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Indications
TRAZIMERA is a HER2/neu receptor antagonist indicated in adults for:
The treatment of HER2-overexpressing breast cancer. ( 1.1 , 1.2 )
The treatment of HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma. ( 1.3 ) Select patients for therapy based on an FDA-approved companion diagnostic for a trastuzumab product. ( 1 , 2.2 )
1.1Adjuvant Breast Cancer
TRAZIMERA is indicated in adults for adjuvant treatment of HER2-overexpressing node positive or node negative (ER/PR negative or with one high risk feature [see Clinical Studies (14.1) ] ) breast cancer
as part of a treatment regimen consisting of doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel
as part of a treatment regimen with docetaxel and carboplatin
as a single agent following multi-modality anthracycline based therapy. Select patients for therapy based on an FDA-approved companion diagnostic for a trastuzumab product [see Dosage and Administration (2.2) ] .
1.2Metastatic Breast Cancer
TRAZIMERA is indicated in adults:
In combination with paclitaxel for first-line treatment of HER2-overexpressing metastatic breast cancer
As a single agent for treatment of HER2-overexpressing breast cancer in patients who have received one or more chemotherapy regimens for metastatic disease. Select patients for therapy based on an FDA-approved companion diagnostic for a trastuzumab product [see Dosage and Administration (2.2) ].
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TRAZIMERA is indicated in adults, in combination with cisplatin and capecitabine or 5-fluorouracil, for the treatment of patients with HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma who have not received prior treatment for metastatic disease. Select patients for therapy based on an FDA-approved companion diagnostic for a trastuzumab product [see Dosage and Administration (2.2) ].
Contraindications
None.
None. ( 4 )
Warnings and precautions
Exacerbation of Chemotherapy-Induced Neutropenia. ( 5.5 , 6.1 )
5.1Cardiomyopathy
Trastuzumab products can cause left ventricular cardiac dysfunction, arrhythmias, hypertension, disabling cardiac failure, cardiomyopathy, and cardiac death [see Boxed Warning ] . 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 TRAZIMERA 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 (2.5) ] . The safety of continuation or resumption of trastuzumab products in patients with trastuzumab product-induced left ventricular cardiac dysfunction has not been studied.
Patients who receive anthracycline after stopping trastuzumab products 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 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 ventricular cardiac dysfunction [see Dosage and Administration (2.5) ]
LVEF measurements every 6 months for at least 2 years following completion of TRAZIMERA as a component of adjuvant therapy. In NSABP B31, 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 HERA (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 BCIRG006, 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 (NSABP B31 and NCCTG N9831) 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 congestive heart failure is presented in Table 1. The safety of continuation or resumption of trastuzumab products in patients with trastuzumab product-induced left ventricular cardiac dysfunction has not been studied. Table 1: Incidence of Congestive Heart Failure in Adjuvant Breast Cancer Studies Incidence of Congestive Heart Failure % (n) Study Regimen Trastuzumab Control NSABP B31 & NCCTG N9831 Median follow-up duration for NSABP B31 & NCCTG N9831 combined was 8.3 years in the AC→paclitaxel+trastuzumab arm. AC Anthracycline (doxorubicin) and cyclophosphamide. → Paclitaxel+Trastuzumab 3.2% (64/2000) Includes 1 patient with fatal cardiomyopathy and 1 patient with sudden death without documented etiology. 1.3% (21/1655) HERA Includes NYHA II-IV and cardiac death at 12.6 months median duration of follow-up in the one-year trastuzumab arm. Chemotherapy → Trastuzumab 2% (30/1678) 0.3% (5/1708) BCIRG006 AC → Docetaxel+Trastuzumab 2% (20/1068) 0.3% (3/1050) BCIRG006 Docetaxel+Carboplatin+Trastuzumab 0.4% (4/1056) 0.3% (3/1050) In HERA (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: Incidence of Cardiac Dysfunction Congestive heart failure or significant asymptomatic decrease in LVEF. in Metastatic Breast Cancer Studies Incidence NYHA I–IV NYHA III–IV Study Event Trastuzumab Control Trastuzumab Control H0648g (AC) Anthracycline (doxorubicin or epirubicin) and cyclophosphamide. Cardiac Dysfunction 28% 7% 19% 3% H0648g (paclitaxel) Cardiac Dysfunction 11% 1% 4% 1% H0649g Cardiac Dysfunction Includes 1 patient with fatal cardiomyopathy. 7% N/A 5% N/A In BCIRG006, 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.
5.2Infusion 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 TRAZIMERA 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.
5.3Embryo-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 TRAZIMERA. Advise pregnant women and females of reproductive potential that exposure to TRAZIMERA 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 TRAZIMERA [see Use in Specific Populations (8.1 , 8.3) and Clinical Pharmacology (12.3) ].
