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 can result in subclinical and clinical cardiac failure, including congestive heart failure and decreased left ventricular ejection fraction (LVEF). The risk is greatest when trastuzumab is administered concurrently with anthracyclines. Evaluate cardiac function before and during treatment. Discontinue trastuzumab for cardiomyopathy. Infusion reactions and pulmonary toxicity: Serious and fatal infusion reactions and pulmonary toxicity can occur. Discontinue trastuzumab for anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome. Embryo-fetal toxicity: Exposure during pregnancy can result in oligohydramnios, in some cases complicated by pulmonary hypoplasia and neonatal death. Advise patients of these risks and the need for effective contraception.

Overview

Trastuzumab is a HER2/neu receptor antagonist that is FDA approved for the treatment of adjuvant treatment of HER2-overexpressing node-positive or high-risk node-negative breast cancer; first-line treatment of HER2-overexpressing metastatic breast cancer in combination with paclitaxel or as a single agent after one or more prior chemotherapy regimens for metastatic disease; and treatment of HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma in combination with cisplatin and capecitabine or 5-fluorouracil in patients who have not received prior treatment for metastatic disease. There is a Black Box Warning for this drug as shown here. Common adverse reactions include headache, diarrhea, nausea, chills, fever, infection, congestive heart failure, insomnia, cough, rash, neutropenia, fatigue, anemia, stomatitis, weight loss, upper respiratory tract infections, thrombocytopenia, mucosal inflammation, nasopharyngitis, and dysgeusia.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

FDA-Labeled Indications

• Adjuvant Breast Cancer: Adjuvant treatment of HER2-overexpressing node-positive or node-negative (ER/PR-negative, or with one high-risk feature) breast cancer, as part of a regimen with doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel; as part of a regimen with docetaxel and carboplatin; or as a single agent following multi-modality anthracycline-based therapy.
• Metastatic Breast Cancer: In combination with paclitaxel for first-line treatment of HER2-overexpressing metastatic breast cancer; or as a single agent for HER2-overexpressing metastatic breast cancer in patients who have received one or more chemotherapy regimens for metastatic disease.
• Metastatic Gastric Cancer: In combination with cisplatin and capecitabine or 5-fluorouracil, for HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma in patients who have not received prior treatment for metastatic disease.

Patient Selection

• Select patients based on HER2 protein overexpression or HER2 gene amplification in tumor specimens.
• Assessment of HER2 protein overexpression and HER2 gene amplification should be performed using FDA-authorized tests specific for breast or gastric cancers by laboratories with demonstrated proficiency.
• 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.

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 trastuzumab with other drugs.

• Do not substitute trastuzumab for or with ado-trastuzumab emtansine or fam-trastuzumab deruxtecan.

Trastuzumab Dosage by Indication

Trastuzumab Dosage by Indication

Indication	Regimen/Phase	Initial Dose	Subsequent Dose	Frequency	Duration
Adjuvant Treatment of Breast Cancer (total 52 weeks of therapy)	During and following paclitaxel, docetaxel, or docetaxel/carboplatin: initial dose over 90 min, then weekly dosing during chemotherapy for first 12 weeks (paclitaxel or docetaxel) or 18 weeks (docetaxel/carboplatin); one week after last weekly dose, switch to every-3-week dosing	4 mg/kg IV infusion over 90 minutes	2 mg/kg IV infusion over 30 minutes (weekly during chemo phase); then 6 mg/kg IV infusion over 30–90 minutes (every-3-week phase)	Weekly during chemotherapy (12 or 18 weeks), then every 3 weeks	Total of 52 weeks; extending beyond 1 year not recommended
	As a single agent within 3 weeks following completion of multi-modality, anthracycline-based chemotherapy regimens	8 mg/kg IV infusion over 90 minutes	6 mg/kg IV infusion over 30–90 minutes	Every 3 weeks	Total of 52 weeks; extending beyond 1 year not recommended
Metastatic Breast Cancer	Alone or in combination with paclitaxel	4 mg/kg IV infusion over 90 minutes	2 mg/kg IV infusion over 30 minutes	Weekly	Until disease progression
Metastatic Gastric Cancer	In combination with cisplatin and capecitabine or 5-fluorouracil	8 mg/kg IV infusion over 90 minutes	6 mg/kg IV infusion over 30–90 minutes	Every 3 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 for Adverse Reactions

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.

