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Trastuzumab

Pronunciation

(tras TU zoo mab)

Index Terms

  • anti-c-erB-2
  • anti-ERB-2
  • Conventional Trastuzumab
  • MOAB HER2
  • rhuMAb HER2
  • Trastuzumab (Conventional)

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Reconstituted, Intravenous:

Herceptin: 440 mg (1 ea) [contains benzyl alcohol, mouse (murine) and/or hamster protein]

Brand Names: U.S.

  • Herceptin

Pharmacologic Category

  • Antineoplastic Agent, Anti-HER2
  • Antineoplastic Agent, Monoclonal Antibody

Pharmacology

Trastuzumab is a monoclonal antibody which binds to the extracellular domain of the human epidermal growth factor receptor 2 protein (HER-2); it mediates antibody-dependent cellular cytotoxicity by inhibiting proliferation of cells which overexpress HER-2 protein.

Use: Labeled Indications

Breast cancer, adjuvant treatment: Treatment (adjuvant) of human epidermal growth receptor 2 (HER2)-overexpressing node positive or node negative (estrogen receptor/progesterone receptor negative or with 1 high risk feature) breast cancer as part of a treatment regimen consisting of doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel; with docetaxel and carboplatin; or as a single agent following multimodality anthracycline-based therapy.

Breast cancer, metastatic: First-line treatment of HER2-overexpressing metastatic breast cancer (in combination with paclitaxel); single agent treatment of HER2-overexpressing breast cancer in patients who have received 1 or more chemotherapy regimens for metastatic disease.

Gastric cancer, metastatic: Treatment of HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma (in combination with cisplatin and either capecitabine or 5-fluorouracil) in patients who have not received prior treatment for metastatic disease.

Use: Unlabeled

Neoadjuvant treatment for locally advanced, inflammatory, or early stage breast cancer (in combination with pertuzumab and docetaxel) in patients who have not received any prior chemotherapy; treatment of HER2-positive metastatic breast cancer (in combination with pertuzumab and docetaxel) in patients who have not received prior anti-HER2 therapy or chemotherapy to treat metastatic disease; treatment of HER2 overexpressing metastatic breast cancer (in combination with lapatinib) which had progressed on prior trastuzumab containing therapy.

Contraindications

There are no contraindications listed in the manufacturer’s US labeling.

Canadian labeling: Hypersensitivity to trastuzumab, Chinese hamster ovary (CHO) cell proteins, or any component of the formulation

Dosing: Adult

Note: Do NOT substitute conventional trastuzumab for or with ado-trastuzumab emtansine; products are different and are NOT interchangeable. Details concerning dosing in combination regimens should also be consulted.

Breast cancer, adjuvant treatment, HER2+: IV: Note: Extending adjuvant treatment beyond 1 year is not recommended

With concurrent paclitaxel or docetaxel:

Initial loading dose: 4 mg/kg infused over 90 minutes, followed by

Maintenance dose: 2 mg/kg infused over 30 minutes weekly for total of 12 weeks, followed 1 week later (when concurrent chemotherapy completed) by 6 mg/kg infused over 30 to 90 minutes every 3 weeks for total therapy duration of 52 weeks

With concurrent docetaxel/carboplatin:

Initial loading dose: 4 mg/kg infused over 90 minutes, followed by

Maintenance dose: 2 mg/kg infused over 30 minutes weekly for total of 18 weeks, followed 1 week later (when concurrent chemotherapy completed) by 6 mg/kg infused over 30 to 90 minutes every 3 weeks for total therapy duration of 52 weeks

Following completion of multi-modality anthracycline-based chemotherapy:

Initial loading dose: 8 mg/kg infused over 90 minutes, followed by

Maintenance dose: 6 mg/kg infused over 30 to 90 minutes every 3 weeks for total therapy duration of 52 weeks

Breast cancer, metastatic, HER2+ (either as a single agent or in combination with paclitaxel): IV:

Initial loading dose: 4 mg/kg infused over 90 minutes, followed by

Maintenance dose: 2 mg/kg infused over 30 minutes weekly until disease progression

Gastric cancer, metastatic, HER2+ (in combination with cisplatin and either capecitabine or fluorouracil for 6 cycles followed by trastuzumab monotherapy; Bang, 2010): IV:

Initial loading dose: 8 mg/kg infused over 90 minutes, followed by

Maintenance dose: 6 mg/kg infused over 30 to 90 minutes every 3 weeks until disease progression

Missed doses: If a dose is missed by ≤1 week, the usual maintenance dose should be administered as soon as possible (do not wait until the next planned cycle) and subsequent maintenance doses should be administered 7 or 21 days later (based on patient’s maintenance dose/schedule); if a dose is missed by >1 week, then a re-loading dose (4 mg/kg if patient receives trastuzumab weekly; 8 mg/kg if on an every-3-week schedule) should be administered, followed by the usual maintenance dose administered 7 or 21 days later (based on patient’s maintenance dose/schedule).