5.4Pulmonary Toxicity
Trastuzumab product use can result in serious and fatal pulmonary toxicity. Pulmonary toxicity includes dyspnea, interstitial pneumonitis, pulmonary infiltrates, pleural effusions, non-ca
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Interactions
Anthracyclines Patients who receive anthracycline after stopping trastuzumab products may be at increased risk of cardiac dysfunction because of trastuzumab products estimated long washout period [see Clinical Pharmacology (12.3) ] . If possible, avoid anthracycline-based therapy for up to 7 months after stopping trastuzumab products. If anthracyclines are used, closely monitor the patient's cardiac function.
Pregnancy and breastfeeding
8.1Pregnancy Risk Summary
Trastuzumab products can cause fetal harm when administered to a pregnant woman. In post-marketing reports and published literature, use of trastuzumab products during pregnancy resulted in cases of oligohydramnios and of oligohydramnios sequence, manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death (see Data ) . Apprise the patient of the potential risks to a fetus. There are clinical considerations if a trastuzumab product is used in a pregnant woman or if a patient becomes pregnant within 7 months following the last dose of a trastuzumab product (see Clinical Considerations ).
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. Clinical Considerations Fetal/Neonatal Adverse Reactions Monitor women who received TRAZIMERA during pregnancy or within 7 months prior to conception for oligohydramnios.
If oligohydramnios occurs, perform fetal/neonatal testing that is appropriate for gestational age and consistent with community standards of care. Data Human Data In post-marketing reports and published literature, use of trastuzumab products during pregnancy resulted in cases of oligohydramnios and of oligohydramnios sequence. Fetal manifestations included pulmonary hypoplasia, skeletal abnormalities and neonatal death.
These case reports described oligohydramnios in pregnant women who received trastuzumab either alone or in combination with chemotherapy. In most reported cases, amniotic fluid index increased after trastuzumab was stopped. In reported cases where trastuzumab therapy was resumed after amniotic index improved, oligohydramnios recurred. Animal Data In studies where trastuzumab was administered to pregnant cynomolgus monkeys during the period of organogenesis at doses up to 25 mg/kg given twice weekly (up to 25 times the recommended weekly human dose of 2 mg/kg), trastuzumab crossed the placental barrier during the early (Gestation Days 20 to 50) and late (Gestation Days 120 to 150) phases of gestation.
The resulting concentrations of trastuzumab in fetal serum and amniotic fluid were approximately 33% and 25%, respectively, of those present in the maternal serum but were not associated with adverse developmental effects.
Adverse reactions
The following adverse reactions are discussed in greater detail in other sections of the label:
Cardiomyopathy [see Warnings and Precautions (5.1) ]
Infusion Reactions [see Warnings and Precautions (5.2) ]
Embryo-Fetal Toxicity [see Warnings and Precautions (5.3) ]
Pulmonary Toxicity [see Warnings and Precautions (5.4) ]
Exacerbation of Chemotherapy-Induced Neutropenia [see Warnings and Precautions (5.5) ] Adjuvant Breast Cancer
Most common adverse reactions (≥ 5%) are headache, diarrhea, nausea, and chills. ( 6.1 ) Metastatic Breast Cancer
Most common adverse reactions (≥ 10%) are fever, chills, headache, infection, congestive heart failure, insomnia, cough, and rash. ( 6.1 ) Metastatic Gastric Cancer
Most common adverse reactions (≥ 10%) are neutropenia, diarrhea, fatigue, anemia, stomatitis, weight loss, upper respiratory tract infections, fever, thrombocytopenia, mucosal inflammation, nasopharyngitis, and dysgeusia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 and www.Pfizer.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
6.1Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The most common adverse reactions in patients receiving trastuzumab products in the adjuvant and metastatic breast cancer setting are fever, nausea, vomiting, infusion reactions, diarrhea, infections, increased cough, headache, fatigue, dyspnea, rash, neutropenia, anemia, and myalgia.
Adverse reactions requiring interruption or discontinuation of trastuzumab product treatment include CHF, significant decline in left ventricular cardiac function, severe infusion reactions, and pulmonary toxicity [see Dosage and Administration (2.5) ] . In the metastatic gastric cancer setting, the most common adverse reactions (≥ 10%) that were increased (≥ 5% difference) in the trastuzumab arm as compared to the chemotherapy alone arm were neutropenia, diarrhea, fatigue, anemia, stomatitis, weight loss, upper respiratory tract infections, fever, thrombocytopenia, mucosal inflammation, nasopharyngitis, and dysgeusia.
The most common adverse reactions which resulted in discontinuation of treatment on the trastuzumab-containing arm in the absence of disease progression were infection, diarrhea, and febrile neutropenia. Adjuvant Breast Cancer The information below reflects exposure to one-year trastuzumab therapy across three randomized, open-label studies, NSABP B31, NCCTG N9831, and HERA, with (n = 3678) or without (n = 3363) trastuzumab in the adjuvant treatment of breast cancer.
