Trastuzumab

Trastuzumab
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Joseph Nasr, M.D.[2]; Bezalel Hakkeem, M.B.B.S[3]

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Black Box Warning

WARNING: CARDIOMYOPATHY, INFUSION REACTIONS, EMBRYO-FETAL TOXICITY, and PULMONARY TOXICITY See full prescribing information for complete Boxed Warning. Cardiomyopathy: Trastuzumab administration can result in sub-clinical and clinical cardiac failure. The incidence and severity was highest in patients receiving Trastuzumab with anthracycline-containing chemotherapy regimens. Evaluate left ventricular function in all patients prior to and during treatment. Discontinue treatment in patients receiving adjuvant therapy and withhold in patients with metastatic disease for clinically significant decrease in left ventricular function. Infusion reactions, Pulmonary toxicity: Symptoms usually occur during or within 24 hours of administration. Interrupt Trastuzumab infusion for dyspnea or clinically significant hypotension. Monitor patients until symptoms completely resolve. Discontinue for anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome. Embryo-Fetal Toxicity: Exposure to Trastuzumab during pregnancy can result in oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death. Advise patients of these risks and the need for effective contraception.

Overview

Trastuzumab is a Monoclonal antibody that is FDA approved for the treatment of Adjuvant Breast Cancer, Metastatic Breast Cancer, Metastatic Gastric Cancer. There is a Black Box Warning for this drug as shown here. Common adverse reactions include edema， peripheral edema，tachycardia, rash, weight loss, abdominal pain，diarrhea，loss of appetite, nausea, stomatitis, vomiting, anemia, neutropenia, thrombocytopenia, infection, arthralgia, backache, myalgia, asthenia, dizziness, headache, insomnia, renal impairment, cough, dyspnea, nasopharyngitis, pharyngitis, rhinitis, upper respiratory infection, fatigue, fever, mucosal inflammation, Chills, Dysgeusia,.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Recommended Doses and Schedules

• Herceptin (trastuzumab) is for intravenous (IV) infusion only. Do not administer as an intravenous push or bolus.
• Herceptin has different dosage and administration instructions than subcutaneous trastuzumab products.
• Do not mix Herceptin with other drugs.
• Do not substitute Herceptin (trastuzumab) for or with ado-trastuzumab emtansine or fam-trastuzumab deruxtecan.
• Perform HER2 testing using FDA-authorized tests by laboratories with demonstrated proficiency, and select patients for therapy based on an FDA-authorized companion diagnostic.

Adjuvant Treatment of Breast Cancer

• Dosing information
• Administer according to one of the following doses and schedules for a total of 52 weeks of Trastuzumab therapy:
• During and following paclitaxel, docetaxel, or docetaxel/carboplatin:

• Initial dosage: 4 mg/kg as an intravenous infusion over 90 minutes, then 2 mg/kg as an intravenous infusion over 30 minutes weekly during chemotherapy for the first 12 weeks (paclitaxel or docetaxel) or 18 weeks (docetaxel/carboplatin).
• One week following the last weekly dose of Trastuzumab, administer Trastuzumab at 6 mg/kg as an intravenous infusion over 30–90 minutes every three weeks.

• As a single agent within three weeks following completion of multi-modality, anthracycline-based chemotherapy regimens:

• Initial dosage: 8 mg/kg as an intravenous infusion over 90 minutes.
• Subsequent doses: 6 mg/kg as an intravenous infusion over 30–90 minutes every three weeks.
• Extending adjuvant treatment beyond one year is not recommended.

Metastatic Breast Cancer

• Dosing information

• Administer Herceptin, alone or in combination with paclitaxel, at an initial dosage of 4 mg/kg as a 90-minute intravenous infusion, followed by subsequent once-weekly doses of 2 mg/kg as 30-minute intravenous infusions until disease progression.

Metastatic Gastric Cancer

• Dosing information

• Initial dosage: 8 mg/kg as a 90 minute intravenous infusion
• Subsequent dosage: 6 mg/kg as an intravenous infusion over 30-90 minutes every three weeks until disease progression

Important Dosing Considerations

Missed Dose

• If a dose is missed by one week or less, administer the usual maintenance dose (weekly schedule: 2 mg/kg; every-three-week schedule: 6 mg/kg) as soon as possible — do not wait until the next planned cycle. Resume subsequent maintenance doses 7 days or 21 days later according to the weekly or three-weekly schedule, respectively.
• If a dose is missed by more than one week, administer a re-loading dose over approximately 90 minutes (weekly schedule: 4 mg/kg; every-three-week schedule: 8 mg/kg) as soon as possible. Resume subsequent maintenance doses (weekly: 2 mg/kg; three-weekly: 6 mg/kg) 7 days or 21 days later according to the weekly or three-weekly schedule, respectively.

Dose Modifications

Infusion Reactions

• Decrease the rate of infusion for mild or moderate infusion reactions
• Interrupt the infusion in patients with dyspnea or clinically significant hypotension
• Discontinue Trastuzumab for severe or life-threatening infusion reactions.

Cardiomyopathy

• Assess left ventricular ejection fraction (LVEF) prior to initiation of Trastuzumab and at regular intervals during treatment. Withhold Trastuzumab dosing for at least 4 weeks for either of the following:

• ≥ 16% absolute decrease in LVEF from pre-treatment values
• LVEF below institutional limits of normal and ≥ 10% absolute decrease in LVEF from pretreatment values.

• Trastuzumab may be resumed if, within 4–8 weeks, the LVEF returns to normal limits and the absolute decrease from baseline is ≤ 15%.
• Permanently discontinue Trastuzumab for a persistent (> 8 weeks) LVEF decline, or for suspension of Trastuzumab dosing on more than 3 occasions for cardiomyopathy.

Preparation and Administration

Reconstitution (150 mg Single-Dose Vial)

• Reconstitute each 150 mg vial with 7.4 mL of Sterile Water for Injection (SWFI) (not supplied) to yield a single-dose solution containing 21 mg/mL trastuzumab that delivers 7.15 mL (150 mg trastuzumab).
• Use appropriate aseptic technique:

• Using a sterile syringe, slowly inject 7.4 mL of SWFI into the vial, directing the stream into the lyophilized cake.
• Swirl the vial gently to aid reconstitution. Do not shake.
• Slight foaming may occur; allow the vial to stand undisturbed for approximately 5 minutes.
• Inspect visually for particulates and discoloration. Solution should be free of visible particulates, clear to slightly opalescent, and colorless to pale yellow.

• Use immediately following reconstitution, as the product contains no preservative and is intended for single-dose use only.
• If not used immediately, store the reconstituted solution for up to 24 hours at 2°C to 8°C (36°F to 46°F); discard any unused Herceptin after 24 hours. Do not freeze.

Dilution

• Determine the required dose (mg) and calculate the volume of the 21 mg/mL reconstituted solution needed.
• Withdraw this amount using a sterile needle and syringe and add it to an infusion bag containing '250 mL of 0.9% Sodium Chloride Injection, USP’.
• ’Do not use dextrose (5%) solution.’
• Gently invert the bag to mix.
• Diluted solution in PVC or polyethylene bags containing 0.9% Sodium Chloride Injection should be stored at 2°C to 8°C (36°F to 46°F) for no more than 24 hours prior to use; discard after 24 hours. This storage time is additional to the time allowed for the reconstituted vial. Do not freeze.

Medication Error Prevention

• To prevent medication errors, check the vial labels to ensure the drug being prepared and administered is Herceptin (trastuzumab) and not ado-trastuzumab emtansine or fam-trastuzumab deruxtecan.

How Supplied/Storage

• Herceptin 150 mg/vial is supplied as a preservative-free, white to pale yellow lyophilized sterile powder under vacuum, in a single-dose vial.

• NDC 50242-132-01: carton containing one single-dose vial
• NDC 50242-132-10: carton containing 10 single-dose vials

• Store vials in the refrigerator at 2°C to 8°C (36°F to 46°F) until time of reconstitution.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

Beyond its FDA-approved indications in breast and gastric/GEJ cancer, Herceptin (trastuzumab) has a number of off-label uses supported by NCCN and ASCO guidelines and by prospective clinical trial data, reflecting the fact that HER2 overexpression/amplification is found across a range of solid tumors — including biliary tract, colorectal, salivary gland, endometrial, and esophageal/GEJ cancers.

1. Neoadjuvant Treatment of HER2-Positive Breast Cancer (TCHP, with Pertuzumab)

• Trastuzumab’s FDA label covers adjuvant, not neoadjuvant, breast cancer use, although pertuzumab itself carries an FDA-approved neoadjuvant indication in combination with trastuzumab. NCCN Breast Cancer Guidelines list the TCHP regimen (docetaxel/carboplatin + trastuzumab + pertuzumab) as a preferred preoperative option for HER2-positive disease.
• Dosing information

• Trastuzumab: 8 mg/kg IV loading dose Day 1, then 6 mg/kg IV every 21 days
• Pertuzumab: 840 mg IV loading dose Day 1, then 420 mg IV every 21 days
• Docetaxel: 75 mg/m² IV Day 1 every 21 days for 6 cycles
• Carboplatin: AUC 6 IV Day 1 every 21 days for 6 cycles
• Following surgery, continue trastuzumab 6 mg/kg (± pertuzumab 420 mg) IV every 21 days to complete 1 year of total anti-HER2 therapy

2. HER2-Positive Metastatic Breast Cancer, First-Line (with Pertuzumab)

• NCCN instead designates a taxane + pertuzumab + trastuzumab regimen as preferred first-line therapy, based on the CLEOPATRA trial.
• Dosing information

• Trastuzumab: 8 mg/kg IV loading dose, then 6 mg/kg IV every 21 days
• Pertuzumab: 840 mg IV loading dose, then 420 mg IV every 21 days
• Docetaxel 75–100 mg/m² IV every 21 days, or paclitaxel 80 mg/m² IV weekly
• Continue trastuzumab and pertuzumab as maintenance until disease progression

3. HER2-Positive Metastatic Colorectal Cancer

• NCCN Colon Cancer Guidelines recommend trastuzumab-based combinations (Category 2A) for RAS/BRAF wild-type, HER2-overexpressed/amplified metastatic colorectal cancer, as a subsequent-line or less-intensive therapy option.
• Regimens and dosing

• 'Pertuzumab + Trastuzumab’

Trastuzumab 8 mg/kg IV load → 6 mg/kg IV every 21 days; Pertuzumab 840 mg IV load → 420 mg IV every 21 days

• Tucatinib + Trastuzumab: Trastuzumab 8 mg/kg IV load → 6 mg/kg IV every 21 days; tucatinib 300 mg orally twice daily.

