Generic Name: Trastuzumab
Class: Antineoplastic Agents
- HER2 Dimerization Inhibitors
VA Class: AN900
CAS Number: 180288-69-1
Medically reviewed by Drugs.com. Last updated on Aug 27, 2018.
Do not confuse trastuzumab (Herceptin) with ado-trastuzumab emtansine (Kadcyla).1001 1005 1006 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).1002 1004
Original generic name for Kadcyla was trastuzumab emtansine (established by the US Adopted Name [USAN] Council).1003 1006 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).1004 1005 However, potential exists for dispensing or prescribing errors involving these drugs.1001 1004 1005 1006
Exercise extra care to ensure accuracy of prescriptions.1001 1002 1005 1006 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.1001 1002 1005 1006 (See Possible Prescribing and Dispensing Errors under General Precautions, in Cautions.)
Risk of cardiotoxicity (e.g., ventricular dysfunction, CHF).1
- Anthracyclines and Cyclophosphamide
- Hypersensitivity, Infusion, and Pulmonary Reactions
Onset of symptoms generally occurs during or within 24 hours of initiation of the infusion.1
Interrupt infusion in patients who develop dyspnea or clinically important hypotension.1
Patients should be monitored until signs and symptoms of these effects completely resolve.1
Discontinuance of trastuzumab should be strongly considered in patients who develop anaphylaxis, angioedema, or acute respiratory distress syndrome (ARDS).1
Uses for Herceptin
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.1 4 5 16 25 26
Evaluation of HER2 status is required prior to initiating therapy.1 (See Evaluation of HER2 under Cautions.) Use only in patients whose tumors overexpress HER2 protein.1 Not indicated for use in patients with tumors that do not overexpress the HER2 protein.1 5
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,1 3 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.6 17 19
Herceptin Dosage and Administration
Observe patients for fever and chills or other infusion-associated symptoms during infusion.1 (See Infusion-related Effects under Cautions.)
Infusion should be interrupted in patients experiencing dyspnea or clinically important hypotension.1 Discontinuance of therapy should be considered strongly in patients who develop ARDS, anaphylaxis, or angioedema.1 Immediately discontinue infusion and initiate appropriate medical treatment if severe trastuzumab-induced reactions occur.1 24 Patients should be monitored carefully until signs and symptoms have resolved completely.1
Administer by IV infusion.1
Do not administer by rapid IV injection (e.g., IV push or bolus).1
Reconstitute prior to administration.1
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.1 22
Alternatively, for patients sensitive to benzyl alcohol, reconstitute using 20 mL of sterile water for injection.1
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.1 22
Slowly inject 20 mL of diluent into the vial with the stream of diluent directed into the lyophilized cake of trastuzumab.1 22 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).1 22
Allow vial to stand undisturbed for 5 minutes following reconstitution; slight foaming of the reconstituted solution is not unusual.1 22 Reconstituted solution should be clear to slightly opalescent, colorless to pale yellow, and free of visible particulate matter.1 22
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.1
Vials reconstituted with sterile water for injection should be used immediately; discard any unused solution.1
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.1
Do not dilute infusion solutions in or administer with 5% dextrose injection; do not mix or dilute trastuzumab with other drugs.1
Rate of Administration
Administer initial loading dose over 90 minutes; if initial dose is well tolerated, administer maintenance doses over 30 minutes.1
Metastatic Breast CancerIV
Initially, 4 mg/kg as a loading dose followed by once-weekly maintenance doses of 2 mg/kg.1 4 Continue once-weekly administration until disease progression or intolerable toxicity is observed.4 6 7 18 19
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.28 Trastuzumab was initiated concurrently with paclitaxel after doxorubicin and cyclophosphamide in these studies.28 Other regimens also have been investigated.29 30
Cautions for Herceptin
Risk of cardiotoxicity (e.g., dyspnea [including paroxysmal nocturnal], increased cough, peripheral edema, S3 gallop, cardiomyopathy, CHF, and reduced ejection fraction [decrease of >10%]).1 4 CHF1 may be severe and may result in disabling heart failure, mural thrombosis and stroke, and/or death.1
Discontinue therapy if a clinically important decrease in left ventricular function or CHF occurs.1 18 19 If trastuzumab is used in early breast cancer, therapy interruption may be needed in patients experiencing asymptomatic decreases in left ventricular function.31 Institute appropriate medical therapy if cardiac dysfunction occurs.1 21
Monitor patients closely for signs of cardiotoxicity.1 Perform baseline cardiac evaluation including history, physical examination, and cardiac function tests (i.e., ECG, echocardiogram and/or MUGA scan) prior to initiating therapy.1 Monitor cardiac function frequently.1 14 Closely monitor patients who develop asymptomatic decreases in ejection fraction for signs and symptoms of heart failure.1
