Trastuzumab

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Solution Reconstituted, Intravenous:

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

Ogivri: 420 mg (1 ea) [contains polyethylene glycol]

Solution Reconstituted, Intravenous [preservative free]:

Herceptin: 150 mg (1 ea)

Kanjinti: Trastuzumab-anns 150 mg (1 ea); Trastuzumab-anns 420 mg (1 ea)

Ogivri: 420 mg (1 ea); Trastuzumab-dkst 150 mg (1 ea) [contains polyethylene glycol]

Pharmacology

Mechanism of Action

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.

Pharmacokinetics/Pharmacodynamics

Excretion

In most patients, trastuzumab concentrations will decrease to ~3% (~97% washout) by 7 months following discontinuation.

Clearance: Every week dosing: 0.201 to 0.244 L/day; Every 3 week dosing: 0.173 to 0.337 L/day (Quartino 2018).

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; as part of a treatment regimen 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.

Limitations of use: Patients should be selected for breast and gastric cancer therapy based on an approved companion diagnostic test for tumor specimen for HER2 overexpression or HER2 gene amplification. Due to differences in disease histopathology (eg, incomplete membrane staining, more frequent heterogeneous HER2 expression in gastric cancer), tests appropriate for the specific tumor type (breast or gastric) should be used to assess HER2 status.

Note: Kanjinti (trastuzumab-anns) and Ogivri (trastuzumab-dkst) are approved as biosimilars to Herceptin (trastuzumab).

Use: Off Label

Breast cancer, locally advanced, inflammatory or early, human epidermal growth receptor 2 (HER2)-positive (neoadjuvant treatment)a

Data from a large randomized phase II study support the use of trastuzumab in combination with pertuzumab and docetaxel in the neoadjuvant management of HER2-positive locally advanced, inflammatory or early breast cancer Gianni 2012.

Breast cancer, metastatic, HER2-positive (in combination with pertuzumab and docetaxel) in patients who have not received prior anti-HER2 therapy or chemotherapy to treat metastatic diseaseayes

Data from a large, randomized, controlled phase III study support the use of trastuzumab in combination with pertuzumab and docetaxel in the management of metastatic breast cancer Baselga 2012.

Based on the American Society of Clinical Oncology (ASCO), Systemic Therapy for Patients with Advanced HER2-Positive Breast Cancer guidelines, trastuzumab in combination with pertuzumab and a taxane is recommended as first-line treatment, unless there are contraindications to taxanes.

Breast cancer, metastatic, HER2-positive (in combination with pertuzumab and weekly paclitaxel)byes

Data from a small phase II study support the use of trastuzumab in combination with pertuzumab and weekly paclitaxel in the management of metastatic breast cancer Dang 2015. Based on the ASCO, Systemic Therapy for Patients with Advanced HER2-Positive Breast Cancer guidelines, trastuzumab in combination with pertuzumab and a taxane is recommended as first-line treatment, unless there are contraindications to taxanes; paclitaxel is a reasonable alternative in patients who are not good candidates for docetaxel Giordano 2014.

Breast cancer, metastatic, HER2-positive (in combination with either docetaxel or vinorelbine)a

Data from a large phase III study support the use of trastuzumab (in combination with either docetaxel or vinorelbine) for the treatment of metastatic or locally advanced HER2-positive breast cancer Andersson 2011. Additionally, a large randomized phase II trial supports the combination of trastuzumab and docetaxel for the management of metastatic HER2-positive disease Marty 2005.

Breast cancer, metastatic, HER2-positive, hormone receptor-positive (in combination with an aromatase inhibitor)ayes

Data from a phase III study support the use of trastuzumab in combination with an aromatase inhibitor (but without concurrent chemotherapy) in the treatment of postmenopausal patients with HER2-positive, hormone receptor-positive metastatic breast cancer Kaufman 2009; in some patients who experience clinical benefit, the combination of trastuzumab and an aromatase inhibitor may help to delay chemotherapy.

Guidelines from the ASCO for endocrine therapy in hormone receptor-positive metastatic breast cancer recommend adding HER2-directed therapy to first-line aromatase inhibitor therapy in patients with HR-positive, HER2-positive metastatic breast cancer where chemotherapy is not immediately indicated.

Breast cancer, metastatic, HER2-positive (in combination with lapatinib) which had progressed on prior trastuzumab containing therapyayes

Data from a phase III randomized controlled study support the use of trastuzumab in combination with lapatinib in the management of metastatic breast cancer which has progressed on prior trastuzumab therapy Blackwell 2012.