Breast cancer (early stage, locally advanced, or inflammatory), neoadjuvant treatment, HER2+ (off-label use): IV: Trastuzumab, pertuzumab, and docetaxel (in patients with operable disease who had received no prior chemotherapy): Initial: 8 mg/kg (cycle 1) followed by 6 mg/kg every 3 weeks for a total of 4 neoadjuvant cycles; postoperatively, administer 3 cycles of adjuvant FEC [fluorouracil, epirubicin, and cyclophosphamide] chemotherapy and continue trastuzumab to complete 1 year of treatment (Gianni, 2012)

Breast cancer, metastatic, HER2+ (off-label combinations): IV: Note: There are multiple trastuzumab-containing regimens for the treatment of HER2+ metastatic breast cancer; commonly used regimens are listed below:

Trastuzumab, pertuzumab, and docetaxel (in patients with no prior anti-HER2 therapy or chemotherapy to treat metastatic disease): Initial: 8 mg/kg followed by a maintenance dose of 6 mg/kg every 3 weeks until disease progression or unacceptable toxicity (Baselga, 2012)

Trastuzumab, pertuzumab, and weekly paclitaxel: Initial: 8 mg/kg followed by a maintenance dose of 6 mg/kg every 3 weeks until disease progression (Dang, 2015)

Trastuzumab and lapatinib (in patients with progression on prior trastuzumab containing therapy): Initial: 4 mg/kg followed by a maintenance dose of 2 mg/kg every week (Blackwell, 2010; Blackwell, 2012)

Other trastuzumab combinations: Initial: 8 mg/kg followed by a maintenance dose of 6 mg/kg every 3 weeks until disease progression or unacceptable toxicity (in combination with docetaxel or vinorelbine) (Andersson, 2011) or 4 mg/kg loading dose followed by a maintenance dose of 2 mg/kg weekly until disease progression (in combination with docetaxel) (Marty, 2005)

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer’s labeling, although data suggest that the disposition of trastuzumab is not altered based on serum creatinine (up to 2 mg/dL)

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling.

Dosing: Adjustment for Toxicity

Cardiotoxicity: LVEF ≥16% decrease from baseline or LVEF below normal limits and ≥10% decrease from baseline: Withhold treatment for at least 4 weeks and repeat LVEF every 4 weeks. May resume trastuzumab treatment if LVEF returns to normal limits within 4 to 8 weeks and remains at ≤15% decrease from baseline value. Discontinue permanently for persistent (>8 weeks) LVEF decline or for >3 incidents of treatment interruptions for cardiomyopathy.

Infusion-related events:

Mild-moderate infusion reactions: Decrease infusion rate.

Dyspnea, clinically significant hypotension: Interrupt infusion.

Severe or life-threatening infusion reactions: Discontinue.

Reconstitution

Hazardous agent; use appropriate precautions for handling and disposal (meets NIOSH 2014 criteria). Check vial labels to assure appropriate product is being reconstituted (conventional trastuzumab and ado-trastuzumab emtansine are different products and are NOT interchangeable).

Reconstitute each vial with 20 mL of bacteriostatic sterile water for injection to a concentration of 21 mg/mL. Swirl gently; do not shake. Allow vial to rest for ~5 minutes. If the patient has a known hypersensitivity to benzyl alcohol, trastuzumab may be reconstituted with sterile water for injection without preservatives, which must be used immediately. Further dilute the appropriate volume for the trastuzumab dose in 250 mL NS prior to administration. Gently invert bag to mix.

Administration

Check label to ensure appropriate product is being administered (conventional trastuzumab and ado-trastuzumab emtansine are different products and are NOT interchangeable).

Administered by IV infusion; loading doses are infused over 90 minutes; maintenance doses may be infused over 30 minutes if tolerated. Do not administer with D5W. Do not administer IV push or by rapid bolus. Do not mix with any other medications.

Observe patients closely during the infusion for fever, chills, or other infusion-related symptoms. Treatment with acetaminophen, diphenhydramine, and/or meperidine is usually effective for managing infusion-related events.

