process of neoplastic transformation.
Trastuzumab-mediated antibody-dependent cellular cytotoxicity (ADCC) has been demonstrated and occurs preferentially in cells that overexpress the HER2 protein compared with cells that do not.
Advice to Patients
Patients should be informed of possible delayed (after completion of the infusion) severe reactions.
Possibility of cardiotoxicity.
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses (e.g., cardiovascular disease).
Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.
Importance of informing patients of other important precautionary information. (See Cautions.)
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Do not confuse trastuzumab (Herceptin) with ado-trastuzumab emtansine (Kadcyla). (See Special Alerts.)
For injection, for IV infusion
Herceptin (supplied with 20 mL bacteriostatic water for injection containing 1.1% benzyl alcohol)
AHFS DI Essentials™. © Copyright 2021, Selected Revisions August 27, 2014. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.
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- Drug class: HER2 inhibitors