Trastuzumab

Trastuzumab products are 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-

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.

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.

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 HF. The incidence of renal impairment was increased in metastatic gastric cancer patients when trastuzumab is added to chemotherapy. Concurrent drug therapy issues:

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.

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:

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:

Conventional trastuzumab products 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 or trastuzumab-dkst) and ado-trastuzumab emtansine (Kadcyla) are different; confusion between the products may potentially cause harm to the patient. Other warnings/precautions:

Establish human epidermal growth receptor 2 (HER2) status prior to treatment with an approved test, either HER2 protein overexpression by validated immunohistochemistry (IHC) assay or gene amplification by fluorescence in situ hybridization (FISH) 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.