Hazardous agent; use appropriate precautions for handling and disposal (meets NIOSH 2014 criteria).

Compatibility

Stable in NS; incompatible with D5W.

Storage

Prior to reconstitution, store intact vials under refrigeration at 2°C to 8°C (36°F to 46°F). Following reconstitution with bacteriostatic SWFI, the solution in the vial is stable refrigerated for 28 days from the date of reconstitution; do not freeze. Solutions reconstituted with sterile water for injection without preservatives must be used immediately. The solution diluted in 250 mL NS for infusion may be stored refrigerated for up to 24 hours prior to use; do not freeze.

Drug Interactions

Antineoplastic Agents (Anthracycline, Systemic): Trastuzumab may enhance the cardiotoxic effect of Antineoplastic Agents (Anthracycline, Systemic). Management: When possible, patients treated with trastuzumab should avoid anthracycline-based therapy for up to 7 months after stopping trastuzumab. Monitor closely for cardiac dysfunction in patients receiving anthracyclines with trastuzumab. Consider therapy modification

Belimumab: Monoclonal Antibodies may enhance the adverse/toxic effect of Belimumab. Avoid combination

Immunosuppressants: Trastuzumab may enhance the neutropenic effect of Immunosuppressants. Exceptions: Cytarabine (Liposomal). Monitor therapy

PACLitaxel (Conventional): Trastuzumab may decrease the serum concentration of PACLitaxel (Conventional). PACLitaxel (Conventional) may increase the serum concentration of Trastuzumab. Monitor therapy

Adverse Reactions

Note: Percentages reported with single-agent therapy.

>10%:

Cardiovascular: Decreased left ventricular ejection fraction (4% to 22%)

Central nervous system: Pain (47%), chills (5% to 32%), headache (10% to 26%), insomnia (14%), dizziness (4% to 13%)

Dermatologic: Skin rash (4% to 18%)

Gastrointestinal: Nausea (6% to 33%), diarrhea (7% to 25%), vomiting (4% to 23%), abdominal pain (2% to 22%), anorexia (14%)

Infection: Infection (20%)

Neuromuscular & skeletal: Weakness (4% to 42%), back pain (5% to 22%)

Respiratory: Cough (5% to 26%), dyspnea (3% to 22%), rhinitis (2% to 14%), pharyngitis (12%)

Miscellaneous: Infusion related reaction (21% to 40%, chills and fever most common; severe: 1%), fever (6% to 36%)

1% to 10%:

Cardiovascular: Peripheral edema (5% to 10%), edema (8%), cardiac failure (2% to 7%; severe: <1%), tachycardia (5%), hypertension (4%), arrhythmia (3%), palpitations (3%)

Central nervous system: Paresthesia (2% to 9%), depression (6%), peripheral neuritis (2%), neuropathy (1%)

Dermatologic: Acne vulgaris (2%), nail disease (2%), pruritus (2%)

Gastrointestinal: Constipation (2%), dyspepsia (2%)

Genitourinary: Urinary tract infection (3% to 5%)

Hematologic & oncologic: Anemia (4%; grade 3: <1%), leukopenia (3%)

Hypersensitivity: Hypersensitivity reaction (3%)

Infection: Influenza (4%), herpes simplex infection (2%)

Neuromuscular & skeletal: Arthralgia (6% to 8%), ostealgia (3% to 7%), myalgia (4%), muscle spasm (3%)

Respiratory: Flu-like symptoms (2% to 10%), sinusitis (2% to 9%), nasopharyngitis (8%), upper respiratory tract infection (3%), epistaxis (2%), pharyngolaryngeal pain (2%)

Miscellaneous: Accidental injury (6%)

<1% (Limited to important or life-threatening; as a single-agent or with combination chemotherapy): Adult respiratory distress syndrome, amblyopia, anaphylaxis, apnea, ascites, asthma, ataxia, blood coagulation disorder, bronchitis, cardiogenic shock, cardiomyopathy, cellulitis, cerebrovascular accident, colitis, coma, confusion, deafness, dermal ulcer, erysipelas, esophageal ulcer, febrile neutropenia, gastroenteritis, glomerulopathy, hematemesis, hemorrhage, hemorrhagic cystitis, hepatic failure, hepatitis, herpes zoster, hydrocephalus, hydronephrosis, hypercalcemia, hypotension, hypothyroidism, hypoxia, intestinal obstruction, interstitial pneumonitis, leukemia (acute), lymphangitis, madarosis, mania, meningitis, myopathy, neutropenia, neutropenic sepsis, oligohydramnios, onychoclasis, osteonecrosis, pancreatitis, pancytopenia, paresis, paroxysmal nocturnal dyspnea, pathological fracture, pericardial effusion, pleural effusion, pneumonitis, pneumothorax, pulmonary edema (noncardiogenic), pulmonary fibrosis, pulmonary hypertension, pyelonephritis, radiation injury, renal failure, respiratory failure, seizure, sepsis, syncope, stomatitis, thyroiditis (autoimmune), ventricular dysfunction