Based on the ASCO, Systemic Therapy for Patients with Advanced HER2-Positive Breast Cancer guidelines, trastuzumab in combination with lapatinib is a third-line treatment option in patients whose disease has progressed during or after second line or greater HER2-targeted therapy.

Endometrial cancer (uterine serous), advanced or recurrent, HER2-positiveb

Data from a small randomized, controlled phase II study support the use of trastuzumab (when used in combination with paclitaxel and carboplatin) for the treatment of advanced (stage III or IV) or recurrent, HER2-positive serous endometrial cancer Fader 2018.

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

Dosage and Administration

Dosing: Adult

Note: Do NOT substitute conventional trastuzumab products for or with ado-trastuzumab emtansine, fam-trastuzumab deruxtecan, or trastuzumab/hyaluronidase; products are different and are NOT interchangeable. Kanjinti (trastuzumab-anns) and Ogivri (trastuzumab-dkst) are approved as biosimilars to Herceptin.

Breast cancer, adjuvant treatment, human epidermal growth receptor 2-positive (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 multimodality 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

Duration of therapy: The standard duration of adjuvant trastuzumab therapy in early breast cancer is 1 year (52 weeks); however, for patients unable to tolerate 1 year of trastuzumab, a noninferiority study comparing 12 months versus 6 months of adjuvant trastuzumab therapy in early breast cancer suggests disease-free survival may not be inferior with a 6-month duration (Earl 2018).

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+ (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

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).

Trastuzumab and an aromatase inhibitor: Initial: 4 mg/kg followed by a maintenance dose of 2 mg/kg every week (in combination with anastrozole); continue until disease progression (Kaufman 2009).

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).

Endometrial cancer (uterine serous), advanced or recurrent, HER2-positive (off-label use): IV: Initial: 8 mg/kg (cycle 1) followed by a maintenance dose of 6 mg/kg every 3 weeks (in combination with carboplatin and paclitaxel for ~6 cycles), followed by trastuzumab maintenance of 6 mg/kg every 3 weeks until disease progression or unacceptable toxicity (Fader 2018).

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: A dose delay >1 week would require ~6 weeks to return to steady state range; if a maintenance dose is missed by >1 week, a reloading dose is required (Quartino 2018). If a dose is missed by 1 week or less, the usual maintenance dose (2 mg/kg weekly schedule or 6 mg/kg every 3 week schedule) 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 more than 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 (over 90 minutes) as soon as possible, followed by the usual maintenance dose administered 7 or 21 days later (based on patient's maintenance dose/schedule).

Dosing: Geriatric

Refer to adult dosing.

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 or clinically significant hypotension: Interrupt infusion

Severe or life-threatening infusion reactions: Discontinue trastuzumab

Reconstitution

Check vial labels to ensure appropriate product is being reconstituted (conventional trastuzumab products and ado-trastuzumab emtansine, fam-trastuzumab deruxtecan, or trastuzumab/hyaluronidase are different products and are NOT interchangeable).

Reconstitute each 150 mg vial (single use vial) with 7.4 mL of SWFI. Reconstitute each 420 mg vial (multidose vial) with 20 mL of bacteriostatic sterile water for injection (SWFI may be used if a patient has a known hypersensitivity to benzyl alcohol). Direct the stream of diluent into the lyophilized powder (which has a cake-like appearance). The reconstituted solutions (in the vial) will have a concentration of 21 mg/mL. Swirl vial gently to mix; do not shake. Slight foaming may occur during reconstitution. Allow vial to rest undisturbed for ~5 minutes. Prior to administration, further dilute the appropriate volume for the trastuzumab dose in polyvinylchloride or polyethylene bags containing 250 mL NS; do not use D5W. Gently invert bag to mix; do not shake. Do not mix trastuzumab products with other medications.

440 mg vial [Canadian product]: Reconstitute each 440 mg vial with 20 mL bacteriostatic sterile water for injection (SWFI may be used if a patient has a known hypersensitivity to benzyl alcohol) to a concentration of 21 mg/mL, then follow above for further instructions.

Administration

IV: Check label to ensure appropriate product is being administered (conventional trastuzumab products and ado-trastuzumab emtansine, fam-trastuzumab deruxtecan, or trastuzumab/hyaluronidase 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.

