WARNINGS AND PRECAUTIONS
Herceptin can cause left ventricular cardiac dysfunction, arrhythmias, hypertension, disabling cardiac failure, cardiomyopathy, and cardiac death [ see Boxed Warning: Cardiomyopathy ]. Herceptin can also cause a symptomatic decline in left ventricular ejection fraction (LVEF).
There is a 4—6 fold increase in the incidence of symptomatic myocardial dysfunction among patients receiving Herceptin as a single agent or in combination therapy compared with those not receiving Herceptin. The highest absolute incidence occurs when Herceptin is administered with an anthracycline.
Withhold Herceptin for ≥ 16% absolute decrease in LVEF from pre‑treatment values or an LVEF value below institutional limits of normal and ≥ 10% absolute decrease in LVEF from pretreatment values. [ see Dosage and Administration (2.2) ] The safety of continuation or resumption of Herceptin in patients with Herceptin‑induced left ventricular cardiac dysfunction has not been studied.
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
LVEF measurements every 3 months during and upon completion of Herceptin
Repeat LVEF measurement at 4 week intervals if Herceptin is withheld for significant left ventricular cardiac dysfunction [ see Dosage and Administration (2.2) ]
LVEF measurements every 6 months for at least 2 years following completion of Herceptin as a component of adjuvant therapy.
In Study 1, 16% (136/844) of patients discontinued Herceptin due to clinical evidence of myocardial dysfunction or significant decline in LVEF. In Study 3, the number of patients who discontinued Herceptin due to cardiac toxicity was 2.6% (44/1678). In Study 4, a total of 2.9% (31/1056) patients in the TCH arm (1.5% during the chemotherapy phase and 1.4% during the monotherapy phase) and 5.7% (61/1068) patients in the AC‑TH arm (1.5% during the chemotherapy phase and 4.2% during the monotherapy phase) discontinued Herceptin due to cardiac toxicity.
Among 32 patients receiving adjuvant chemotherapy (Studies 1 and 2) who developed congestive heart failure, one patient died of cardiomyopathy and all other patients were receiving cardiac medication at last follow‑up. Approximately half of the surviving patients had recovery to a normal LVEF (defined as ≥50%) on continuing medical management at the time of last follow‑up. Incidence of congestive heart failure is presented in Table 1. The safety of continuation or resumption of Herceptin in patients with Herceptin‑induced left ventricular cardiac dysfunction has not been studied.
Table 1: Incidence of Congestive Heart Failure in Adjuvant Breast Cancer Studies
| || ||Incidence of CHF|
|1 & 2
→ Paclitaxel+Herceptin||2% (32/1677)||0.4% (7/1600)|
|3||Chemo → Herceptin||2% (30/1678)||0.3% (5/1708)|
|4||AC → Docetaxel+Herceptin||2% (20/1068)||0.3% (3/1050)|
|4||Docetaxel+Carbo+Herceptin||0.4% (4/1056)||0.3% (3/1050)|
Table 2: Incidence of Cardiac DysfunctionCongestive heart failure or significant asymptomatic decrease in LVEF. in Metastatic Breast Cancer Studies
| || ||Incidence|
| || ||NYHA I‑IV||NYHA III‑IV|
|5 (AC)Anthracycline (doxorubicin or epirubicin) and cyclophosphamide||Cardiac Dysfunction||28%||7%||19%||3%|
|5 (paclitaxel)||Cardiac Dysfunction||11%||1%||4%||1%|
|6||Cardiac DysfunctionIncludes 1 patient with fatal cardiomyopathy.||7%||N/A||5%||N/A|
In Study 4, the incidence of NCI‑CTC Grade 3/4 cardiac ischemia/infarction was higher in the Herceptin containing regimens: (AC‑TH: 0.3% (3/1068) and TCH 0.2% (: 2/1056)) as compared to none in AC‑T.
Infusion reactions consist of a symptom complex characterized by fever and chills, and on occasion included nausea, vomiting, pain (in some cases at tumor sites), headache, dizziness, dyspnea, hypotension, rash, and asthenia [see Adverse Reactions ].
