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warnings and cautions
5 WARNINGS AND PRECAUTIONS Exacerbation of Chemotherapy-Induced Neutropenia. ( 5.5 , 6.1 ) 5.1 Cardiomyopathy Trastuzumab products can cause left ventricular cardiac dysfunction, arrhythmias, hypertension, disabling cardiac failure, cardiomyopathy, and cardiac death [see Boxed Warning: Cardiomyopathy ] . Trastuzumab products can also cause asymptomatic decline in left ventricular ejection fraction (LVEF). There is a 4 to 6 fold increase in the incidence of symptomatic myocardial dysfunction among patients receiving trastuzumab 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 Ontruzant 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 ( 2.3 )] . The safety of continuation or resumption of Ontruzant in patients with trastuzumab product-induced left ventricular cardiac dysfunction has not been studied. Patients who receive anthracycline after stopping Ontruzant may also be at increased risk of cardiac dysfunction [see Drug Interactions ( 7 ) and Clinical Pharmacology ( 12.3 )] . Cardiac Monitoring: 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 Ontruzant LVEF measurements every 3 months during and upon completion of Ontruzant Repeat LVEF measurement at 4 week intervals if Ontruzant is withheld for significant left ventricular cardiac dysfunction [see Dosage and Administration ( 2.3 )] LVEF measurements every 6 months for at least 2 years following completion of Ontruzant as a component of adjuvant therapy. In Study 1, 15% (158/1031) of patients discontinued 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 (anthracycline, cyclophosphamide, paclitaxel, and trastuzumab) arm. In Study 3 (one-year trastuzumab treatment), the number of patients who discontinued trastuzumab due to cardiac toxicity at 12.6 months median duration 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 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 trastuzumab due to cardiac toxicity. Among 64 patients receiving adjuvant chemotherapy (Studies 1 and 2) who developed congestive heart failure, 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 congestive heart failure (CHF) is presented in Table 1 . The safety of continuation or resumption of Ontruzant in patients with trastuzumab product-induced left ventricular cardiac dysfunction has not been studied. Table 1 a Median follow-up duration for studies 1 and 2 combined was 8.3 years in the AC → TH arm. b Anthracycline (doxorubicin) and cyclophosphamide. c Includes 1 patient with fatal cardiomyopathy and 1 patient with sudden death without documented etiology. d Includes NYHA II-IV and cardiac death at 12.6 months median duration of follow-up in the one-year trastuzumab arm. Incidence of Congestive Heart Failure in Adjuvant Breast Cancer Studies Incidence of CHF Study Regimen Trastuzumab Control 1 & 2 a AC b → Paclitaxel + Trastuzumab 3.2% (64/2000) c 1.3% (21/1655) 3 d Chemo → Trastuzumab 2% (30/1678) 0.3% (5/1708) 4 AC b → Docetaxel + Trastuzumab 2% (20/1068) 0.3% (3/1050) 4 Docetaxel + Carbo + Trastuzumab 0.4% (4/1056) 0.3% (3/1050) In Study 3 (one-year 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%. Table 2 a Congestive heart failure or significant asymptomatic decrease in LVEF. b Anthracycline (doxorubicin or epirubicin) and cyclophosphamide. c Includes 1 patient with fatal cardiomyopathy. Incidence of Cardiac Dysfunction a in Metastatic Breast Cancer Studies Incidence NYHA I-IV NYHA III−IV Study Event Trastuzumab Control Trastuzumab Control 5 (AC) b Cardiac Dysfunction 28% 7% 19% 3% 5 (paclitaxel) Cardiac Dysfunction 11% 1% 4% 1% 6 Cardiac Dysfunction c 7% N/A 5% N/A In Study 4, the incidence of NCI-CTC Grade 3/4 cardiac ischemia/infarction was higher in the trastuzumab containing regimens (AC-TH: 0.3% (3/1068) and TCH: 0.2% (2/1056)) as compared to none in AC-T. 5.2 Infusion Reactions 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 ( 6.1 )]. In post-marketing 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 Ontruzant 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 trastuzumab products after experiencing a severe infusion reaction. Prior to resumption of trastuzumab infusion, the majority of patients who experienced a severe infusion reaction were pre-medicated with antihistamines and/or corticosteroids. While some patients tolerated trastuzumab infusions, others had recurrent severe infusion reactions despite pre-medications. 5.3 Embryo-Fetal Toxicity Trastuzumab products can cause fetal harm when administered to a pregnant woman. In post-marketing reports, use of trastuzumab during pregnancy resulted in cases of oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death. Verify the pregnancy status of females of reproductive potential prior to the initiation of Ontruzant. Advise pregnant women and females of reproductive potential that exposure to Ontruzant during pregnancy or within 7 months prior to conception can result in fetal harm. Advise females of reproductive potential to use effective contraception during treatment and for 7 months following the last dose of Ontruzant [see Use in Specific Populations ( 8.1 , 8.3 ) and Clinical Pharmacology ( 12.3 )]. 5.4 Pulmonary Toxicity Trastuzumab product 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 ( 5.2 )] . 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. 5.5 Exacerbation of Chemotherapy-Induced Neutropenia In randomized, controlled clinical trials, the per-patient incidences of NCI-CTC Grade 3 to 4 neutropenia and of febrile neutropenia were higher in patients receiving trastuzumab in combination with myelosuppressive chemotherapy as compared to those who received chemotherapy alone. The incidence of septic death was similar among patients who received trastuzumab and those who did not [see Adverse Reactions ( 6.1 )].