Storage

Storage time varies by product; refer to individual product labeling for details. Prior to reconstitution, store intact vials at 2°C to 8°C (36°F to 46°F). Some products recommend storing intact vials in the original carton to protect from light. Solutions reconstituted with SWFI without preservatives should be used immediately; however, reconstituted trastuzumab vials may be stored for up to 4 or 24 hours (depending on product and/or vial size) at 2°C to 8°C (36°F to 46°F); do not freeze. Discard after 4 or 24 hours (depending on product and/or vial size). Following reconstitution with bacteriostatic SWFI, the solution in the 420 mg (multidose) vial is stable refrigerated for 28 days from the date of reconstitution; do not freeze. The solution diluted for infusion in polyvinylchloride or polyethylene bags containing 250 mL NS may be stored refrigerated for up to 4 or 24 hours (depending on product) prior to use; do not freeze.

Drug Interactions

Anthracyclines: Trastuzumab may enhance the cardiotoxic effect of Anthracyclines. 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

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

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%, postmarketing, and/or case reports (as a single-agent or with combination chemotherapy): Abnormality in thinking, adult respiratory distress syndrome, amblyopia, anaphylactic shock, anaphylactoid reaction, anaphylaxis, angioedema, apnea, ascites, asthma, ataxia, blood coagulation disorder, bradycardia, bronchitis, bronchospasm, cardiogenic shock, cardiomyopathy, cellulitis, cerebral edema, cerebrovascular accident, cerebrovascular disease, chest discomfort, colitis, coma, confusion, cystitis, deafness, dermal ulcer, dermatitis, dyspnea on exertion, dysuria, erysipelas, esophageal ulcer, febrile neutropenia, focal segmental glomerulosclerosis, gastritis, gastroenteritis, glomerulonephritis (membraneous, focal and fibrillary), glomerulopathy, hematemesis, hemorrhage, hemorrhagic cystitis, hepatic failure, hepatic injury, hepatitis, herpes zoster, hiccups, hydrocephalus, hydronephrosis, hypercalcemia, hypervolemia, hypoprothrombinemia, hypotension, hypothyroidism, hypoxia, immune thrombocytopenia, intestinal obstruction, interstitial pneumonitis, interstitial pulmonary disease, jaundice, laryngeal edema, laryngitis, lethargy, leukemia (acute), limb pain, lymphangitis, madarosis, mania, mastalgia, meningitis, musculoskeletal pain, myopathy, nephrotic syndrome, neutropenia, neutropenic sepsis, oligohydramnios, onychoclasis, osteonecrosis, oxygen desaturation, pancreatitis, pancytopenia, paresis, paroxysmal nocturnal dyspnea, pathological fracture, pericardial effusion, pericarditis, pleural effusion, pneumonitis, pneumothorax, pulmonary edema (noncardiogenic), pulmonary fibrosis, pulmonary hypertension, pulmonary infiltrates, pyelonephritis, radiation injury, renal failure, respiratory distress, respiratory failure, seizure, sepsis, shock, syncope, stomatitis, thrombosis (including mural), thyroiditis (autoimmune), urticaria, vertigo, ventricular dysfunction, wheezing

Warnings/Precautions

Concerns related to adverse effects:

• Cardiomyopathy: [US Boxed Warning]: Trastuzumab products are associated with symptomatic and asymptomatic reductions in left ventricular ejection fraction (LVEF) and heart failure; 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 heart failure 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.

ASCO has developed guidelines for prevention and monitoring of cardiac dysfunction in adult survivors of cancer (ASCO [Armenian 2017]). According to the guidelines, the risk of cardiac dysfunction related to trastuzumab is increased with the following:

- Trastuzumab alone AND any of the following risk factors: Multiple cardiovascular risk factors (≥2 risk factors), including smoking, hypertension, diabetes, dyslipidemia, and obesity (during or after completion of therapy), or older age (≥60 years of age) at cancer treatment, or compromised cardiac function (eg, borderline low LVEF [50% to 55%], history of myocardial infarction, moderate or higher valvular heart disease) before or during treatment.

- Treatment with lower-dose anthracycline (eg, doxorubicin <250 mg/m², epirubicin <600 mg/m²) followed by trastuzumab (sequential therapy)

The ASCO guidelines recommend a comprehensive assessment in patients with cancer that includes a history and physical examination, screening for cardiovascular disease risk factors such as hypertension, diabetes, dyslipidemia, obesity, and smoking. An echocardiogram should be obtained prior to initiating potentially cardiotoxic therapies. Modifiable risk factors (smoking, hypertension, diabetes, dyslipidemia, obesity) should be actively managed before initiating potentially cardiotoxic therapies. In patients who develop signs/symptoms of cardiac dysfunction during therapy, in addition to the above LVEF monitoring recommendations, an echocardiogram is recommended for diagnostic workup; if echocardiogram is not available or feasible, a cardiac MRI (preferred) or MUGA scan may be utilized. Serum cardiac biomarkers are recommended, along with referral to a cardiologist if indicated. Routine echocardiographic surveillance may be utilized in patients with metastatic breast cancer receiving trastuzumab indefinitely.