Dosage Modifications for Adverse Reactions (Cardiomyopathy)

Condition	Action / Outcome
≥16% absolute decrease in LVEF from pretreatment values	Withhold trastuzumab dosing for at least 4 weeks
LVEF below institutional limits of normal and ≥10% absolute decrease in LVEF from pretreatment values	Withhold trastuzumab dosing for at least 4 weeks
LVEF returns to normal limits within 4–8 weeks, with absolute decrease from baseline ≤15%	Trastuzumab may be resumed
Persistent (>8 weeks) LVEF decline	Permanently discontinue trastuzumab
Trastuzumab dosing suspended on more than 3 occasions for cardiomyopathy	Permanently discontinue trastuzumab

Medication Error Prevention

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

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

Beyond its FDA-approved indications in breast and gastric/GEJ cancer, trastuzumab is used in several guideline-supported regimens for selected HER2-positive solid tumors. Each use below should be interpreted according to the cited disease-specific guideline, biomarker criteria, and treatment setting.

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

• The trastuzumab FDA label covers adjuvant, but not neoadjuvant, breast cancer use. Pertuzumab carries an FDA-approved neoadjuvant indication in combination with trastuzumab and chemotherapy. NCCN Breast Cancer Guidelines list TCHP (docetaxel/carboplatin + trastuzumab + pertuzumab) as a preferred preoperative option for selected 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

Supporting trials: NeoSphere and TRYPHAENA.

2. 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 loading dose then 6 mg/kg IV every 21 days; Pertuzumab 840 mg IV loading dose then 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.

Supporting trial (MOUNTAINEER)

3. HER2-Positive Biliary Tract Cancer

• 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.

Supporting trial: MyPathway basket study.

4. 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

Supporting trial: Fader et al.

5. 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.
• Dosing information (docetaxel + trastuzumab)

• Trastuzumab: 8 mg/kg IV loading dose, then 6 mg/kg IV every 21 days
• Docetaxel: 75 mg/m² IV every 21 days

Supporting trial: Takahashi et al.

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

• 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

For gastric/GEJ adenocarcinoma with PD-L1 CPS ≥1, pembrolizumab with trastuzumab and fluoropyrimidine- and platinum-containing chemotherapy has FDA approval in the first-line locally advanced unresectable or metastatic setting.

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

• Palbociclib (Ibrance) received FDA approval for HR-positive, HER2-positive locally advanced or metastatic breast cancer maintenance, in combination with trastuzumab ± pertuzumab and endocrine therapy.
• Dosing information
• 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.

Supporting trial: PATINA.

Non–Guideline-Supported Use

There is limited information regarding off-label non-guideline-supported use.

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 can result in subclinical and clinical cardiac failure, including congestive heart failure and decreased left ventricular ejection fraction (LVEF). The risk is greatest when trastuzumab is administered concurrently with anthracyclines. Evaluate cardiac function before and during treatment. Discontinue trastuzumab for cardiomyopathy. Infusion reactions and pulmonary toxicity: Serious and fatal infusion reactions and pulmonary toxicity can occur. Discontinue trastuzumab for anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome. Embryo-fetal toxicity: Exposure during pregnancy can result in oligohydramnios, in some cases complicated by pulmonary hypoplasia 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 pretreatment 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.

Incidence of congestive heart failure (CHF) in different trials is presented in Table 1.

This image is provided by the National Library of Medicine.

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 post-marketing 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 patients experiencing dyspnea or clinically significant hypotension. Provide appropriate medical therapy, which may include epinephrine, corticosteroids, diphenhydramine, bronchodilators, and oxygen, and monitor until complete resolution of signs and symptoms. Permanent discontinuation should be strongly considered after a severe infusion reaction. 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 postmarketing 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.

Adverse Reactions

Clinical Trials Experience

Common Adverse Reactions

• 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.