HERA Table 3 reflects exposure to trastuzumab in 1678 patients in HERA; the median treatment duration was 51 weeks and median number of infusions was 18 [see Clinical Studies (14.1) ]. Table 3: Adverse Reactions (≥ 1%) in HERA (All Grades) The incidence of Grade 3 or higher adverse reactions was < 1% in both arms for each listed term. Adverse Reactions Trastuzumab (n = 1678) % Observation (n = 1708) % Nervous System Headache 10 3 Paresthesia 2
0.6Musculoskeletal Arthralgia 8 6
Back pain 5 3 Myalgia 4 1 Bone pain 3 2 Muscle spasm 3
0.6 Clinically relevant adverse reactions in < 1% of patients who received trastuzumab in HERA included hypersensitivity (0.6%), cardiac failure (0.5%), cardiac disorder (0.3%), interstitial pneumonitis (0.2%), pulmonary hypertension (0.2%), ventricular disorder (0.2%), autoimmune thyroiditis (0.3%), and sudden death (0.06%). Adjuvant Treatment of Breast Cancer with Trastuzumab Beyond One Year Extending adjuvant treatment beyond one year is not recommended [see Dosage and Administration (2.3) ] .
In HERA, a comparison of trastuzumab administered once every 3 weeks for two years versus one year was performed. The rate of asymptomatic cardiac dysfunction was increased in the 2-year trastuzumab compared to the 1-year trastuzumab treatment arm (8.1% versus 4.6%, respectively). More patients experienced at least one adverse reaction of Grade 3 or higher in the 2-year trastuzumab treatment arm (20.4%) compared with the one-year trastuzumab treatment arm (16.3%).
NSABP B31 and NCCTG N9831 The safety data from NSABP B31 and NCCTG N9831 were obtained from 3655 patients, of whom 2000 received trastuzumab; the median treatment duration was 51 weeks [see Clinical Studies (14.1) ] . In NSABP B31, only Grade 3 to 5 adverse events, treatment-related Grade 2 events, and Grade 2 to 5 dyspnea were collected during and for up to 3 months following protocol-specified treatment. The following non-cardiac adverse reactions of Grade 2 to 5 occurred at an incidence of at least 2% greater among patients receiving trastuzumab plus chemotherapy as compared to chemotherapy alone: fatigue (29.5% vs. 22.4%), infection (24.0% vs. 12.8%), hot flashes (17.1% vs. 15%), anemia (12.3% vs. 6.7%), dyspnea (11.8% vs. 4.6%), rash/desquamation (10.9% vs. 7.6%), leukopenia (10.5% vs. 8.4%), neutropenia (6.4% vs. 4.3%), headache (6.2% vs. 3.8%), pain (5.5% vs. 3%), edema (4.7% vs. 2.7%), and insomnia (4.3% vs. 1.5%).
The majority of these events were Grade 2 in severity. In NCCTG N9831, data collection was limited to the following investigator-attributed treatment-related adverse reactions: NCI-CTC Grade 4 and 5 hematologic toxicities, Grade 3 to 5 non-hematologic toxicities, selected Grade 2 to 5 toxicities associated with taxanes (myalgia, arthralgias, nail changes, motor neuropathy, and sensory neuropathy) and Grade 1 to 5 cardiac toxicities occurring during chemotherapy and/or trastuzumab treatment.
The following non-cardiac adverse reactions of Grade 2 to 5 occurred at an incidence of at least 2% greater among patients receiving trastuzumab plus chemotherapy as compared to chemotherapy alone: arthralgia (12.2% vs. 9.1%), nail changes (11.5% vs. 6.8%), dyspnea (2.4% vs. 0.2%), and diarrhea (2.2% vs. 0%). The majority of these events were Grade 2 in severity. BCIRG006 Safety data from BCIRG006 reflect exposure to trastuzumab as part of an adjuvant treatment regimen from 2124 patients receiving at least one dose of study treatment [AC-TH: n = 1068; TCH: n = 1056].
The overall median treatment duration was 54 weeks in both the AC-TH and TCH arms. The median number of infusions was 26 in the AC-TH arm and 30 in the TCH arm, including weekly infusions during the chemotherapy phase and once every three weeks dosing in the monotherapy period [see Clinical Studies (14.1) ] . In BCIRG006, the toxicity profile was similar to that reported in NSABP B31, NCCTG N9831, and HERA with the exception of a lower incidence of CHF in the TCH arm.
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Composition
Active ingredients
TRASTUZUMAB-QYYP 420MG
Official product information
Drugs@FDA lists the approved labels, letters and reviews for application BLA761081.
Prognia shows this product information for reference and learning. It is not treatment advice and can lag behind the official text. Always check the current product information and local protocols before prescribing.
Metastatic Breast Cancer Studies The safety of trastuzumab was evaluated in one randomized, open-label study (H0648g) of chemotherapy with (n = 235) or without (n = 234) intravenous trastuzumab in patients with metastatic breast cancer, and in one single-arm study (H0649g) in patients with metastatic breast cancer (n = 222) [see Clinical Studies (14.1) ] . Patients received 4 mg/kg initial dose of trastuzumab followed by 2 mg/kg weekly.
In H0648g, 58% of patients received trastuzumab for ≥ 6 months and 9% received tr