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).1
Extreme caution is advised during trastuzumab therapy for metastatic breast cancer in patients with preexisting cardiac dysfunction.1
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).1 24
Risk of symptoms worsening progressively and leading to further pulmonary complications.1
Risk of marked clinical deterioration following initial improvement in those with acute signs and symptoms.1
Risk of delayed adverse events with rapid clinical deterioration occurring following completion of trastuzumab infusion.1
Severe infusion-related reactions may result in death within hours of the infusion or up to 1 week after the infusion.1
Interrupt infusion and administer supportive therapy (e.g., oxygen, IV fluids, β-adrenergic agonists, corticosteroids) if severe infusion-related reactions occur.1
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.1
Preexisting pulmonary compromise may increase risk of serious infusion-related adverse effects.24
Risk of mild to moderate infusion-related symptoms1 (e.g., chills,1 2 fever,1 2 nausea,1 vomiting,1 pain [including at tumor sites],1 rigors,1 headache,1 dizziness,1 dyspnea,1 hypotension,1 rash,1 asthenia)1 occurring during the first infusion or possibly with subsequent infusions.1 4 Administer acetaminophen, diphenhydramine, and/or meperidine, and reduce infusion rate if such infusion-related symptoms occur.1 4 Discontinuance of therapy is required infrequently.1
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.1 24 ARDS also may occur.1 (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.1 24 Administer with extreme caution in such patients; carefully weigh the risks and benefits of therapy.24
Possible exacerbation of chemotherapy-induced neutropenia (including fatal sepsis associated with neutropenia) in patients receiving trastuzumab in combination with myelosuppressive chemotherapy.1
Risk of leukopenia and anemia especially in those receiving trastuzumab in combination with paclitaxel.1 These reactions occur frequently with combination chemotherapy, but rarely in those receiving monotherapy;1 they are mild to moderate in severity, reversible, and do not require discontinuance of therapy.1
Risk of severe hypersensitivity reactions (e.g., fatal anaphylaxis).1 24 Signs and symptoms of hypersensitivity reactions include anaphylaxis, urticaria, bronchospasm, angioedema, and/or hypotension.1 Onset usually during initial infusion, but may occur following completion of an infusion.1
If a severe hypersensitivity reaction occurs, interrupt infusion and administer appropriate medical therapy (e.g., epinephrine, corticosteroids, diphenhydramine, bronchodilators, oxygen).1 Monitor patients carefully until signs and symptoms have resolved completely.1 Discontinuance of therapy should be considered strongly in patients who develop anaphylaxis or angioedema.1 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.1
Administer with caution in patients with known hypersensitivity to trastuzumab, Chinese Hamster Ovary (CHO) cell proteins, or any component of the formulation.1
Evaluation of HER2
Assess breast tumors for HER2 overexpression prior to initiating therapy.1 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.9
Possible Prescribing and Dispensing Errors
Ensure accuracy of prescriptions;1001 1002 1005 1006 similarity in generic name of Herceptin (trastuzumab) and Kadcyla (ado-trastuzumab emtansine) may result in medication errors.1001 1004 1005 1006 Such errors may be associated with severe toxicity or lack of appropriate therapy.1001 1004 1005 (See Special Alerts.)
Distributed into milk in monkeys; not known whether distributed into human milk.1 Discontinue nursing during trastuzumab therapy and for 6 months following the last dose of the drug because of potential risk to nursing infants.1
Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.1 18 19 Possible increased frequency of cardiotoxicity and cardiac dysfunction compared with younger adults.1 Pharmacokinetics not affected by age.1
Pharmacokinetics are not affected by increased Scr concentrations up to 2 mg/dL.1
Common Adverse Effects
Fever, diarrhea, infections, chills, increased cough, headache, rash, insomnia.1
Interactions for Herceptin
Peak and trough plasma concentrations at steady state (between weeks 16 and 32) approximately 123 and 79 mcg/mL, respectively.1
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).1
Not known whether trastuzumab crosses the placenta or distributes into milk in humans; however, placental transfer of trastuzumab and distribution of the drug into milk have been observed in monkeys.1
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.1 16 Following IV infusion of 10 or 500 mg of trastuzumab, elimination half-life averaged 1.7 or 12 days, respectively.1
Pharmacokinetics are nonlinear; increased doses are associated with increased mean half-life and decreased clearance.1
Powder for Injection
Solutions reconstituted with sterile water for injection should be used immediately and unused portions discarded.1
5% dextrose injection should not be used as a diluent for trastuzumab solutions;1 diluents other than those recommended by the manufacturer may not maintain the stability or sterility of the antibody solution.1 18 22
For information on systemic interactions resulting from concomitant use, see Interactions.