4. HER2-Positive Biliary Tract Cancer (Subsequent-Line)

• NCCN Biliary Tract Cancers Guidelines list trastuzumab-based regimens as subsequent-line options ("useful in certain circumstances") for HER2-positive (IHC 3+/ISH+/NGS+) disease.
• Regimens: Pertuzumab + Trastuzumab or Tucatinib + Trastuzumab, dosed as in the colorectal cancer section above.

5. HER2-Positive Uterine Serous Carcinoma / Endometrial Carcinosarcoma

• NCCN Uterine Neoplasms Guidelines list carboplatin/paclitaxel + trastuzumab as a preferred primary systemic therapy option for stage III–IV HER2-positive uterine serous carcinoma or carcinosarcoma in trastuzumab-naïve patients.
• Dosing information

• Trastuzumab 8 mg/kg IV loading dose, then 6 mg/kg IV every 21 days, with carboplatin (AUC 5–6) and paclitaxel (175 mg/m²) every 21 days
• Trastuzumab may be continued as maintenance after chemotherapy completion

6. HER2-Positive Salivary Gland Cancer (Recurrent/Metastatic)

• NCCN Head and Neck Cancers Guidelines list several trastuzumab-based options as "useful in certain circumstances" for HER2-positive recurrent, unresectable, or metastatic salivary gland tumors: single-agent trastuzumab, docetaxel + trastuzumab, pertuzumab + trastuzumab, ado-trastuzumab emtansine (T-DM1), and fam-trastuzumab deruxtecan.
• Dosing information (docetaxel + trastuzumab)

• Trastuzumab: 8 mg/kg IV loading dose, then 6 mg/kg IV every 21 days
• Docetaxel: 70 mg/m² IV every 21 days for up to 8 cycles

7. HER2-Positive Esophageal and Esophagogastric Junction Adenocarcinoma (First-Line, Advanced)

• NCCN Esophageal and EGJ Cancers Guidelines support adding trastuzumab to first-line chemotherapy for advanced HER2-positive (IHC 3+, or IHC 2+/ISH+) esophageal or EGJ adenocarcinoma. The FDA label restricts trastuzumab to cisplatin + capecitabine/5-FU specifically for gastric/GEJ cancer, but NCCN also supports pairing it with other first-line backbones (e.g., FOLFOX, CAPEOX) and with pembrolizumab in PD-L1 CPS ≥1 tumors.
• Dosing information

• Trastuzumab 8 mg/kg IV loading dose, then 6 mg/kg IV every 21 days, added to the selected first-line chemotherapy regimen

8. Maintenance Treatment of HR-Positive, HER2-Positive Locally Advanced or Metastatic Breast Cancer (with Palbociclib ± Pertuzumab and Endocrine Therapy)

• Continue trastuzumab, with or without pertuzumab, at the previously established induction dosage and schedule, in combination with:

• Palbociclib 125 mg orally once daily for 21 days followed by 7 days off treatment (28-day cycle), and
• Endocrine therapy (fulvestrant or an aromatase inhibitor such as anastrozole, letrozole, or exemestane)

• Indicated for adult patients with HR-positive, HER2-positive locally advanced or metastatic breast cancer who have not progressed following induction treatment with a taxane and trastuzumab, with or without pertuzumab.

Non–Guideline-Supported Use

Use of trastuzumab in Carcinoma of prostate and Non-small cell lung cancer are not supported by current NCCN, ASCO, or EAU guidelines.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

The safety and effectiveness of Trastuzumab in pediatric patients has not been established.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Trastuzumab in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Trastuzumab in pediatric patients.

Contraindications

None.

Warnings

WARNING: CARDIOMYOPATHY, INFUSION REACTIONS, EMBRYO-FETAL TOXICITY, and PULMONARY TOXICITY See full prescribing information for complete Boxed Warning. Cardiomyopathy: Trastuzumab administration can result in sub-clinical and clinical cardiac failure. The incidence and severity was highest in patients receiving Trastuzumab with anthracycline-containing chemotherapy regimens. Evaluate left ventricular function in all patients prior to and during treatment. Discontinue treatment in patients receiving adjuvant therapy and withhold in patients with metastatic disease for clinically significant decrease in left ventricular function. Infusion reactions, Pulmonary toxicity: Symptoms usually occur during or within 24 hours of administration. Interrupt Trastuzumab infusion for dyspnea or clinically significant hypotension. Monitor patients until symptoms completely resolve. Discontinue for anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome. Embryo-Fetal Toxicity: Exposure to Trastuzumab during pregnancy can result in oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death. Advise patients of these risks and the need for effective contraception.

Cardiomyopathy

• Trastuzumab can cause left ventricular cardiac dysfunction, arrhythmias, hypertension, disabling cardiac failure, cardiomyopathy, and cardiac death. Trastuzumab can also cause asymptomatic decline in left ventricular ejection fraction (LVEF). There is a 4–6 fold increase in the incidence of symptomatic myocardial dysfunction among patients receiving Trastuzumab as a single agent or in combination therapy compared with those not receiving Trastuzumab. The highest absolute incidence occurs when Trastuzumab is administered with an anthracycline. Withhold Trastuzumab for ≥ 16% absolute decrease in LVEF from pre-treatment values or an LVEF value below institutional limits of normal and ≥ 10% absolute decrease in LVEF from pretreatment values. The safety of continuation or resumption of Trastuzumab in patients with Trastuzumab-induced left ventricular cardiac dysfunction has not been studied.

Cardiac Monitoring

• Conduct thorough cardiac assessment, including history, physical examination, and determination of LVEF by echocardiogram or MUGA scan. The following schedule is recommended:
• Baseline LVEF measurement immediately prior to initiation of Trastuzumab
• LVEF measurements every 3 months during and upon completion of Trastuzumab
• Repeat LVEF measurement at 4 week intervals if Trastuzumab is withheld for significant left ventricular cardiac dysfunction
• LVEF measurements every 6 months for at least 2 years following completion of Trastuzumab as a component of adjuvant therapy.

In NSABP B31, 15% (158/1031) of patients discontinued Trastuzumab due to clinical evidence of myocardial dysfunction or significant decline in LVEF after a median follow-up duration of 8.7 years in the AC-TH arm. In HERA (one-year Trastuzumab treatment), the number of patients who discontinued Trastuzumab due to cardiac toxicity at 12.6 months median duration of follow-up was 2.6% (44/1678). In BCIRG006, a total of 2.9% (31/1056) patients in the TCH arm (1.5% during the chemotherapy phase and 1.4% during the monotherapy phase) and 5.7% (61/1068) patients in the AC-TH arm (1.5% during the chemotherapy phase and 4.2% during the monotherapy phase) discontinued Trastuzumab due to cardiac toxicity. Among 64 patients receiving adjuvant chemotherapy (NSABP B31 and NCCTG N9831) who developed congestive heart failure, one patient died of cardiomyopathy, one patient died suddenly without documented etiology and 33 patients were receiving cardiac medication at last follow-up. Approximately 24% of the surviving patients had recovery to a normal LVEF (defined as ≥50%) and no symptoms on continuing medical management at the time of last follow-up. Incidence of congestive heart failure (CHF) is presented in Table 1. The safety of continuation or resumption of Trastuzumab in patients with Trastuzumab-induced left ventricular cardiac dysfunction has not been studied.

This image is provided by the National Library of Medicine.

• In HERA (one-year Trastuzumab treatment), at a median follow-up duration of 8 years, the incidence of severe CHF (NYHA III & IV) was 0.8%, and the rate of mild symptomatic and asymptomatic left ventricular dysfunction was 4.6%.

• In BCIRG006, the incidence of NCI-CTC Grade 3/4 cardiac ischemia/infarction was higher in the Trastuzumab containing regimens: (AC-TH: 0.3% (3/1068) and TCH 0.2% (2/1056)) as compared to none in AC-T.

Infusion Reactions

• Infusion reactions consist of a symptom complex characterized by fever and chills, and on occasion included nausea, vomiting, pain (in some cases at tumor sites), headache, dizziness, dyspnea, hypotension, rash, and asthenia.

In postmarketing reports, serious and fatal infusion reactions have been reported. Severe reactions which include bronchospasm, anaphylaxis, angioedema, hypoxia, and severe hypotension, were usually reported during or immediately following the initial infusion. However, the onset and clinical course were variable including progressive worsening, initial improvement followed by clinical deterioration, or delayed post-infusion events with rapid clinical deterioration. For fatal events, death occurred within hours to days following a serious infusion reaction. Interrupt Trastuzumab infusion in all patients experiencing dyspnea, clinically significant hypotension, and intervention of medical therapy administered, which may include: epinephrine, corticosteroids, diphenhydramine, bronchodilators, and oxygen. Patients should be evaluated and carefully monitored until complete resolution of signs and symptoms. Permanent discontinuation should be strongly considered in all patients with severe infusion reactions. There are no data regarding the most appropriate method of identification of patients who may safely be retreated with Trastuzumab after experiencing a severe infusion reaction. Prior to resumption of Trastuzumab infusion, the majority of patients who experienced a severe infusion reaction were pre-medicated with antihistamines and/or corticosteroids. While some patients tolerated Trastuzumab infusions, others had recurrent severe infusion reactions despite pre-medications.