In postmarketing reports, serious and fatal infusion reactions have been reported. Severe reactions which include bronchospasm, anaphylaxis, angioedema, hypoxia, and severe hypotension, were usually reported during or immediately following the initial infusion. However, the onset and clinical course were variable including progressive worsening, initial improvement followed by clinical deterioration, or delayed post‑infusion events with rapid clinical deterioration. For fatal events, death occurred within hours to days following a serious infusion reaction
Interrupt Herceptin infusion in all patients experiencing dyspnea, clinically significant hypotension, and intervention of medical therapy administered, which may include: epinephrine, corticosteroids, diphenhydramine, bronchodilators, and oxygen. Patients should be evaluated and carefully monitored until complete resolution of signs and symptoms. Permanent discontinuation should be strongly considered in all patients with severe infusion reactions.
There are no data regarding the most appropriate method of identification of patients who may safely be retreated with Herceptin after experiencing a severe infusion reaction. Prior to resumption of Herceptin infusion, the majority of patients who experienced a severe infusion reaction were pre‑medicated with antihistamines and/or corticosteroids. While some patients tolerated Herceptin infusions, others had recurrent severe infusion reactions despite pre‑medications.
Exacerbation of Chemotherapy‑Induced Neutropenia
In randomized, controlled clinical trials in women with metastatic breast cancer, the per‑patient incidences of NCI CTC Grade 3—4 neutropenia and of febrile neutropenia were higher in patients receiving Herceptin in combination with myelosuppressive chemotherapy as compared to those who received chemotherapy alone. The incidence of septic death was not significantly increased. [ see Adverse Reactions (6.1) ].
Herceptin use can result in serious and fatal pulmonary toxicity. Pulmonary toxicity includes dyspnea, interstitial pneumonitis, pulmonary infiltrates, pleural effusions, non‑cardiogenic pulmonary edema, pulmonary insufficiency and hypoxia, acute respiratory distress syndrome, and pulmonary fibrosis. Such events can occur as sequelae of infusion reactions [see Warnings and Precautions ]. Patients with symptomatic intrinsic lung disease or with extensive tumor involvement of the lungs, resulting in dyspnea at rest, appear to have more severe toxicity.
Detection of HER2 protein overexpression is necessary for selection of patients appropriate for Herceptin therapy because these are the only patients studied and for whom benefit has been shown. Assessment for HER2 overexpression and of HER2 gene amplification should be performed by laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance, including use of suboptimally fixed tissue, failure to utilize specified reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results.
Several FDA‑approved commercial assays are available to aid in the selection of patients for Herceptin therapy. These include HercepTest™ and Pathway® HER‑2/neu (IHC assays) and PathVysion® and HER2 FISH pharmDx™ (FISH assays). Users should refer to the package inserts of specific assay kits for information on the validation and performance of each assay.
Limitations in assay precision (particularly for the IHC method) and in the direct linkage between assay result and overexpression of the Herceptin target (for the FISH method) make it inadvisable to rely on a single method to rule out potential Herceptin benefit. A negative FISH result does not rule out HER2 overexpression and potential benefit from Herceptin. Treatment outcomes for metastatic breast cancer (Study 5) as a function of IHC and FISH testing are provided in Table 9. Treatment outcomes for adjuvant breast cancer (Studies 2 and 3) as a function of IHC and FISH testing are provided in Table 7.
HER2 Protein Overexpression Detection Methods
HER2 protein overexpression can be established by measuring HER2 protein using an IHC method. HercepTest®, one test approved for this use, was assessed for concordance with the Clinical Trial Assay (CTA), using tumor specimens collected and stored independently from those obtained in Herceptin clinical studies in women with metastatic breast cancer. Data are provided in the package insert for HercepTest®.