Trastuzumab should not be used with diluents containing dextrose.1
Sodium chloride 0.9%
Inhibits proliferation of tumor cells that overexpress HER2.1 7 The HER2 proto-oncogene encodes a 185-kd transmembrane tyrosine kinase receptor known as p185HER2 or human epidermal growth factor receptor 2 (HER2).1 4 19
Binds specifically to the extracellular domain of the HER2 receptor or HER2 protein.1
The HER2 receptor participates in receptor-receptor interactions that regulate cell differentiation, growth, and proliferation.6 7 Overexpression of the HER2 receptor contributes to the process of neoplastic transformation.6 7
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.1
Advice to Patients
Possibility of cardiotoxicity.1
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).1
Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.1
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.
For injection, for IV infusion
Herceptin (supplied with 20 mL bacteriostatic water for injection containing 1.1% benzyl alcohol)
AHFS DI Essentials™. © Copyright 2019, Selected Revisions August 27, 2014. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.
1. Genentech, Inc. Herceptin (trastuzumab) prescribing information. South San Francisco, CA; 2005 Feb.
2. Pegram MD, Lipton A, Hayes DF et al. Phase II study of receptor-enhanced chemosensitivity using recombinant humanized anti-p185HER2/neu monoclonal antibody plus cisplatin in patients with HER2/neu-overexpressing metastatic breast cancer refractory to chemotherapy treatment. J Clin Oncol. 1998; 16:2659-71. http://www.ncbi.nlm.nih.gov/pubmed/9704716?dopt=AbstractPlus
3. Slamon D, Leyland-Jones B, Shak S et al. Addition of HerceptinTM (humanized anti-HER2 antibody) to first line chemotherapy for HER2 overexpressing metastatic breast cancer (HER2+/MBC) markedly increases anticancer activity: a randomized, multinational controlled phase III trial. Proc Am Soc Clin Oncol. 1998; 17:A377.
4. Cobleigh MA, Vogel CL, Tripathy D et al. Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol. 1999; 17:2639-48. http://www.ncbi.nlm.nih.gov/pubmed/10561337?dopt=AbstractPlus
5. Anon. Trastuzumab and capecitabine for metastatic breast cancer. Med Lett Drugs Ther. 1998; 40:106-8. http://www.ncbi.nlm.nih.gov/pubmed/9814369?dopt=AbstractPlus
6. Oncologic Drugs Advisory Committee Meeting. 58th meeting. Bethesda, MD: Food and Drug Administration; 1998 Sep 2.
7. Goldenberg MM. Trastuzumab, a recombinant DNA-derived humanized monoclonal antibody, a novel agent for the treatment of metastatic breast cancer. Clin Ther. 1999; 21:309-18. http://www.ncbi.nlm.nih.gov/pubmed/10211534?dopt=AbstractPlus
8. Slamon DJ, Godolphin W, Jones LA et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science. 1989; 244:707-12. http://www.ncbi.nlm.nih.gov/pubmed/2470152?dopt=AbstractPlus
9. Jacobs TW, Gown AM, Yaziji H et al. Comparison of fluorescence in situ hybridization and immunohistochemistry for the evaluation of HER-2/neu in breast cancer. J Clin Oncol. 1999; 17:1974-82. http://www.ncbi.nlm.nih.gov/pubmed/10561247?dopt=AbstractPlus
10. Jacobs TW, Gown AM, Yaziji H et al. Specificity of HercepTest in determining HER-2/neu status of breast cancers using the United States Food and Drug Administration-approved scoring system. J Clin Oncol. 1999; 17:1983-7. http://www.ncbi.nlm.nih.gov/pubmed/10561248?dopt=AbstractPlus
11. Slamon DJ, Clark GM, Wong SG et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987; 235:177-82. http://www.ncbi.nlm.nih.gov/pubmed/3798106?dopt=AbstractPlus
12. Norton L, Slamon D, Leyland-Jones B et al. Overall survival (OS) advantage to simultaneous chemotherapy (CRx) plus the humanized anti-HER2 monoclonal antibody Herceptin (H) in HER2-overexpressing (HER2+) metastatic breast cancer (MBC). Proc Am Soc Clin Oncol. 1999; 18:A483.