Embryo-Fetal Toxicity

• Trastuzumab can cause fetal harm when administered to a pregnant woman. In post marketing reports, use of Trastuzumab during pregnancy resulted in cases of oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death. Advise women of the potential hazard to the fetus resulting from Trastuzumab exposure during pregnancy and provide contraception counseling to women of childbearing potential.

Pulmonary Toxicity

• Trastuzumab use can result in serious and fatal pulmonary toxicity. Pulmonary toxicity includes dyspnea, interstitial pneumonitis, pulmonary infiltrates, pleural effusions, non-cardiogenic pulmonary edema, pulmonary insufficiency and hypoxia, acute respiratory distress syndrome, and pulmonary fibrosis. Such events can occur as sequelae of infusion reactions. Patients with symptomatic intrinsic lung disease or with extensive tumor involvement of the lungs, resulting in dyspnea at rest, appear to have more severe toxicity.

Exacerbation of Chemotherapy-Induced Neutropenia

• In randomized, controlled clinical trials the per-patient incidences of NCI CTC Grade 3–4 neutropenia and of febrile neutropenia were higher in patients receiving Trastuzumab in combination with myelosuppressive chemotherapy as compared to those who received chemotherapy alone. The incidence of septic death was similar among patients who received Trastuzumab and those who did not.

HER2 Testing

• Detection of HER2 protein overexpression is necessary for selection of patients appropriate for Trastuzumab therapy because these are the only patients studied and for whom benefit has been shown. Due to differences in tumor histopathology, use FDA-approved tests for the specific tumor type (breast or gastric/gastroesophageal adenocarcinoma) to assess HER2 protein overexpression and HER2 gene amplification. Tests should be performed by laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance, including use of suboptimally fixed tissue, failure to utilize specified reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results.

Several FDA-approved commercial assays are available to aid in the selection of breast cancer and metastatic gastric cancer patients for Trastuzumab therapy. Users should refer to the package inserts of specific assay kits for information on the Intended Use, and the validation and performance of each assay. Limitations in assay precision make it inadvisable to rely on a single method to rule out potential Trastuzumab benefit.

• Treatment outcomes for adjuvant breast cancer (NCCTG N9831 and HERA) as a function of IHC and FISH testing are provided in Table 10;

This image is provided by the National Library of Medicine.

• treatment outcomes for metastatic breast cancer (H0648g) are provided in Table 12.

This image is provided by the National Library of Medicine.

• Assessment of HER2 protein overexpression and HER2 gene amplification in metastatic gastric cancer should be performed using FDA-approved tests specifically for gastric cancers due to differences in gastric vs. breast histopathology, including incomplete membrane staining and more frequent heterogeneous expression of HER2 seen in gastric cancers. The ToGA trial demonstrated that gene amplification and protein overexpression were not as well correlated as with breast cancer. Treatment outcomes for metastatic gastric cancer (ToGA), based on HER2 gene amplification (FISH) and HER2 protein overexpression (IHC) test results, are provided in Table 14.

This image is provided by the National Library of Medicine.

Adverse Reactions

Clinical Trials Experience

• Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
• The most common adverse reactions in patients receiving Trastuzumab in the adjuvant and metastatic breast cancer setting are fever, nausea, vomiting, infusion reactions, diarrhea, infections, increased cough, headache, fatigue, dyspnea, rash, neutropenia, anemia, and myalgia. Adverse reactions requiring interruption or discontinuation of Trastuzumab treatment include CHF, significant decline in left ventricular cardiac function, severe infusion reactions, and pulmonary toxicity.
• In the metastatic gastric cancer setting, the most common adverse reactions (≥ 10%) that were increased (≥ 5% difference) in the Trastuzumab arm as compared to the chemotherapy alone arm were neutropenia, diarrhea, fatigue, anemia, stomatitis, weight loss, upper respiratory tract infections, fever, thrombocytopenia, mucosal inflammation, nasopharyngitis, and dysgeusia. The most common adverse reactions which resulted in discontinuation of treatment on the Trastuzumab-containing arm, in the absence of disease progression, were infection, diarrhea, and febrile neutropenia.

Study Populations

Adjuvant Breast Cancer

• The data below reflect exposure to one-year Trastuzumab therapy across three randomized, open-label studies — NSABP B31, NCCTG N9831, and HERA — with (n=3678) or without (n=3363) trastuzumab in the adjuvant treatment of breast cancer.

HERA

Table 3 reflects exposure to Herceptin in 1678 patients in HERA; the median treatment duration was 51 weeks and median number of infusions was 18. Clinically relevant adverse reactions in <1% of patients who received Herceptin in HERA included hypersensitivity (0.6%), cardiac failure (0.5%), cardiac disorder (0.3%), interstitial pneumonitis (0.2%), pulmonary hypertension (0.2%), ventricular disorder (0.2%), autoimmune thyroiditis (0.3%), and sudden death (0.06%).

• Table 3

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NSABP B31 and NCCTG N9831

The safety data from NSABP B31 and NCCTG N9831 were obtained from 3655 patients, of whom 2000 received Herceptin; the median treatment duration was 51 weeks.

• In NSABP B31, only Grade 3–5 adverse events, treatment-related Grade 2 events, and Grade 2–5 dyspnea were collected during and for up to 3 months following protocol-specified treatment. The following non-cardiac adverse reactions of Grade 2–5 occurred at an incidence of at least 2% greater among patients receiving Herceptin plus chemotherapy as compared to chemotherapy alone:Fatigue: 29.5% vs. 22.4% Infection: 24.0% vs. 12.8% Hot flashes: 17.1% vs. 15% Anemia: 12.3% vs. 6.7% Dyspnea: 11.8% vs. 4.6% Rash/desquamation: 10.9% vs. 7.6% Leukopenia: 10.5% vs. 8.4% Neutropenia: 6.4% vs. 4.3% Headache: 6.2% vs. 3.8% Pain: 5.5% vs. 3% Edema: 4.7% vs. 2.7% Insomnia: 4.3% vs. 1.5%. The majority of these events were Grade 2 in severity.

• In NCCTG N9831, data collection was limited to the following investigator-attributed treatment-related adverse reactions: NCI-CTC Grade 4 and 5 hematologic toxicities, Grade 3–5 non-hematologic toxicities, selected Grade 2–5 toxicities associated with taxanes (myalgia, arthralgias, nail changes, motor neuropathy, and sensory neuropathy), and Grade 1–5 cardiac toxicities occurring during chemotherapy and/or Herceptin treatment. The following non-cardiac adverse reactions of Grade 2–5 occurred at an incidence of at least 2% greater among patients receiving Herceptin plus chemotherapy as compared to chemotherapy alone: Arthralgia: 12.2% vs. 9.1% Nail changes: 11.5% vs. 6.8% Dyspnea: 2.4% vs. 0.2% Diarrhea: 2.2% vs. 0% The majority of these events were Grade 2 in severity.

BCIRG006

Safety data from BCIRG006 reflect exposure to Herceptin as part of an adjuvant treatment regimen from 2124 patients receiving at least one dose of study treatment [AC-TH: n=1068; TCH: n=1056]. The overall median treatment duration was 54 weeks in both the AC-TH and TCH arms. The median number of infusions was 26 in the AC-TH arm and 30 in the TCH arm, including weekly infusions during the chemotherapy phase and once-every-three-week dosing in the monotherapy period. In BCIRG006, the toxicity profile was similar to that reported in NSABP B31, NCCTG N9831, and HERA, with the exception of a lower incidence of CHF in the TCH arm.

Metastatic Breast Cancer Studies

The safety of Herceptin was evaluated in one randomized, open-label study (H0648g) of chemotherapy with (n=235) or without (n=234) intravenous trastuzumab in patients with metastatic breast cancer, and in one single-arm study (H0649g; n=222) in patients with metastatic breast cancer [see Clinical Studies (14.1)]. Patients received a 4 mg/kg initial dose of Herceptin followed by 2 mg/kg weekly. In H0648g, 58% of patients received Herceptin for ≥6 months and 9% received Herceptin for ≥12 months. In H0649g, 31% of patients received Herceptin for ≥6 months and 16% received Herceptin for ≥12 months. Table 4 shows the adverse reactions (≥5%) in patients from H0648g and H0649g.

• Table 4

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Metastatic Gastric Cancer

The safety of Herceptin was evaluated in previously untreated patients with metastatic gastric or gastroesophageal junction adenocarcinoma in an open-label, multicenter trial (ToGA). Patients were randomized (1:1) to receive Herceptin in combination with cisplatin and a fluoropyrimidine (FC+H) (n=294) or chemotherapy alone (FC) (n=290). Patients in the Herceptin plus chemotherapy arm received Herceptin 8 mg/kg on Day 1 (prior to chemotherapy) followed by 6 mg/kg every 21 days until disease progression. Cisplatin was administered at 80 mg/m² on Day 1, and the fluoropyrimidine was administered as either capecitabine 1000 mg/m² orally twice daily on Days 1–14, or 5-fluorouracil 800 mg/m²/day as a continuous intravenous infusion on Days 1 through 5. Chemotherapy was administered for six 21-day cycles. Median duration of Herceptin treatment was 21 weeks, and the median number of Herceptin infusions administered was eight.