Adverse Reactions on Specific Organ Systems

Adverse Reactions on Specific Organ Systems

Organ System	Adverse Reactions / Details
Cardiovascular System	Congestive heart failure / cardiac dysfunction is the signature cardiac toxicity of trastuzumab (see Boxed Warning and Warnings and Precautions, Cardiomyopathy); Ejection fraction decreased; Cardiac arrhythmias; Palpitations; Hypertension; Cardiac ischemia/infarction; Tachycardia; Dizziness
Infusion-Related/Hypersensitivity Reactions	Infusion reactions consist of a symptom complex characterized by fever and chills, and on occasion nausea, vomiting, pain (in some cases at tumor sites), headache, dizziness, dyspnea, hypotension, elevated blood pressure, rash, and asthenia. During the first infusion, chills and fever were the most commonly reported symptoms. On second or subsequent infusions, infusion reactions occurred in 21% (monotherapy) and 35% (combination with chemotherapy) of patients, and were severe in 1.4% and 9%, respectively.
Respiratory System	Pulmonary toxicity: includes dyspnea, interstitial pneumonitis, pulmonary infiltrates, pleural effusions, non-cardiogenic pulmonary edema, pulmonary insufficiency and hypoxia, acute respiratory distress syndrome, bronchospasm, hypoxia, and pulmonary fibrosis; can occur as a sequela of infusion reactions. Also: cough, influenza / upper respiratory infection, rhinitis, pharyngolaryngeal pain / pharyngitis
Gastrointestinal System	Diarrhea, nausea, vomiting, stomatitis, dysphagia, constipation, dyspepsia, abdominal pain (upper), anorexia
Blood and Lymphatic System	Anemia, neutropenia, febrile neutropenia, thrombocytopenia, leukopenia
Infections	Overall incidence of infection is higher. Most common sites are upper respiratory tract, skin, and urinary tract.
Renal and Urinary System	Renal impairment/failure, may lead to treatment discontinuation for renal insufficiency/failure
Musculoskeletal System	Arthralgia, back pain, myalgia, bone pain, muscle spasm
Nervous System	Headache, paresthesia, dizziness, insomnia, peripheral neuritis / neuropathy, depression, dysgeusia
Skin and Subcutaneous Tissue	Rash, pruritus, nail changes
Vascular Disorders	Thrombosis/embolism
Reproductive System (Embryo-Fetal Toxicity)	Trastuzumab can cause fetal harm when administered during pregnancy

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 reactions including bronchospasm, anaphylaxis, angioedema, hypoxia, and severe hypotension, have been reported
• Oligohydramnios or oligohydramnios sequence, including pulmonary hypoplasia, skeletal abnormalities, and neonatal death
• Glomerulopathy- membranous glomerulonephritis, focal glomerulosclerosis, and fibrillary glomerulonephritis
• 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 trastuzumab.

• Contraception (Females): trastuzumab can cause embryo-fetal harm when administered during pregnancy. Advise females of reproductive potential to use effective contraception during treatment with trastuzumab 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: Herceptin 150 mg Single-Dose Vial

• The following preparation and storage instructions apply specifically to the Herceptin reference-product 150 mg single-dose vial; consult the individual prescribing information for biosimilars and subcutaneous trastuzumab products.
• 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

Pretreatment 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.

Monitoring

Monitoring Parameters

Parameter	Timing	Purpose/action
LVEF	Baseline, immediately prior to initiation of Trastuzumab	Establish pretreatment cardiac function
	Every 3 months during treatment and upon completion of Trastuzumab	Detect cardiac dysfunction
	Every 4 weeks while dosing is withheld (after withholding for dysfunction)	Determine recovery and resumption eligibility
LVEF (after adjuvant therapy)	Every 6 months for at least 2 years following completion of Trastuzumab as a component of adjuvant therapy	Delayed cardiac surveillance
Pregnancy status	Before initiation, in females of reproductive potential	Assess embryo-fetal toxicity risk; guide contraception counseling
Pregnancy exposure reporting	If pregnancy occurs during treatment, or within 7 months following the last dose	Report Trastuzumab exposure to Genentech (1-888-835-2555) for pharmacovigilance tracking
Infusion-related signs/symptoms (fever, chills, dyspnea, hypotension, rash, etc.)	During infusion and after administration as clinically indicated; symptoms usually occur during or within 24 hours	Detect infusion reactions; interrupt the infusion for dyspnea or clinically significant hypotension and monitor until symptoms completely resolve
Pulmonary signs/symptoms (dyspnea, interstitial pneumonitis, pulmonary infiltrates, ARDS, pulmonary fibrosis)	Throughout treatment, particularly in patients with symptomatic intrinsic lung disease or extensive pulmonary tumor involvement	Detect pulmonary toxicity, which can occur as a sequela of infusion reactions
Complete blood count / neutrophil count	During combination therapy with myelosuppressive chemotherapy	Detect exacerbation of chemotherapy-induced neutropenia or febrile neutropenia
Renal function	Particularly in metastatic gastric cancer patients with high tumor burden or other renal risk factors	Detect renal impairment/failure; not an explicit FDA-mandated schedule, but a reasonable clinical consideration based on ToGA trial data
Uric acid, phosphate, renal function	Particularly in patients with significant tumor burden (e.g., bulky metastases)	Detect possible tumor lysis syndrome

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	Not directly stated
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.
• 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 trastuzumab 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

• Trastuzumab 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 trastuzumab.
• 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 trastuzumab, 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).