13. Roche PC, Ingle JN. Increased HER2 with U.S. Food and Drug Administration-approved antibody. J Clin Oncol. 1999; 17:434-5. http://www.ncbi.nlm.nih.gov/pubmed/10458264?dopt=AbstractPlus
14. Perez EA. Cardiotoxicity associated with paclitaxel/trastuzumab combination therapy. J Clin Oncol. 1999; 17:1648. http://www.ncbi.nlm.nih.gov/pubmed/10334561?dopt=AbstractPlus
15. Tandon AK, Clark GM, Chamness GC et al. HER-2/neu oncogene protein and prognosis in breast cancer. J Clin Oncol. 1989; 7:1120-8. http://www.ncbi.nlm.nih.gov/pubmed/2569032?dopt=AbstractPlus
16. Baselga J, Tripathy D, Mendelsohn J et al. Phase II study of weekly intravenous recombinant humanized anti-p185HER2 monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer. J Clin Oncol. 1996; 14:737-44. http://www.ncbi.nlm.nih.gov/pubmed/8622019?dopt=AbstractPlus
17. Gelb L. New monoclonal antibody approved for advanced breast cancer. Rockville, MD: US Food and Drug Administration; 1998 Sep 25. Press release.
18. Genentech, South San Francisco, CA: Personal communication.
19. Reviewers’ comments (personal observations).
20. Vogel CL, Cobleigh MA, Tripathy D et al. Efficacy and safety of HerceptinTM (trastuzumab, humanized anti-HER2 antibody) as a single agent in first-line treatment of HER2 overexpressing metastatic breast cancer (HER2+/MBC). Breast Ca Res Treat. 1998; 50:232.
21. Hudis C, Seidman A, Paton V et al. Characterization of cardiac dysfunction observed in the HerceptinTM (trastuzumab) clinical trials. Breast Ca Res Treat. 1998; 50:232.
22. Hellmann SD. Dear healthcare provider letter regarding important prescribing information for Herceptin (trastuzumab). South San Francisco, CA: Genentech; 1999 Sep 23.
23. Genentech, Inc. Herceptin (trastuzumab) material safety data sheet. South San Francisco, CA; 1999 Jan 1.
24. Hellmann SD. Dear healthcare provider letter: important drug warning regarding Herceptin (trastuzumab). South San Francisco, CA: Genentech; 2000 May 3.
25. Anon. Drugs of choice for cancer. Treat Guidel Med Lett. 2003; 1:41-52. http://www.ncbi.nlm.nih.gov/pubmed/15529105?dopt=AbstractPlus
26. Breast cancer. From PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2005 Oct 21.
27. Eisenhauer EA. From the molecule to the clinic—inhibiting HER2 to treat breast cancer. N Engl J Med. 2001; 344:841-2. http://www.ncbi.nlm.nih.gov/pubmed/11248162?dopt=AbstractPlus
28. Romond EH, Perez EA, Bryant J et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005; 353:1673-84. http://www.ncbi.nlm.nih.gov/pubmed/16236738?dopt=AbstractPlus
29. Piccart-Gebhart MJ, Procter M, Leyland-Jones B et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005; 353:1659-72. http://www.ncbi.nlm.nih.gov/pubmed/16236737?dopt=AbstractPlus
30. Hortobagyi GN. Trastuzumab in the treatment of breast cancer. N Engl J Med. 2005; 353:1734-36. http://www.ncbi.nlm.nih.gov/pubmed/16236745?dopt=AbstractPlus
31. Barron H. Dear healthcare provider letter regarding important drug warning for cardiotoxicity related to the use of Herceptin (trastuzumab). South San Francisco, CA: Genentech; 2005 Aug.
32. Pegram MD, Pienkowski T, Northfelt DW et al. Results of two open-label, multicenter phase II studies of docetaxel, platinum salts, and trastuzumab in HER2-positive advanced breast cancer. J Natl Cancer Inst. 2004; 96:759-69. http://www.ncbi.nlm.nih.gov/pubmed/15150304?dopt=AbstractPlus
33. Trastuzumab. In: Briggs GG, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005:1608-9.
1001. Institute for Safe Medication Practices. Confusion between two HER2-targeted monoclonal antibodies. ISMP Medication Safety Alert! Horsham, PA; 2013 Mar 7.
1002. Genentech, Inc. Kadcyla (ado-trastuzumab emtansine) injection for intravenous use prescribing information. South San Francisco, CA; 2013 May.
1003. US Adopted Name (USAN) Council. Trastuzumab emtansine. From USAN website. Accessed 2013 Apr 22. http://www.uspusan.com
1004. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 125427orig1s000: Proprietary name review(s). From FDA website. Accessed 2013 Apr 22. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/125427Orig1s000NameR.pdf
1005. National Alert Network (NAN). Confusion regarding the generic name of the HER2-targeted drug KADCYLA (ado-trastuzumab emtansine). NAN Alert. Horsham, PA; 2013 Apr 17.
1006. US Food and Drug Administration. FDA Drug Safety Communication: Kadcyla (ado-trastuzumab emtansine) potential medication errors resulting from name confusion. Rockville, MD; 2013 May 6. From FDA website. Accessed 2013 May 15. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm350817.htm
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