ALERT: U.S. Boxed Warning

Cardiomyopathy:

Trastuzumab can result in subclinical and clinical cardiac failure. The incidence and severity was highest in patients who received trastuzumab concurrently with anthracycline-containing chemotherapy regimens.

Evaluate left ventricular function in all patients prior to and during treatment with trastuzumab. Discontinue trastuzumab treatment in patients receiving adjuvant therapy, and withhold trastuzumab treatment in patients with metastatic disease for clinically significant decrease in left ventricular function.

Infusion reactions and pulmonary toxicity:

Trastuzumab administration can result in serious and fatal infusion reactions and pulmonary toxicity. Symptoms usually occur during or within 24 hours of administration of trastuzumab. Interrupt trastuzumab infusion for patients experiencing dyspnea or clinically significant hypotension. Monitor patients until signs and symptoms resolve completely. Discontinue trastuzumab for anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome.

Pregnancy:

Exposure to trastuzumab during pregnancy can result in oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death.

Warnings/Precautions

Concerns related to adverse effects:

• Cardiomyopathy: [US Boxed Warning]: Trastuzumab is associated with symptomatic and asymptomatic reductions in left ventricular ejection fraction (LVEF) and heart failure (HF); the incidence is highest in patients receiving trastuzumab with an anthracycline-containing chemotherapy regimen. Evaluate LVEF in all patients prior to and during treatment; discontinue for cardiomyopathy. Extreme caution should be used in patients with pre-existing cardiac disease or dysfunction. Prior or concurrent exposure to anthracyclines or radiation therapy significantly increases the risk of cardiomyopathy; other potential risk factors include advanced age, high or low body mass index, smoking, diabetes, hypertension, and hyper-/hypothyroidism. Patients who receive anthracyclines after completion or discontinuation of trastuzumab are at increased risk of cardiac dysfunction (anthracyclines should be avoided for at least 7 months after the last trastuzumab dose, and then monitor cardiac function closely if anthracyclines are used. Discontinuation should be strongly considered in patients who develop a clinically significant reduction in LVEF during therapy; treatment with HF medications (eg, ACE inhibitors, beta-blockers) should be initiated. Withhold treatment for ≥16% decrease from pretreatment levels or LVEF below normal limits and ≥10% decrease from baseline (see Dosage Adjustment for Cardiotoxicity). Cardiomyopathy due to trastuzumab is generally reversible over a period of 1 to 3 months after discontinuation. Long-term (8 years) follow-up in the adjuvant setting (trastuzumab for 1 or 2 years administered sequentially following chemotherapy and radiation therapy) has demonstrated a low incidence of cardiac events, which were generally reversible in most patients (de Azambuja, 2014). Trastuzumab is also associated with arrhythmias, hypertension, mural thrombus formation, stroke, and even cardiac death.

• Infusion reactions: [US Boxed Warning]: Infusion reactions (including fatalities) have been associated with use; discontinue for anaphylaxis or angioedema. Most reactions occur during or within 24 hours of the first infusion; interrupt infusion for dyspnea or significant hypotension; monitor until symptoms resolve. Infusion reactions may consist of fever and chills, and may also include nausea, vomiting, pain, headache, dizziness, dyspnea, hypotension, rash, and weakness. Re-treatment of patients who experienced severe hypersensitivity reactions has been attempted (with premedication). Some patients tolerated re-treatment, while others experienced a second severe reaction.

• Pulmonary toxicity: [US Boxed Warning]: May cause serious pulmonary toxicity (dyspnea, hypoxia, interstitial pneumonitis, pulmonary infiltrates, pleural effusion, noncardiogenic pulmonary edema, pulmonary insufficiency, acute respiratory distress syndrome [ARDS], and/or pulmonary fibrosis); discontinue for ARDS or interstitial pneumonitis. Use caution in patients with pre-existing pulmonary disease or patients with extensive pulmonary tumor involvement; these patient populations may have more severe toxicity. Pulmonary events may occur during or within 24 hours of administration; delayed reactions have occurred.