• Table 5

This image is provided by the National Library of Medicine.

• The following subsections provide additional detail regarding adverse reactions observed in clinical trials of adjuvant breast cancer, metastatic breast cancer, metastatic gastric cancer, or post-marketing experience.

Cardiomyopathy Serial measurement of cardiac function (LVEF) was obtained in clinical trials in the adjuvant treatment of breast cancer. In HERA, the median duration of follow-up was 12.6 months (12.4 months in the observation arm; 12.6 months in the 1-year Herceptin arm); in NSABP B31 and NCCTG N9831, follow-up was 7.9 years in the AC-T arm and 8.3 years in the AC-TH arm. Following initiation of Herceptin therapy, the incidence of new-onset dose-limiting myocardial dysfunction was higher among patients receiving Herceptin and paclitaxel compared with paclitaxel alone in NSABP B31 and NCCTG N9831, and in patients receiving one-year Herceptin monotherapy compared with observation in HERA. The incidence of new-onset cardiac dysfunction, as measured by LVEF, remained similar when compared with the analysis performed at a median follow-up of 2.0 years in the AC-TH arm. This analysis also showed evidence of reversibility of left ventricular dysfunction: 64.5% of patients who experienced symptomatic CHF in the AC-TH group were asymptomatic at latest follow-up, and 90.3% had full or partial LVEF recovery.

• Table 6

This image is provided by the National Library of Medicine.

Figure 1 NSABP B31 and NCCTG N9831: Cumulative Incidence of Time to First LVEF Decline of ≥10 Percentage Points from Baseline and to Below 50% with Death as a Competing Risk Event

This image is provided by the National Library of Medicine.

Time 0 is initiation of paclitaxel or Trastuzumab + paclitaxel therapy. 'Figure 2’ HERA: Cumulative Incidence of Time to First LVEF Decline of ≥10 Percentage Points from Baseline and to Below 50% with Death as a Competing Risk Event

This image is provided by the National Library of Medicine.

Time 0 is the date of randomization. Figure 3 BCIRG006: Cumulative Incidence of Time to First LVEF Decline of ≥10 Percentage Points from Baseline and to Below 50% with Death as a Competing Risk Event

This image is provided by the National Library of Medicine.

Time 0 is the date of randomization. The incidence of congestive heart failure among patients in the metastatic breast cancer trials was classified for severity using the New York Heart Association classification system (I–IV, where IV is the most severe level of cardiac failure) (see Table 2). In the metastatic breast cancer trials, the probability of cardiac dysfunction was highest in patients who received Herceptin concurrently with anthracyclines. In ToGA, 5% of patients in the Herceptin plus chemotherapy arm compared to 1.1% of patients in the chemotherapy-alone arm had an LVEF value below 50% with a ≥10% absolute decrease in LVEF from pretreatment values. Infusion Reactions During the first infusion with Herceptin, the symptoms most commonly reported were chills and fever, occurring in approximately 40% of patients in clinical trials. Symptoms were treated with acetaminophen, diphenhydramine, and meperidine (with or without reduction in the rate of Herceptin infusion); permanent discontinuation of Herceptin for infusion reactions was required in <1% of patients. Other signs and/or symptoms may include nausea, vomiting, pain (in some cases at tumor sites), rigors, headache, dizziness, dyspnea, hypotension, elevated blood pressure, rash, and asthenia. Infusion reactions occurred in 21% and 35% of patients, and were severe in 1.4% and 9% of patients, on second or subsequent Herceptin infusions administered as monotherapy or in combination with chemotherapy, respectively. In the post-marketing setting, severe infusion reactions — including hypersensitivity, anaphylaxis, and angioedema — have been reported. Anemia In randomized controlled clinical trials, the overall incidence of anemia (30% vs. 21% [H0648g]), of selected NCI-CTC Grade 2–5 anemia (12.3% vs. 6.7% [NSABP B31]), and of anemia requiring transfusions (0.1% vs. 0 patients [NCCTG N9831]) were increased in patients receiving Herceptin and chemotherapy compared with those receiving chemotherapy alone. Following administration of Herceptin as a single agent (H0649g), the incidence of NCI-CTC Grade 3 anemia was <1%. In ToGA (metastatic gastric cancer), on the Herceptin-containing arm as compared to the chemotherapy-alone arm, the overall incidence of anemia was 28% compared to 21%, and of NCI-CTC Grade 3/4 anemia was 12.2% compared to 10.3%. Neutropenia In randomized controlled clinical trials in the adjuvant setting, the incidence of selected NCI-CTC Grade 4–5 neutropenia (1.7% vs. 0.8% [NCCTG N9831]) and of selected Grade 2–5 neutropenia (6.4% vs. 4.3% [NSABP B31]) were increased in patients receiving Herceptin and chemotherapy compared with those receiving chemotherapy alone. In a randomized, controlled trial in patients with metastatic breast cancer, the incidences of NCI-CTC Grade 3/4 neutropenia (32% vs. 22%) and of febrile neutropenia (23% vs. 17%) were also increased in patients randomized to Herceptin in combination with myelosuppressive chemotherapy as compared to chemotherapy alone. In ToGA (metastatic gastric cancer), on the Herceptin-containing arm as compared to the chemotherapy-alone arm, the incidence of NCI-CTC Grade 3/4 neutropenia was 36.8% compared to 28.9%; febrile neutropenia was 5.1% compared to 2.8%.

Infection The overall incidences of infection (46% vs. 30% [H0648g]), of selected NCI-CTC Grade 2–5 infection/febrile neutropenia (24.3% vs. 13.4% [NSABP B31]), and of selected Grade 3–5 infection/febrile neutropenia (2.9% vs. 1.4% [NCCTG N9831]) were higher in patients receiving Herceptin and chemotherapy compared with those receiving chemotherapy alone. The most common sites of infection in the adjuvant setting involved the upper respiratory tract, skin, and urinary tract. In BCIRG006, the overall incidence of infection was higher with the addition of Herceptin to AC-T but not to TCH [44% (AC-TH), 37% (TCH), 38% (AC-T)]. The incidences of NCI-CTC Grade 3–4 infection were similar across the three arms [25% (AC-TH), 21% (TCH), 23% (AC-T)]. In a randomized, controlled trial in the treatment of metastatic breast cancer, the reported incidence of febrile neutropenia was higher (23% vs. 17%) in patients receiving Herceptin in combination with myelosuppressive chemotherapy as compared to chemotherapy alone. Pulmonary Toxicity Adjuvant Breast Cancer Among women receiving adjuvant therapy for breast cancer, the incidence of selected NCI-CTC Grade 2–5 pulmonary toxicity (14.3% vs. 5.4% [NSABP B31]) and of selected NCI-CTC Grade 3–5 pulmonary toxicity and spontaneously reported Grade 2 dyspnea (3.4% vs. 0.9% [NCCTG N9831]) was higher in patients receiving Herceptin and chemotherapy compared with chemotherapy alone. The most common pulmonary toxicity was dyspnea (NCI-CTC Grade 2–5: 11.8% vs. 4.6% [NSABP B31]; NCI-CTC Grade 2–5: 2.4% vs. 0.2% [NCCTG N9831]). Pneumonitis/pulmonary infiltrates occurred in 0.7% of patients receiving Herceptin compared with 0.3% of those receiving chemotherapy alone. Fatal respiratory failure occurred in 3 patients receiving Herceptin (one as a component of multi-organ system failure), as compared to 1 patient receiving chemotherapy alone. In HERA, there were 4 cases of interstitial pneumonitis in the one-year Herceptin treatment arm compared to none in the observation arm, at a median follow-up duration of 12.6 months. Metastatic Breast Cancer Among women receiving Herceptin for treatment of metastatic breast cancer, the incidence of pulmonary toxicity was also increased. Pulmonary adverse events have been reported in the post-marketing experience as part of the symptom complex of infusion reactions. Pulmonary events include bronchospasm, hypoxia, dyspnea, pulmonary infiltrates, pleural effusions, non-cardiogenic pulmonary edema, and acute respiratory distress syndrome. Thrombosis/Embolism In 4 randomized, controlled clinical trials, the incidence of thrombotic adverse events was higher in patients receiving Herceptin and chemotherapy compared to chemotherapy alone in three studies: 2.6% vs. 1.5% (NSABP B31); 2.5% and 3.7% vs. 2.2% (BCIRG006); and 2.1% vs. 0% (H0648g). Diarrhea Among women receiving adjuvant therapy for breast cancer, the incidence of NCI-CTC Grade 2–5 diarrhea (6.7% vs. 5.4% [NSABP B31]), of NCI-CTC Grade 3–5 diarrhea (2.2% vs. 0% [NCCTG N9831]), and of Grade 1–4 diarrhea (7% vs. 1% [HERA; one-year Herceptin treatment at 12.6 months median follow-up]) were higher in patients receiving Herceptin as compared to controls. In BCIRG006, the incidence of Grade 3–4 diarrhea was higher [5.7% AC-TH, 5.5% TCH vs. 3.0% AC-T], as was Grade 1–4 diarrhea [51% AC-TH, 63% TCH vs. 43% AC-T], among women receiving Herceptin. Of patients receiving Herceptin as a single agent for the treatment of metastatic breast cancer, 25% experienced diarrhea. An increased incidence of diarrhea was observed in patients receiving Herceptin in combination with chemotherapy for treatment of metastatic breast cancer. Renal Toxicity In ToGA (metastatic gastric cancer), on the Herceptin-containing arm as compared to the chemotherapy-alone arm, the incidence of renal impairment was 18% compared to 14.5%. Severe (Grade 3/4) renal failure was 2.7% on the Herceptin-containing arm compared to 1.7% on the chemotherapy-only arm. Treatment discontinuation for renal insufficiency/failure was 2% on the Herceptin-containing arm and 0.3% on the chemotherapy-only arm. In the post-marketing setting, rare cases of nephrotic syndrome with pathologic evidence of glomerulopathy have been reported. Time to onset ranged from 4 months to approximately 18 months from initiation of Herceptin therapy. Pathologic findings included membranous glomerulonephritis, focal glomerulosclerosis, and fibrillary glomerulonephritis. Complications included volume overload and congestive heart failure.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Trastuzumab. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Infusion reaction
• Oligohydramnios or oligohydramnios sequence, including pulmonary hypoplasia, skeletal abnormalities, and neonatal death
• Glomerulopathy
• Immune thrombocytopenia
• ’Tumor lysis syndrome (TLS):' Cases of possible TLS have been reported in patients treated with Trastuzumab. Patients with significant tumor burden (e.g., bulky metastases) may be at higher risk. Patients could present with hyperuricemia, hyperphosphatemia, and acute renal failure, which may represent possible TLS. Providers should consider additional monitoring and/or treatment as clinically indicated.