HER2 Gene Amplification Detection Method
The presence of HER2 protein overexpression and gene amplification are highly correlated, therefore the use of FISH to detect gene amplification may be employed for selection of patients appropriate for Herceptin therapy. PathVysion®, one test approved for this use, was evaluated in an exploratory, retrospective assessment of available CTA 2+ or 3+ tumor specimens collected as part of patient screening for clinical studies in metastatic breast cancer (Studies 5 and 6). Data are provided in the package insert for PathVysion®.
Embryo‑Fetal Toxicity (Pregnancy Category D)
Herceptin can cause fetal harm when administered to a pregnant woman. Post‑marketing case reports suggest that Herceptin use during pregnancy increases the risk of oligohydramnios during the second and third trimesters. If Herceptin is used during pregnancy or if a woman becomes pregnant while taking Herceptin, she should be apprised of the potential hazard to a fetus. [ see Use in Specific Populations (8.1) ].
USE IN SPECIFIC POPULATIONS
Teratogenic Effects: Category D [ see Warnings and Precautions (5.6) ]
Herceptin can cause fetal harm when administered to a pregnant woman. Post‑marketing case reports suggest that Herceptin use during pregnancy increases the risk for oligohydramnios during the second and third trimester. If Herceptin is used during pregnancy or if a woman becomes pregnant while taking Herceptin, she should be apprised of the potential hazard to a fetus.
In the postmarketing setting, oligohydramnios was reported in women who received Herceptin during pregnancy, either alone or in combination with chemotherapy. In half of these women, amniotic fluid index increased after Herceptin was stopped. In one case, Herceptin was resumed after the amniotic fluid index improved, and oligohydramnios recurred.
Women using Herceptin during pregnancy should be monitored for oligohydramnios. If oligohydramnios occurs, fetal testing should be done that is appropriate for gestational age and consistent with community standards of care. Additional intravenous (IV) hydration has been helpful when oligohydramnios has occurred following administration of other chemotherapy agents, however the effects of additional IV hydration with Herceptin treatment are not known.
Reproduction studies in cynomolgus monkeys at doses up to 25 times the recommended weekly human dose of 2 mg/kg trastuzumab and have revealed no evidence of harm to the fetus. However, HER2 protein expression is high in many embryonic tissues including cardiac and neural tissues; in mutant mice lacking HER2, embryos died in early gestation. Placental transfer of trastuzumab during the early (Days 20—50 of gestation) and late (Days 120—150 of gestation) fetal development period was observed in monkeys. [ See Nonclinical Toxicology (13.2) ]
Because animal reproduction studies are not always predictive of human response, Herceptin should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.
Pregnant women with breast cancer who are using Herceptin are encouraged to enroll in the Cancer and Childbirth Registry: phone 1‑800‑690‑6720.
It is not known whether Herceptin is excreted in human milk, but human IgG is excreted in human milk. Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts.
Trastuzumab was present in the breast milk of lactating cynomolgus monkeys given 12.5 times the recommended weekly human dose of 2 mg/kg of Herceptin. Infant monkeys with detectable serum levels of trastuzumab did not have any adverse effects on growth or development from birth to 3 months of age; however, trastuzumab levels in animal breast milk may not accurately reflect human breast milk levels.
Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from Herceptin, a decision should be made whether to discontinue nursing, or discontinue drug, taking into account the elimination half‑life of trastuzumab and the importance of the drug to the mother.
The safety and effectiveness of Herceptin in pediatric patients has not been established.
Herceptin has been administered to 386 patients who were 65 years of age or over (253 in the adjuvant treatment and 133 in metastatic breast cancer treatment settings). The risk of cardiac dysfunction was increased in geriatric patients as compared to younger patients in both those receiving treatment for metastatic disease in Studies 5 and 6, or adjuvant therapy in Studies 1 and 2. Limitations in data collection and differences in study design of the 4 studies of Herceptin in adjuvant treatment of breast cancer preclude a determination of whether the toxicity profile of Herceptin in older patients is different from younger patients. The reported clinical experience is not adequate to determine whether the efficacy improvements (ORR, TTP, OS, DFS) of Herceptin treatment in older patients is different from that observed in patients <65 years of age for metastatic disease and adjuvant treatment.