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

Summary of Pivotal Trials

Summary of Pivotal Trials

Trial	Population	Regimen	Comparator	Primary outcome	Key result	Clinical relevance
NSABP B31 & NCCTG N9831	HER2-positive (IHC 3+ or FISH+) node-positive or high-risk node-negative breast cancer, post-surgery	AC → paclitaxel + Trastuzumab (52 weeks total Trastuzumab)	AC → paclitaxel alone	DFS, OS	DFS HR 0.48 (95% CI 0.39–0.59, p<0.0001); OS HR 0.64 (95% CI 0.55–0.74, p<0.0001) at 8.3-year median follow-up	Established the AC→paclitaxel+Trastuzumab adjuvant regimen; durable OS benefit maintained long-term
HERA	HER2-positive (IHC 3+ or FISH+) early breast cancer, post-surgery/chemotherapy/radiotherapy	Trastuzumab 8 mg/kg, then 6 mg/kg IV every 3 weeks, for 1 year	Observation	DFS	DFS HR 0.54 (95% CI 0.44–0.67, p<0.0001) at 12.6-month median follow-up. Extending to 2 years showed no added benefit over 1 year (DFS HR 0.99; OS HR 0.98)	Established 1-year duration as standard; confirmed no benefit to extending adjuvant Trastuzumab beyond 1 year
BCIRG006	HER2-positive (FISH+) node-positive or high-risk node-negative breast cancer	AC → docetaxel + Trastuzumab (AC-TH), or docetaxel + carboplatin + Trastuzumab (TCH)	AC → docetaxel alone (AC-T)	DFS	AC-TH: DFS HR 0.60 (95% CI 0.48–0.76, p<0.0001); TCH: DFS HR 0.67 (95% CI 0.54–0.84, p=0.0006)	Established both an anthracycline-containing (AC-TH) and an anthracycline-free (TCH) adjuvant option; TCH carries a lower cardiotoxicity risk
H0648g	HER2-overexpressing (CTA 2+ or 3+) metastatic breast cancer, no prior chemotherapy for metastatic disease	Chemotherapy (paclitaxel or AC) + Trastuzumab (4 mg/kg load, then 2 mg/kg weekly)	Chemotherapy alone	TTP, ORR, OS	TTP 7.2 vs. 4.5 months (p<0.0001); ORR 45% vs. 29% (p<0.001); OS 25.1 vs. 20.3 months (p=0.05)	Established first-line metastatic breast cancer indication in combination with paclitaxel; benefit concentrated in HER2 IHC 3+ tumors
H0649g	HER2-overexpressing (CTA 2+ or 3+) metastatic breast cancer, relapsed after 1–2 prior chemotherapy regimens	Trastuzumab single agent (4 mg/kg load, then 2 mg/kg weekly)	None (single-arm trial)	ORR	ORR 14% (2% CR, 12% PR); ORR 18% in CTA 3+ vs. 6% in CTA 2+	Established single-agent metastatic breast cancer indication after prior chemotherapy; reinforced IHC 3+ as the responsive subgroup
ToGA	HER2-positive (FISH+ or IHC 3+) metastatic gastric or GEJ adenocarcinoma, no prior treatment for metastatic disease	Cisplatin + fluoropyrimidine (capecitabine or 5-FU) + Trastuzumab (8 mg/kg load, then 6 mg/kg every 3 weeks)	Cisplatin + fluoropyrimidine alone	OS	OS 13.5 vs. 11.0 months, HR 0.73 (95% CI 0.60–0.91, p=0.0038) at interim analysis	Established first-line metastatic gastric/GEJ cancer indication; benefit concentrated in tumors with higher HER2 protein expression (IHC 2+/3+)

How Supplied

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

Storage

Herceptin Reference Product: 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

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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
• Hercessi
• Herzuma
• Kanjinti
• Ogivri
• Ontruzant
• Trazimera

Related Subcutaneous Formulation

• Herceptin Hylecta (trastuzumab and hyaluronidase-oysk) is a distinct subcutaneous formulation with different dosing and administration instructions; the IV preparation instructions on this page do not apply to that product.

Look-Alike Drug Names

Ado-trastuzumab emtansine (Kadcyla)

• Trastuzumab 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 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 trastuzumab also explicitly warns against substituting trastuzumab 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.