Drug Interactions

Established Drug Interactions

Anthracyclines

• Patients who receive an anthracycline after stopping Trastuzumab may be at increased risk of cardiac dysfunction because of trastuzumab's estimated long washout period.
• If possible, avoid anthracycline-based therapy for up to 7 months after stopping Trastuzumab.
• If anthracyclines are used within this window, closely monitor the patient's cardiac function.

Drug Interaction Studies (Pharmacokinetic Data)

• There have been no formal drug interaction studies performed with Trastuzumab in humans. Clinically significant interactions between Trastuzumab and concomitant medications used in clinical trials have not been observed.
• ’Paclitaxel and doxorubicin:' Concentrations of paclitaxel and doxorubicin, and their major metabolites (6-α hydroxyl-paclitaxel [POH] and doxorubicinol [DOL], respectively), were not altered in the presence of trastuzumab when used as combination therapy. Trastuzumab concentrations were not altered as part of this combination.
• ’Docetaxel and carboplatin:' When Trastuzumab was administered with docetaxel or carboplatin, neither the plasma concentrations of docetaxel or carboplatin, nor the plasma concentrations of trastuzumab, were altered.
• ’Cisplatin and capecitabine:' In a drug interaction substudy conducted in ToGA, the pharmacokinetics of cisplatin, capecitabine, and their metabolites were not altered when administered in combination with Trastuzumab.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA):

• Trastuzumab can cause fetal harm when administered to a pregnant woman.
• In post-marketing reports and published literature, use of Trastuzumab during pregnancy resulted in cases of oligohydramnios and of oligohydramnios sequence, manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death.
• Apprise the patient of the potential risks to a fetus.
• The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

• ’Fetal/Neonatal Adverse Reactions:' Monitor women who received Trastuzumab during pregnancy, or within 7 months prior to conception, for oligohydramnios. If oligohydramnios occurs, perform fetal/neonatal testing appropriate for gestational age and consistent with community standards of care.
• Human Data

• Post-marketing reports and published literature describe oligohydramnios and oligohydramnios sequence with Trastuzumab exposure during pregnancy; fetal manifestations included pulmonary hypoplasia, skeletal abnormalities, and neonatal death.

• These case reports described oligohydramnios in pregnant women who received Trastuzumab either alone or in combination with chemotherapy.
• In most reported cases, amniotic fluid index increased after Trastuzumab was stopped.
• In reported cases where Trastuzumab therapy was resumed after the amniotic fluid index improved, oligohydramnios recurred.
• Animal Data

• In studies where trastuzumab was administered to pregnant Cynomolgus monkeys during the period of organogenesis, at doses up to 25 mg/kg given twice weekly (up to 25 times the recommended weekly human dose of 2 mg/kg), trastuzumab crossed the placental barrier during both the early (Gestation Days 20–50) and late (Gestation Days 120–150) phases of gestation.

• The resulting concentrations of trastuzumab in fetal serum and amniotic fluid were approximately 33% and 25%, respectively, of those present in maternal serum.
• These exposures were 'not associated with adverse developmental effects’.

Reporting Pregnancy Exposure

• If Trastuzumab is administered during pregnancy, or if a patient becomes pregnant while receiving Trastuzumab or within 7 months following the last dose, health care providers and patients should immediately report Trastuzumab exposure to Genentech at 1-888-835-2555.

Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Trastuzumab in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Trastuzumab during labor and delivery.

Nursing Mothers

• There is no information regarding the presence of trastuzumab in human milk, its effects on the breastfed infant, or its effects on milk production.
• Published data suggest human IgG is present in human milk but does not enter the neonatal and infant circulation in substantial amounts.
• Trastuzumab was present in the milk of lactating Cynomolgus monkeys but was not associated with neonatal toxicity (see Data, below).
• Consider the developmental and health benefits of breastfeeding along with the mother's clinical need for Trastuzumab treatment, and any potential adverse effects on the breastfed child from Trastuzumab or from the underlying maternal condition. This consideration should also take into account the trastuzumab washout period of 7 months.
• In lactating Cynomolgus monkeys, trastuzumab was present in breast milk at approximately 0.3% of maternal serum concentrations after pre-partum (beginning Gestation Day 120) and post-partum (through Postpartum Day 28) doses of 25 mg/kg administered twice weekly (25 times the recommended weekly human dose of 2 mg/kg of Trastuzumab).
• Infant monkeys with detectable serum levels of trastuzumab did not exhibit any adverse effects on growth or development from birth to 1 month of age.

Pediatric Use

The safety and effectiveness of Trastuzumab in pediatric patients has not been established.

Geriatic Use

• Trastuzumab has been administered to 386 patients who were 65 years of age or over (253 in the adjuvant treatment setting and 133 in the metastatic breast cancer treatment setting).
• The risk of cardiac dysfunction was increased in geriatric patients compared with younger patients — both in those receiving treatment for metastatic disease ('H0648g and H0649g) and in those receiving adjuvant therapy (NSABP B31 and NCCTG N9831’).
• Limitations in data collection and differences in study design across the 4 adjuvant breast cancer studies of Trastuzumab preclude a determination of whether the toxicity profile of Trastuzumab in older patients differs from that in younger patients.
• The reported clinical experience is not adequate to determine whether the efficacy improvements (ORR, TTP, OS, DFS) of Trastuzumab treatment in older patients differ from those observed in patients <65 years of age, for either metastatic disease or adjuvant treatment.
• In ToGA (metastatic gastric cancer), of the 294 patients treated with Trastuzumab, 108 (37%) were 65 years of age or older, while 13 (4.4%) were 75 and over. No overall differences in safety or effectiveness were observed.

Gender

There is no FDA guidance on the use of Trastuzumab with respect to specific gender populations.

Race

• Based on a population pharmacokinetic analysis, no clinically significant differences were observed in the pharmacokinetics of trastuzumab based on race: Asian (n=264) versus non-Asian (n=1324).

Renal Impairment

• Based on a population pharmacokinetic analysis, no clinically significant differences were observed in the pharmacokinetics of trastuzumab in patients with:

• Mild renal impairment (creatinine clearance [CLcr] 60 to 90 mL/min) (n=636)
• Moderate renal impairment (CLcr 30 to 60 mL/min) (n=133)

• The pharmacokinetics of trastuzumab in patients with severe renal impairment, end-stage renal disease with or without hemodialysis is unknown — this has not been studied.

Hepatic Impairment

• The pharmacokinetics of trastuzumab in patients with hepatic impairment is unknown — the label states this has not been studied. No dosing recommendation is provided for hepatic impairment.

Females of Reproductive Potential and Males

Pregnancy Testing: Verify the pregnancy status of females of reproductive potential prior to initiation of Herceptin.

• ’Contraception (Females):' Herceptin can cause embryo-fetal harm when administered during pregnancy. Advise females of reproductive potential to use effective contraception during treatment with Herceptin and for 7 months following the last dose

Immunocompromised Patients

There is no FDA guidance one the use of Trastuzumab in patients who are immunocompromised.

Administration and Monitoring

Administration

General Administration Instructions

• Trastuzumab is for intravenous (IV) infusion only. Do not administer as an intravenous push or bolus.
• Trastuzumab has different dosage and administration instructions than subcutaneous trastuzumab products.
• Do not mix Trastuzumab with other drugs.
• Do not substitute Trastuzumab for or with ado-trastuzumab emtansine or fam-trastuzumab deruxtecan.
• To prevent medication errors, check the vial labels to ensure that the drug being prepared and administered is Trastuzumab and not ado-trastuzumab emtansine or fam-trastuzumab deruxtecan.

Reconstitution(150 mg Single-Dose Vial)

• Reconstitute each 150 mg vial of Trastuzumab with 7.4 mL of Sterile Water for Injection (SWFI) (not supplied) to yield a single-dose solution containing 21 mg/mL trastuzumab that delivers 7.15 mL (150 mg trastuzumab).
• Use appropriate aseptic technique when performing the following reconstitution steps:

• Using a sterile syringe, slowly inject 7.4 mL of SWFI into the vial containing the lyophilized cake of Trastuzumab. The stream of diluent should be directed into the lyophilized cake.
• Swirl the vial gently to aid reconstitution. Do not shake.
• Slight foaming of the product may be present upon reconstitution. Allow the vial to stand undisturbed for approximately 5 minutes.
• Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The solution should be free of visible particulates, clear to slightly opalescent, and colorless to pale yellow.

• Use the reconstituted solution immediately' following reconstitution, as it contains no preservative and is intended for single-dose use only’.
• If not used immediately, store the reconstituted solution for up to 24 hours at 2°C to 8°C (36°F to 46°F); discard any unused Trastuzumab after 24 hours. Do not freeze.

