ophilized powder in a multiple-dose vial.
4 CONTRAINDICATIONS
None.
5 WARNINGS AND PRECAUTIONS
5.1 Cardiomyopathy
Trastuzumab products can cause left ventricular cardiac dysfunction, arrhythmias, hypertension, disablingcardiac failure, cardiomyopathy, and cardiac death [see Boxed Warning]. Trastuzumab products can also causeasymptomatic decline in left ventricular ejection fraction (LVEF).
There is a 4 to 6 fold increase in the incidence of symptomatic myocardial dysfunction among patients receivingtrastuzumab products as a single agent or in combination therapy compared with those not receiving trastuzumab products. The highest absolute incidence occurs when a trastuzumab product is administered with
an anthracycline.
Withhold TRAZIMERA for ≥ 16% absolute decrease in LVEF from pre-treatment values or an LVEF valuebelow institutional limits of normal and ≥ 10% absolute decrease in LVEF from pretreatment values [seeDosage and Administration (2.3)]. The safety of continuation or resumption of TRAZIMERA in patients withtrastuzumab product-induced left ventricular cardiac dysfunction has not been studied.
Patients who receive anthracycline after stopping TRAZIMERA may also be at increased risk of cardiacdysfunction [see Drug Interactions (7) and Clinical Pharmacology (12.3)].
Cardiac Monitoring
Conduct thorough cardiac assessment, including history, physical examination, and determination of LVEF byechocardiogram or MUGA scan. The following schedule is recommended:
• Baseline LVEF measurement immediately prior to initiation of TRAZIMERA
• LVEF measurements every 3 months during and upon completion of TRAZIMERA
• Repeat LVEF measurement at 4 week intervals if TRAZIMERA is withheld for significant left ventricularcardiac dysfunction [see Dosage and Administration (2.3)]
• LVEF measurements every 6 months for at least 2 years following completion of TRAZIMERA as a
component of adjuvant therapy.
In Study 1, 15% (158/1031) of patients discontinued trastuzumab due to clinical evidence of myocardialdysfunction or significant decline in LVEF after a median follow-up duration of 8.7 years in the AC-TH(anthracycline, cyclophosphamide, paclitaxel, and trastuzumab) arm. In Study 3 (one-year trastuzumabtreatment), the number of patients who discontinued trastuzumab due to cardiac toxicity at 12.6 months medianduration of follow-up was 2.6% (44/1678). In Study 4, a total of 2.9% (31/1056) of patients in the TCH(docetaxel, carboplatin, trastuzumab) arm (1.5% during the chemotherapy phase and 1.4% during themonotherapy phase) and 5.7% (61/1068) of patients in the AC-TH arm (1.5% during the chemotherapy phaseand 4.2% during the monotherapy phase) discontinued trastuzumab due to cardiac toxicity.
Among 64 patients receiving adjuvant chemotherapy (Studies 1 and 2) who developed congestive heart failure(CHF), one patient died of cardiomyopathy, one patient died suddenly without documented etiology, and33 patients were receiving cardiac medication at last follow-up. Approximately 24% of the surviving patients
had recovery to a normal LVEF (defined as ≥50%) and no symptoms on continuing medical management at thetime of last follow-up. Incidence of congestive heart failure is presented in Table 1. The safety of continuationor resumption of TRAZIMERA in patients with trastuzumab product-induced left ventricular cardiacdysfunction has not bee |