• Infusion reactions: [US Boxed Warning]: Infusion reactions (including fatalities) have been associated with trastuzumab products; 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 to 18 months from trastuzumab initiation; complications may include volume overload and heart failure. 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). Advise patients of these risks and the need for effective contraception. 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 products and ado-trastuzumab emtansine or trastuzumab/hyaluronidase are not interchangeable. Verify product label prior to reconstitution and administration to prevent medication errors. Dosing and treatment schedules between conventional trastuzumab (Herceptin and trastuzumab biosimilars) and ado-trastuzumab emtansine (Kadcyla), fam-trastuzumab deruxtecan (Enhertu), or trastuzumab/hyaluronidase are different; confusion between the products may potentially cause harm to the patient.

Other warnings/precautions:

• HER2 expression: Establish human epidermal growth receptor 2 (HER2) status prior to treatment with an approved test, either HER2 protein overexpression by validated immunohistochemistry assay or gene amplification by fluorescence in situ hybridization assay. Due to differences in disease histopathology (eg, incomplete membrane staining and more frequent heterogeneous HER2 expression in gastric cancer), tests appropriate for the specific tumor type (breast or gastric) should be used to assess HER2 status. Unreliable results may occur from improper assay performance, such as use of suboptimally fixed tissue, failure to utilize specified reagents or to include appropriate controls for assay validation, or incorrectly following specific assay instructions. Information regarding HER2 diagnostic testing may be found at http://www.fda.gov/CompanionDiagnostics.

Monitoring Parameters

Assessment for human epidermal growth receptor 2 (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 in women of reproductive potential). 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

Additional cardiovascular monitoring (ASCO [Armenian 2017]): Comprehensive assessment prior to treatment including a history and physical examination, screening for cardiovascular disease risk factors such as hypertension, diabetes, dyslipidemia, obesity, and smoking. In patients who develop signs/symptoms of cardiac dysfunction during therapy, an echocardiogram is recommended for diagnostic workup; if echocardiogram is not available or feasible, a cardiac MRI (preferred) or MUGA scan may be utilized; obtain serum cardiac biomarkers. Routine echocardiographic surveillance may be utilized in patients with metastatic breast cancer receiving trastuzumab indefinitely.

Pregnancy

Pregnancy Considerations

Trastuzumab inhibits human epidermal growth receptor 2 (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). Advise patients of these risks and the need for effective contraception. Oligohydramnios (reversible in some cases) has been reported with trastuzumab use alone or with combination chemotherapy. Monitor for oligohydramnios if trastuzumab exposure occurs during pregnancy or within 7 months prior to conception; conduct appropriate fetal testing if oligohydramnios occurs. Verify pregnancy status in females of reproductive potential prior to initiation of therapy. Females of reproductive potential should use effective contraception during treatment and for at least 7 months after the last trastuzumab dose.

Herceptin: If Herceptin 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.

European Society for Medical Oncology guidelines for cancer during pregnancy recommend delaying treatment with trastuzumab (and other HER2-targeted agents) until after delivery in pregnant patients with HER2-positive disease (Peccatori 2013).

Patient Education

What is this drug used for?

• It is used to treat breast cancer and stomach cancer. It may be given to you for other reasons. Talk with the doctor.

Frequently reported side effects of this drug

• Flu-like symptoms
• Diarrhea
• Nausea
• Vomiting
• Lack of appetite
• Abdominal pain
• Weight loss
• Change in taste
• Bone pain
• Joint pain
• Back pain
• Trouble sleeping
• Common cold symptoms
• Sore throat
• Stuffy nose
• Muscle pain
• Mouth irritation
• Mouth sores

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Infusion reaction
• Severe pulmonary disorder like lung or breathing problems like difficulty breathing, shortness of breath, or a cough that is new or worse
• Infection
• Heart problems like cough or shortness of breath that is new or worse, swelling of the ankles or legs, abnormal heartbeat, weight gain of more than five pounds in 24 hours, dizziness, or passing out
• Dizziness
• Passing out
• Vision changes
• Severe headache
• Bruising
• Bleeding
• Severe loss of strength and energy
• Burning or numbness feeling
• Depression
• Signs of a significant reaction like 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. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.