Dilution

• Determine the dose (mg) of Trastuzumab and calculate the volume of the 21 mg/mL reconstituted solution needed.
• Withdraw this amount from the vial using a sterile needle and syringe, and add it to an infusion bag containing '250 mL of 0.9% Sodium Chloride Injection, USP’.
• ’Do not use dextrose (5%) solution.’
• Gently invert the bag to mix the solution.
• The diluted solution, in polyvinylchloride or polyethylene bags containing 0.9% Sodium Chloride Injection, USP, should be stored at 2°C to 8°C (36°F to 46°F) for no more than 24 hours prior to use; discard after 24 hours. This storage time is additional to the time allowed for the reconstituted vial. Do not freeze.

Monitoring

Pre-Treatment Evaluation and Testing

• Cardiac function: Assess left ventricular ejection fraction (LVEF) by echocardiogram or MUGA scan prior to initiation of Trastuzumab.
• HER2 testing: Select patients for therapy based on an FDA-authorized companion diagnostic for HER2 protein overexpression or gene amplification, performed by laboratories with demonstrated proficiency. Use FDA-authorized tests specific to the tumor type (breast vs. gastric/gastroesophageal), given differences in tumor histopathology.
• Pregnancy testing: Verify the pregnancy status of females of reproductive potential prior to initiation of Trastuzumab.

Cardiac Monitoring

• Conduct a thorough cardiac assessment, including history, physical examination, and determination of LVEF by echocardiogram or MUGA scan. Recommended schedule: :* Baseline LVEF measurement immediately prior to initiation of Trastuzumab :* LVEF measurement every 3 months during and upon completion of Trastuzumab :* Repeat LVEF measurement at 4-week intervals if Trastuzumab is withheld for significant left ventricular cardiac dysfunction :* LVEF measurement every 6 months for at least 2 years following completion of Trastuzumab as a component of adjuvant therapy
• ’Dose-modification triggers based on monitoring:' :* Withhold Trastuzumab for ≥16% absolute decrease in LVEF from pretreatment values, or for LVEF below the institutional lower limit of normal and a ≥10% absolute decrease from pretreatment values. :* Trastuzumab may be resumed if, within 4–8 weeks, LVEF returns to normal limits and the absolute decrease from baseline is ≤15%. :* Permanently discontinue Trastuzumab for a persistent (>8 weeks) LVEF decline, or for suspension of dosing on more than 3 occasions for cardiomyopathy.

Infusion Monitoring

• Monitor patients during and for 24 hours after Trastuzumab administration, as infusion reaction symptoms usually occur during or within 24 hours of administration.
• ’Interrupt' the infusion in all patients experiencing dyspnea or clinically significant hypotension.
• Evaluate and carefully monitor patients until complete resolution of signs and symptoms of an infusion reaction.
• Strongly consider permanent discontinuation for severe infusion reactions.
• There are no established data on the best method to identify patients who can safely be retreated after a severe infusion reaction; monitor closely if re-infusion is attempted, typically after premedication with antihistamines and/or corticosteroids.

Pulmonary Monitoring

• Monitor for signs/symptoms of pulmonary toxicity (dyspnea, interstitial pneumonitis, pulmonary infiltrates, pleural effusions, non-cardiogenic pulmonary edema, acute respiratory distress syndrome, pulmonary fibrosis), particularly in patients with symptomatic intrinsic lung disease or extensive pulmonary tumor involvement, who appear to have more severe toxicity.

Hematologic Monitoring

• Monitor for exacerbation of chemotherapy-induced neutropenia and febrile neutropenia when Trastuzumab is combined with myelosuppressive chemotherapy.

Pregnancy-Related Monitoring

• Monitor women who received Trastuzumab during pregnancy, or within 7 months prior to conception, for ‘oligohydramnios'.
• If oligohydramnios occurs, perform fetal/neonatal testing appropriate for gestational age and consistent with community standards of care.
• Report any Trastuzumab exposure during pregnancy immediately to Genentech at 1-888-835-2555.

Renal Monitoring

• In the metastatic gastric cancer setting (ToGA), renal impairment and renal failure were observed at higher rates with Trastuzumab; monitor renal function accordingly, particularly in patients with high tumor burden or other renal risk factors.
• Post-marketing: monitor for rare nephrotic syndrome/glomerulopathy, which has presented from 4 to approximately 18 months after Trastuzumab initiation, with complications including volume overload and congestive heart failure.

Tumor Lysis Syndrome Monitoring

• Consider additional monitoring for possible tumor lysis syndrome (TLS) — hyperuricemia, hyperphosphatemia, acute renal failure — particularly in patients with significant tumor burden (e.g., bulky metastases). Consider additional treatment as clinically indicated.

IV Compatibility

There is limited information about the IV Compatibility.

Overdosage

There is no experience with overdosage in human clinical trials. Single doses higher than 8 mg/kg have not been tested.

Pharmacology

Trastuzumab?
Therapeutic monoclonal antibody
Source	zu/o
Target	HER2/neu
Identifiers
CAS number	180288-69-1
ATC code	L01XC03
PubChem	?
DrugBank	DB00072
Chemical data
Formula	C6470H10012N1726O2013S42
Mol. mass	145531.5 g/mol
Pharmacokinetic data
Bioavailability	?
Metabolism	Unknown, possibly reticuloendothelial system.
Half life	2-12 days
Excretion	?
Therapeutic considerations
Pregnancy cat.	?(US)
Legal status	Template:Unicode Prescription only
Routes	Intravenous

Mechanism of Action

The HER2 (or c-erbB2) proto-oncogene encodes a transmembrane receptor protein of 185 kDa, which is structurally related to the epidermal growth factor receptor. Trastuzumab has been shown, in both in vitro assays and in animals, to inhibit the proliferation of human tumor cells that overexpress HER2. Trastuzumab is a mediator of antibody-dependent cellular cytotoxicity (ADCC). In vitro, Trastuzumab-mediated ADCC has been shown to be preferentially exerted on HER2 overexpressing cancer cells compared with cancer cells that do not overexpress HER2.

Structure

• Trastuzumab is a humanized IgG1 kappa monoclonal antibody that selectively binds with high affinity to the extracellular domain of the human epidermal growth factor receptor 2 protein, HER2.
• Trastuzumab is produced by recombinant DNA technology in a mammalian cell (Chinese Hamster Ovary, CHO) culture.
• Herceptin (trastuzumab) for injection is a sterile, white to pale yellow, preservative-free lyophilized powder with a cake-like appearance, for intravenous administration.

Formulation (150 mg Single-Dose Vial)

• Each single-dose vial of Herceptin delivers: :* 150 mg trastuzumab :* 136.2 mg α,α-trehalose dihydrate :* 3.4 mg L-histidine HCl monohydrate :* 2.2 mg L-histidine :* 0.6 mg polysorbate 20
• Reconstitution with 7.4 mL of Sterile Water for Injection (SWFI) yields a solution containing 21 mg/mL trastuzumab that delivers 7.15 mL (150 mg trastuzumab), at a pH of approximately 6.

Pharmacodynamics

• Herceptin exposure-response relationships and the time course of pharmacodynamic responses are not fully characterized.

Cardiac Electrophysiology

• The effects of trastuzumab on electrocardiographic (ECG) endpoints, including QTc interval duration, were evaluated in patients with HER2-positive solid tumors.
• Trastuzumab had no clinically relevant effect on QTc interval duration.
• There was no apparent relationship between serum trastuzumab concentrations and change in QTcF interval duration in patients with HER2-positive solid tumors.

Pharmacokinetics

• The pharmacokinetics of trastuzumab were evaluated in a pooled population pharmacokinetic (PK) model analysis of 1,582 subjects with primarily breast cancer and metastatic gastric cancer (MGC) receiving intravenous Herceptin.
• Total trastuzumab clearance increases with decreasing concentrations due to parallel linear and non-linear elimination pathways.
• Although average trastuzumab exposure was higher following the first cycle in breast cancer patients receiving the once-every-three-week schedule compared to the weekly schedule, average steady-state exposure was essentially the same at both dosages.
• Average trastuzumab exposure following the first cycle and at steady state, as well as time to steady state, was higher in breast cancer patients compared to MGC patients' at the same dosage; the reason for this difference is ‘unknown.
• Population PK-based simulations indicate that following discontinuation of Herceptin, concentrations in at least 95% of breast cancer and MGC patients will decrease to approximately 3% of the population-predicted steady-state trough serum concentration (approximately 97% washout) by 7 months.

Specific Populations

• Based on a population pharmacokinetic analysis, no clinically significant differences were observed in the pharmacokinetics of trastuzumab based on: :* Age: <65 years (n=1294) vs. ≥65 years (n=288) :* Race: Asian (n=264) vs. non-Asian (n=1324) :* Renal impairment: mild (CLcr 60–90 mL/min, n=636) or moderate (CLcr 30–60 mL/min, n=133)
• The pharmacokinetics of trastuzumab in patients with severe renal impairment, end-stage renal disease with or without hemodialysis, or hepatic impairment is unknown (not studied).

