Herceptin Hylecta

Assess left ventricular ejection fraction (LVEF) prior to initiation of HERCEPTIN HYLECTA and at regular intervals during treatment. Withhold HERCEPTIN HYLECTA dosing for at least 4 weeks for either of the following:

• ≥16% absolute decrease in LVEF from pre-treatment values
• LVEF below institutional limits of normal and ≥10% absolute decrease in LVEF from pretreatment values.

HERCEPTIN HYLECTA may be resumed if, within 4–8 weeks, the LVEF returns to normal limits and the absolute decrease from baseline is ≤15%.

Permanently discontinue HERCEPTIN HYLECTA for a persistent (>8 weeks) LVEF decline or for suspension of HERCEPTIN HYLECTA dosing on more than 3 occasions for cardiomyopathy.

Conduct thorough cardiac assessment, including history, physical examination, and determination of LVEF by echocardiogram or MUGA scan. The following schedule is recommended:

• Baseline LVEF measurement immediately prior to initiation of HERCEPTIN HYLECTA
• LVEF measurements every 3 months during and upon completion of HERCEPTIN HYLECTA
• Repeat LVEF measurement at 4 week intervals if HERCEPTIN HYLECTA is withheld for significant left ventricular cardiac dysfunction
  [see Dosage and Administration (2.4)]
• LVEF measurements every 6 months for at least 2 years following completion of HERCEPTIN HYLECTA as a component of adjuvant therapy.

In the HannaH study, the overall percentage of patients with at least one cardiac disorder was similar in both study arms: 15% (44/297) of patients in the HERCEPTIN HYLECTA arm and 14% (42/298) of patients in the intravenous trastuzumab arm. The most frequent cardiac adverse reactions were left ventricular dysfunction [3.4% (10/297) and 4.0% (12/298)], tachycardia [2% (6/297) and 3% (9/298)] and palpitations [2% (6/297) and 1.3% (4/298)] in the HERCEPTIN HYLECTA arm and the intravenous trastuzumab arm, respectively. The incidence of cardiac failure and congestive cardiac failure was 1% (3/297) in the HERCEPTIN HYLECTA arm and <1% (1/298) in the intravenous trastuzumab arm. The proportion of patients in each treatment arm with a significant decrease in LVEF defined as a drop of ≥10% points to an LVEF of <50% was comparable between treatment arms [3.8% (11/297) in the HERCEPTIN HYLECTA arm and 4.2% (12/298) in the intravenous trastuzumab arm]. In patients with lower body weights (<59 kg, the lowest body weight quartile) the fixed-dose used in the HERCEPTIN HYLECTA arm was not associated with an increased risk of cardiac events or significant drop in LVEF.

In the SafeHER study, in patients treated with HERCEPTIN HYLECTA

In study NSABP B31 (NCT00004067), 15% (158/1031) of patients discontinued intravenous trastuzumab due to clinical evidence of myocardial dysfunction or significant decline in LVEF after a median follow-up duration of 8.7 years in the AC-TH arm. In the HERA study (one-year intravenous trastuzumab treatment; NCT00045032), the number of patients who discontinued intravenous trastuzumab due to cardiac toxicity at 12.6 months median duration of follow-up was 2.6% (44/1678). In the BCIRG006 study (NCT00021255), a total of 2.9% (31/1056) of patients in the TCH arm (1.5% during the chemotherapy phase and 1.4% during the monotherapy phase) and 5.7% (61/1068) of patients in the AC-TH arm (1.5% during the chemotherapy phase and 4.2% during the monotherapy phase) discontinued intravenous trastuzumab due to cardiac toxicity.

Among 64 patients receiving adjuvant chemotherapy (studies NSABP B31 and NCCTG N9831; NCT00005970) who developed congestive heart failure (CHF), one patient died of cardiomyopathy, one patient died suddenly without documented etiology, and 33 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 the time of last follow-up. Incidence of CHF is presented in Table 1. The safety of continuation or resumption of intravenous trastuzumab in patients with trastuzumab-induced left ventricular cardiac dysfunction has not been studied.

In the HERA study (one-year intravenous trastuzumab treatment), at a median follow-up duration of 8 years, the incidence of severe CHF (NYHA III & IV) was 0.8%, and the rate of mild symptomatic and asymptomatic left ventricular dysfunction was 4.6%.

In the BCIRG006 study, the incidence of NCI-CTC Grade 3/4 cardiac ischemia/infarction was higher in the intravenous trastuzumab containing regimens [AC-TH: 0.3% (3/1068) and TCH: 0.2% (2/1056)] as compared to none in AC-T.

There is a pregnancy pharmacovigilance program for HERCEPTIN HYLECTA. If HERCEPTIN HYLECTA is administered during pregnancy, or if a patient becomes pregnant while receiving HERCEPTIN HYLECTA or within 7 months following the last dose of HERCEPTIN HYLECTA, health care providers and patients should immediately report HERCEPTIN HYLECTA exposure to Genentech at 1-888-835-2555.

HERCEPTIN HYLECTA 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

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.

Verify the pregnancy status of females of reproductive potential prior to the initiation of HERCEPTIN HYLECTA.

Patients with adjuvant breast cancer should be treated with HERCEPTIN HYLECTA for 52 weeks or until disease recurrence, whichever occurs first; extending treatment in adjuvant breast cancer beyond one year is not recommended.

Patients with metastatic breast cancer (MBC) should be treated with HERCEPTIN HYLECTA until progression of disease.

If one dose is missed, it is recommended to administer the next 600 mg/10,000 units dose (i.e. the missed dose) as soon as possible. The interval between subsequent HERCEPTIN HYLECTA doses should not be less than three weeks.

Patients with adjuvant breast cancer should be treated with HERCEPTIN HYLECTA for 52 weeks or until disease recurrence, whichever occurs first; extending treatment in adjuvant breast cancer beyond one year is not recommended.

Patients with metastatic breast cancer (MBC) should be treated with HERCEPTIN HYLECTA until progression of disease.

If one dose is missed, it is recommended to administer the next 600 mg/10,000 units dose (i.e. the missed dose) as soon as possible. The interval between subsequent HERCEPTIN HYLECTA doses should not be less than three weeks.