• Renal toxicity: Rare cases of nephrotic syndrome with evidence of glomerulopathy have been reported, with an onset of 4-18 months from trastuzumab initiation; complications may include volume overload and HF. The incidence of renal impairment was increased in metastatic gastric cancer patients when trastuzumab is added to chemotherapy.

Concurrent drug therapy issues:

• Chemotherapy: When used in combination with myelosuppressive chemotherapy, trastuzumab may increase the incidence of neutropenia (moderate-to-severe) and febrile neutropenia. The incidence of anemia may be higher when trastuzumab is added to chemotherapy.

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Pregnancy: [US Boxed Warning]: Trastuzumab exposure during pregnancy may result in oligohydramnios and oligohydramnios sequence (pulmonary hypoplasia, skeletal malformations and neonatal death). Effective contraception is recommended in women of childbearing potential during treatment and for at least 7 months after the last trastuzumab dose.

Dosage form specific issues:

• Do not interchange: Conventional trastuzumab and ado-trastuzumab emtansine are not interchangeable. Verify product label prior to reconstitution and administration to prevent medication errors. Dosing and treatment schedules between conventional trastuzumab (Herceptin) and ado-trastuzumab emtansine (Kadcyla) are different; confusion between the products may potentially cause harm to the patient.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (meets NIOSH 2014 criteria).

Other warnings/precautions:

• HER2 expression: Establish HER2 status prior to treatment; has only been studied in patients with evidence of HER2 protein overexpression, either by validated immunohistochemistry (IHC) assay or fluorescence in situ hybridization (FISH) assay. Tests appropriate for the specific tumor type (breast or gastric) should be used to assess HER2 status.

Monitoring Parameters

Assessment for HER2 overexpression and HER2 gene amplification by validated immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH) methodology (pretherapy); test should be specific for cancer type (breast vs gastric cancer). Pregnancy test (prior to treatment). Monitor vital signs during infusion; signs and symptoms of cardiac dysfunction; LVEF (baseline, every 3 months during treatment, upon therapy completion and if component of adjuvant therapy, every 6 months for at least 2 years; if treatment is withheld for significant LVEF dysfunction, monitor LVEF at 4-week intervals); signs and symptoms of infusion reaction or pulmonary toxicity; if pregnancy inadvertently occurs during treatment, monitor amniotic fluid volume

Pregnancy Risk Factor

D

Pregnancy Considerations

Trastuzumab inhibits HER2 protein, which has a role in embryonic development. [US Boxed Warning]: Trastuzumab exposure during pregnancy may result in oligohydramnios and oligohydramnios sequence (pulmonary hypoplasia, skeletal malformations and neonatal death). Oligohydramnios (reversible in some cases) has been reported with trastuzumab use alone or with combination chemotherapy. If trastuzumab exposure occurs during pregnancy, monitor for oligohydramnios. Women of reproductive potential should use effective contraception during treatment and for at least 7 months after the last trastuzumab dose. If trastuzumab is administered during pregnancy, or if a patient becomes pregnant during or within 7 months after treatment, report exposure to Genentech Adverse Events at 1-888-835-2555. Women exposed to trastuzumab during pregnancy (or within 7 months of conception) are encouraged to enroll in MotHER (the Herceptin Pregnancy Registry; 1-800-690-6720).

European Society for Medical Oncology (ESMO) guidelines for cancer during pregnancy recommend delaying treatment with trastuzumab (and other HER-2 targeted agents) until after delivery in pregnant patients with HER-2 positive disease (Peccatori 2013).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience flu-like symptoms, lack of appetite, abdominal pain, bone pain, joint pain, back pain, insomnia, rhinitis, rhinorrhea, or pharyngitis. Have patient report immediately to prescriber signs of a severe pulmonary disorder (lung or breathing problems like trouble breathing, shortness of breath, or a cough that is new or worse), signs of infection, signs of kidney problems (urinary retention, blood in urine, change in amount of urine passed, or weight gain), angina, tachycardia, shortness of breath, excessive weight gain, swelling of arms or legs, severe dizziness, passing out, severe headache, severe nausea, vomiting, severe diarrhea, bruising, bleeding, loss of strength and energy, burning or numbness feeling, injection site irritation, depression, muscle pain, or muscle cramps (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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