Drug Interaction Studies

• There have been no formal drug interaction studies performed with Trastuzumab in humans. Clinically significant interactions between Trastuzumab and concomitant medications used in clinical trials have not been observed.
• ’Paclitaxel and doxorubicin:' Concentrations of paclitaxel and doxorubicin, and their major metabolites, were not altered in the presence of trastuzumab; trastuzumab concentrations were not altered as part of this combination.
• ’Docetaxel and carboplatin:' Neither plasma concentrations of docetaxel or carboplatin, nor plasma concentrations of trastuzumab, were altered when co-administered.
• ’Cisplatin and capecitabine:' In a drug interaction substudy in ToGA, the pharmacokinetics of cisplatin, capecitabine, and their metabolites were not altered when administered with Trastuzumab.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

• Trastuzumab has 'not been tested for carcinogenic potential’.
• ’No evidence of mutagenic activity was observed when trastuzumab was tested in the standard Ames bacterial and human peripheral blood lymphocyte mutagenicity assays, at concentrations of up to 5000 mcg/mL’.
• In an in vivo micronucleus assay, no evidence of chromosomal damage to mouse bone marrow cells was observed following bolus intravenous doses of up to 118 mg/kg trastuzumab.
• A fertility study conducted in female Cynomolgus monkeys, at doses up to 25 times the weekly recommended human dose of 2 mg/kg trastuzumab, revealed no evidence of impaired fertility, as measured by menstrual cycle duration and female sex hormone levels.

Clinical Studies

Adjuvant Breast Cancer

The safety and efficacy of Trastuzumab in women receiving adjuvant chemotherapy for HER2-overexpressing breast cancer were evaluated in an integrated analysis of two randomized, open-label clinical trials (NSABP B31 and NCCTG N9831) with a total of 4063 women at the protocol-specified final overall survival analysis, a third randomized, open-label clinical trial (HERA) with a total of 3386 women at definitive Disease-Free Survival analysis for one-year Trastuzumab treatment versus observation, and a fourth randomized, open-label clinical trial with a total of 3222 patients (BCIRG006). NSABP B31 and NCCTG N9831 In NSABP B31 and NCCTG N9831, breast tumor specimens were required to show HER2 overexpression (3+ by IHC) or gene amplification (by FISH). HER2 testing was verified by a central laboratory prior to randomization (NCCTG N9831) or was required to be performed at a reference laboratory (NSABP B31). Patients with a history of active cardiac disease based on symptoms, abnormal electrocardiographic, radiologic, or left ventricular ejection fraction findings, or uncontrolled hypertension (diastolic >100 mmHg or systolic >200 mmHg) were not eligible. Patients were randomized (1:1) to receive doxorubicin and cyclophosphamide followed by paclitaxel (AC→paclitaxel) alone, or paclitaxel plus Trastuzumab (AC→paclitaxel + Trastuzumab). In both trials, patients received four 21-day cycles of doxorubicin 60 mg/m² and cyclophosphamide 600 mg/m². Paclitaxel was administered either weekly (80 mg/m²) or every 3 weeks (175 mg/m²) for a total of 12 weeks in NSABP B31; paclitaxel was administered only by the weekly schedule in NCCTG N9831. Trastuzumab was administered at 4 mg/kg on the day of initiation of paclitaxel and then at 2 mg/kg weekly for a total of 52 weeks. Trastuzumab treatment was permanently discontinued in patients who developed congestive heart failure or persistent/recurrent LVEF decline. Radiation therapy, if administered, was initiated after completion of chemotherapy. Patients with ER+ and/or PR+ tumors received hormonal therapy. The major efficacy outcome measure of the combined efficacy analysis was Disease-Free Survival (DFS), defined as the time from randomization to recurrence, occurrence of contralateral breast cancer, other second primary cancer, or death. An additional efficacy outcome measure was overall survival (OS). A total of 3752 patients were included in the joint efficacy analysis of DFS following a median follow-up of 2.0 years in the AC→paclitaxel + Trastuzumab arm. The pre-planned final OS analysis from the joint analysis included 4063 patients and was performed when 707 deaths had occurred after a median follow-up of 8.3 years in the AC→paclitaxel + Trastuzumab arm. Data from both arms in NSABP B31 and two of the three study arms in NCCTG N9831 were pooled for efficacy analyses. The patients included in the DFS analysis had a median age of 49 years (range 22–80 years; 6% >65 years); 84% were White, 7% Black, 4% Hispanic, and 4% Asian/Pacific Islander. Disease characteristics included 90% infiltrating ductal histology, 38% T1, 91% nodal involvement, 27% intermediate and 66% high-grade pathology, and 53% ER+ and/or PR+ tumors. Similar demographic and baseline characteristics were reported for the efficacy-evaluable population after 8.3 years of median follow-up in the AC→paclitaxel + Trastuzumab arm. HERA In HERA, breast tumor specimens were required to show HER2 overexpression (3+ by IHC) or gene amplification (by FISH) as determined at a central laboratory. Patients with node-negative disease were required to have ≥T1c primary tumor. Patients with a history of congestive heart failure or LVEF <55%, uncontrolled arrhythmias, angina requiring medication, clinically significant valvular heart disease, evidence of transmural infarction on ECG, or poorly controlled hypertension (systolic >180 mm Hg or diastolic >100 mm Hg) were not eligible. HERA was designed to compare one and two years of three-weekly Trastuzumab treatment versus observation in patients with HER2-positive early breast cancer (EBC) following surgery, established chemotherapy, and radiotherapy (if applicable). Patients were randomized (1:1:1) upon completion of definitive surgery and at least four cycles of chemotherapy to receive no additional treatment, one year of Trastuzumab treatment, or two years of Trastuzumab treatment. Patients undergoing a lumpectomy had also completed standard radiotherapy. Patients with ER+ and/or PgR+ disease received systemic adjuvant hormonal therapy at investigator discretion. Trastuzumab was administered with an initial dose of 8 mg/kg followed by subsequent doses of 6 mg/kg once every three weeks. The main outcome measure was DFS, defined as in NSABP B31 and NCCTG N9831. A protocol-specified interim efficacy analysis comparing one-year Trastuzumab treatment to observation was performed at a median follow-up duration of 12.6 months in the Trastuzumab arm and formed the basis for the definitive DFS results. Among the 3386 patients randomized to the observation (n=1693) and Trastuzumab one-year (n=1693) treatment arms, the median age was 49 years (range 21–80); 83% were Caucasian and 13% were Asian. Disease characteristics: 94% infiltrating ductal carcinoma, 50% ER+ and/or PgR+, 57% node-positive, 32% node-negative, and in 11% of patients, nodal status was not assessable due to prior neoadjuvant chemotherapy. Ninety-six percent (1055/1098) of patients with node-negative disease had high-risk features: among the 1098 patients with node-negative disease, 49% (543) were ER− and PgR−, and 47% (512) were ER and/or PgR+ with at least one high-risk feature (pathological tumor size >2 cm, Grade 2–3, or age <35 years). Prior to randomization, 94% of patients had received anthracycline-based chemotherapy regimens. After the definitive DFS results comparing observation to one-year Trastuzumab treatment were disclosed, a prospectively planned analysis comparing one year versus two years of Trastuzumab treatment at a median follow-up duration of 8 years was performed. Extending Trastuzumab treatment for two years did not show additional benefit over one year [Hazard Ratio, two years vs. one year, ITT population: DFS = 0.99 (95% CI: 0.87, 1.13), p=0.90; OS = 0.98 (95% CI: 0.83, 1.15), p=0.78]. BCIRG006 In BCIRG006, breast tumor specimens were required to show HER2 gene amplification (FISH+ only) as determined at a central laboratory. Patients were required to have either node-positive disease, or node-negative disease with at least one high-risk feature (ER/PR-negative, tumor size >2 cm, age <35 years, or histologic/nuclear Grade 2 or 3). Patients with a history of CHF, myocardial infarction, Grade 3 or 4 cardiac arrhythmia, angina requiring medication, clinically significant valvular heart disease, poorly controlled hypertension (diastolic >100 mmHg), or any T4, N2, N3, or M1 breast cancer were not eligible. Patients were randomized (1:1:1) to doxorubicin and cyclophosphamide followed by docetaxel (AC-T), doxorubicin and cyclophosphamide followed by docetaxel plus Trastuzumab (AC-TH), or docetaxel and carboplatin plus Trastuzumab (TCH). In the AC-T and AC-TH arms, doxorubicin 60 mg/m² and cyclophosphamide 600 mg/m² were given every 3 weeks for four cycles; docetaxel 100 mg/m² every 3 weeks for four cycles. In the TCH arm, docetaxel 75 mg/m² and carboplatin (target AUC 6 mg/mL/min, 30–60 minute infusion) were given every 3 weeks for six cycles. Trastuzumab was administered weekly (4 mg/kg initial, then 2 mg/kg weekly) concurrently with T or TC, then every 3 weeks (6 mg/kg) as monotherapy for a total of 52 weeks. Radiation therapy, if administered, began after completion of chemotherapy. Patients with ER+ and/or PR+ tumors received hormonal therapy. DFS was the main outcome measure. Among the 3222 patients randomized, median age was 49 years (range 22–74; 6% ≥65 years). Disease characteristics included 54% ER+ and/or PR+ and 71% node-positive. All patients underwent primary surgery for breast cancer prior to randomization.

Combined Efficacy Results

Results for DFS for the integrated analysis of NSABP B31/NCCTG N9831, HERA, and BCIRG006, and OS results for the integrated analysis of NSABP B31/NCCTG N9831 and HERA, are presented in Table 9. For NSABP B31/NCCTG N9831, the duration of DFS following a median follow-up of 2.0 years in the AC→TH arm is presented in Figure 4, and the duration of OS after a median follow-up of 8.3 years in the AC→TH arm is presented in Figure 5. The duration of DFS for BCIRG006 is presented in Figure 6. Across all four studies, at the time of definitive DFS analysis, there were insufficient patients within certain subgroups (low tumor grade, specific ethnic/racial subgroups, patients >65 years) to determine if treatment effect differed from the overall population. Table 9

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Figure 4

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Figure 5

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Figure 6

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• For NSABP B31/NCCTG N9831, the OS hazard ratio was 0.64 (95% CI: 0.55, 0.74). At 8.3 years of median follow-up (AC→TH), the survival rate was estimated to be 86.9% in the AC→TH arm and 79.4% in the AC→T arm. OS benefit by age, hormone receptor status, number of positive lymph nodes, tumor size and grade, and surgery/radiation therapy was consistent with the treatment effect in the overall population:

Patients ≤50 years (n=2197): OS HR 0.65 (95% CI: 0.52, 0.81) Patients >50 years (n=1866): OS HR 0.63 (95% CI: 0.51, 0.78) Hormone receptor-positive (n=2223): OS HR 0.63 (95% CI: 0.51, 0.78) Hormone receptor-negative (n=1830): OS HR 0.64 (95% CI: 0.52, 0.80) Tumor size ≤2 cm (n=1604): OS HR 0.52 (95% CI: 0.39, 0.71) Tumor size >2 cm (n=2448): OS HR 0.67 (95% CI: 0.56, 0.80)

Exploratory analyses of DFS as a function of HER2 overexpression or gene amplification were conducted for patients in NCCTG N9831 and HERA, where central laboratory testing data were available. Results are shown in Table 10. The number of events in NCCTG N9831 was small except for the IHC 3+/FISH+ subgroup (81% of those with data); definitive conclusions cannot be drawn for other subgroups due to small event numbers. The number of events in HERA was adequate to demonstrate significant DFS effects in the IHC 3+/FISH-unknown and FISH+/IHC-unknown subgroups.

• Table 10

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Metastatic Breast Cancer

The safety and efficacy of Trastuzumab in women with metastatic breast cancer were studied in a randomized, controlled clinical trial in combination with chemotherapy (H0648g, n=469) and an open-label single-arm clinical trial (H0649g, n=222). Both trials studied patients with metastatic breast cancer whose tumors overexpress the HER2 protein. Patients were eligible if they had 2+ or 3+ overexpression (0–3 scale) by immunohistochemical assessment at a central testing lab. Previously Untreated Metastatic Breast Cancer (H0648g) H0648g was a multicenter, randomized, open-label trial in 469 women with metastatic breast cancer not previously treated with chemotherapy for metastatic disease. Tumor specimens were tested by IHC (Clinical Trial Assay, CTA) and scored 0, 1+, 2+, or 3+ (3+ = strongest positivity); only 2+ or 3+ tumors were eligible (~33% of those screened). Patients were randomized to chemotherapy alone or with Trastuzumab (4 mg/kg loading dose, then 2 mg/kg weekly). Patients with prior adjuvant anthracycline therapy received paclitaxel (175 mg/m² over 3 hours every 21 days for ≥6 cycles); others received anthracycline plus cyclophosphamide (AC: doxorubicin 60 mg/m² or epirubicin 75 mg/m² plus cyclophosphamide 600 mg/m² every 21 days for 6 cycles). 65% of patients randomized to chemotherapy alone received Trastuzumab at disease progression as part of a separate extension study. Per independent response evaluation committee determination, patients randomized to Trastuzumab plus chemotherapy had significantly longer median time to disease progression, higher overall response rate (ORR), and longer median duration of response than chemotherapy alone. Patients on Trastuzumab plus chemotherapy also had longer median overall survival (Table 11). These effects were seen with both Trastuzumab plus paclitaxel and Trastuzumab plus AC, though the magnitude was greater in the paclitaxel subgroup.

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Data from H0648g suggest the beneficial treatment effects were largely limited to patients with the highest level of HER2 protein overexpression (3+).

• Table 12

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Previously Treated Metastatic Breast Cancer (H0649g) Trastuzumab was studied as a single agent in H0649g, a multicenter, open-label, single-arm trial in patients with HER2-overexpressing metastatic breast cancer relapsed after one or two prior chemotherapy regimens for metastatic disease. Of 222 patients enrolled, 66% had received prior adjuvant chemotherapy, 68% had received two prior chemotherapy regimens for metastatic disease, and 25% had received prior myeloablative treatment with hematopoietic rescue. Patients received a 4 mg/kg loading dose followed by weekly 2 mg/kg IV doses. ORR (complete + partial response), per independent Response Evaluation Committee, was 14% (2% complete response, 12% partial response). Complete responses were observed only in patients with disease limited to skin and lymph nodes. ORR was 18% in patients whose tumors tested CTA 3+, versus 6% in CTA 2+.

Metastatic Gastric Cancer

The safety and efficacy of Trastuzumab in combination with cisplatin and a fluoropyrimidine (capecitabine or 5-fluorouracil) were studied in previously untreated patients with metastatic gastric or gastroesophageal junction adenocarcinoma (ToGA). In this open-label, multicenter trial, 594 patients were randomized 1:1 to Trastuzumab plus cisplatin and a fluoropyrimidine (FC+H) or chemotherapy alone (FC). Randomization was stratified by extent of disease, primary site, tumor measurability, ECOG performance status, and fluoropyrimidine choice. All patients were HER2 gene-amplified (FISH+) or HER2-overexpressing (IHC 3+), and required adequate cardiac function (LVEF >50%). On the Trastuzumab-containing arm, Trastuzumab was given as an initial dose of 8 mg/kg, then 6 mg/kg every 3 weeks until progression. Cisplatin was given at 80 mg/m² Day 1 every 3 weeks for 6 cycles (2-hour IV infusion) on both arms. Capecitabine was given at 1000 mg/m² orally twice daily for 14 days of each 21-day cycle for 6 cycles; alternatively, continuous IV 5-fluorouracil was given at 800 mg/m²/day on Days 1–5 every three weeks for 6 cycles. Median age was 60 years (range 21–83); 76% male; 53% Asian, 38% Caucasian, 5% Hispanic, 5% other racial/ethnic groups; 91% had ECOG PS 0 or 1; 82% had primary gastric cancer and 18% primary gastroesophageal adenocarcinoma. 23% had prior gastrectomy, 7% had prior neoadjuvant/adjuvant therapy, and 2% had prior radiotherapy. The main outcome measure was overall survival (OS), analyzed by unstratified log-rank test. The final OS analysis, based on 351 deaths, was statistically significant (nominal significance level 0.0193). An updated OS analysis was conducted one year after the final analysis. Efficacy results of both analyses are summarized in Table 13 and Figure 7.

• Table 13

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Figure 7

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An exploratory analysis of OS by HER2 gene amplification (FISH) and protein overexpression (IHC) status is summarized in Table 14.

• Table 14

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How Supplied

150 mg Single-Dose Vial

• Herceptin (trastuzumab) for injection, 150 mg/vial, is supplied in a single-dose vial as a preservative-free, white to pale yellow, lyophilized sterile powder, under vacuum.
• Available as: :* A carton containing one single-dose vial' — NDC 50242-132-01 :* A carton containing 10 single-dose vials — NDC 50242-132-10’
• ’Store' Herceptin vials in the refrigerator at 2°C to 8°C (36°F to 46°F) until time of reconstitution.

Storage

Prior to Reconstitution

• Vials of Trastuzumab (150 mg single-dose vial) are stable at 2°C to 8°C (36°F to 46°F) prior to reconstitution.
• Do not use beyond the expiration date stamped on the vial.

After Reconstitution (with SWFI)

• Use the reconstituted Trastuzumab solution immediately' following reconstitution with Sterile Water for Injection (SWFI), as it contains no preservative and is intended for single-dose use only’.
• If not used immediately, the reconstituted solution may be stored for up to 24 hours at 2°C to 8°C (36°F to 46°F); discard any unused Trastuzumab after 24 hours.
• ’Do not freeze' Trastuzumab following reconstitution.

After Dilution

• The diluted Trastuzumab solution for infusion, in polyvinylchloride or polyethylene bags containing 0.9% Sodium Chloride Injection, USP, should be stored at 2°C to 8°C (36°F to 46°F) for no more than 24 hours prior to use; discard after 24 hours. This storage time is additional to the time allowed for the reconstituted vial.
• ’Do not freeze' the diluted solution.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

Cardiomyopathy

• Advise patients to contact a health care professional immediately for any of the following: :* New onset or worsening shortness of breath :* Cough :* Swelling of the ankles/legs :* Swelling of the face :* Palpitations :* Weight gain of more than 5 pounds in 24 hours :* Dizziness or loss of consciousness

Embryo-Fetal Toxicity

• Advise pregnant women and females of reproductive potential that Trastuzumab exposure during pregnancy, or within 7 months prior to conception, can result in fetal harm.
• Advise female patients to contact their healthcare provider with a known or suspected pregnancy.
• Encourage women who are exposed to Trastuzumab during pregnancy, or who become pregnant within 7 months following the last dose of Trastuzumab, to 'report their pregnancy to Genentech at 1-888-835-2555’.
• Advise females of reproductive potential to use effective contraception during treatment and for 7 months following the last dose of Trastuzumab.

Precautions with Alcohol

Alcohol-Trastuzumab interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

• Herceptin

Look-Alike Drug Names

Ado-trastuzumab emtansine (Kadcyla)

• ’Trastuzumab (Herceptin)' and ado-trastuzumab emtansine (Kadcyla) are the most well-documented look-alike/sound-alike pair involving this drug.
• The FDA prescribing information explicitly warns: "Do not substitute Herceptin (trastuzumab) for or with ado-trastuzumab emtansine," and instructs providers to check vial labels carefully before preparation and administration to avoid mix-ups.
• This pair is officially listed on the ISMP List of Confused Drug Names (Institute for Safe Medication Practices).

Fam-trastuzumab deruxtecan (Enhertu)

• The current FDA label for Herceptin also explicitly warns against substituting Herceptin for or with fam-trastuzumab deruxtecan (Enhertu), another HER2-targeted antibody-drug conjugate with a name similar to trastuzumab, but a distinct dosing regimen and toxicity profile.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

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