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Indications
HERCEPTIN HYLECTA is a combination of trastuzumab, a HER2/neu receptor antagonist, and hyaluronidase, an endoglycosidase, indicated in adults for: The treatment of HER2-overexpressing breast cancer. ( 1.1 , 1.2 ) Select patients for therapy based on an FDA-authorized companion diagnostic for trastuzumab. ( 1 , 2.2 )
1.1Adjuvant Breast Cancer
HERCEPTIN HYLECTA is indicated for adjuvant treatment of adults with 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-authorized companion diagnostic for trastuzumab [see Dosage and Administration (2.2) ] .
1.2Metastatic Breast Cancer
HERCEPTIN HYLECTA 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-authorized companion diagnostic for trastuzumab [see Dosage and Administration (2.2) ] .
Contraindications
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Exacerbation of Chemotherapy-Induced Neutropenia. ( 5.4 , 6.1 ) Hypersensitivity and Administration-Related Reactions (ARRs): Severe ARRs, including anaphylaxis, have been reported with HERCEPTIN HYLECTA. Monitor patients for systemic hypersensitivity reactions. Permanently discontinue HERCEPTIN HYLECTA in patients who experience anaphylaxis or severe hypersensitivity reactions. ( 5.5 )
5.1Cardiomyopathy
HERCEPTIN HYLECTA can cause left ventricular cardiac dysfunction, arrhythmias, hypertension, disabling cardiac failure, cardiomyopathy, and cardiac death [see Boxed Warning: Cardiomyopathy ] . HERCEPTIN HYLECTA can also cause asymptomatic decline in LVEF. There is a 4–6 fold increase in the incidence of symptomatic myocardial dysfunction among patients receiving trastuzumab as a single agent or in combination therapy compared with those not receiving trastuzumab.
The highest absolute incidence occurs when trastuzumab is administered with an anthracycline. The incidence of symptomatic myocardial dysfunction for intravenous trastuzumab and HERCEPTIN HYLECTA was similar in clinical trials [see Adverse Reactions (6) ]. Withhold HERCEPTIN HYLECTA 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 (2.4) ] .
The safety of continuation or resumption of HERCEPTIN HYLECTA in patients with HERCEPTIN HYLECTA induced left ventricular cardiac dysfunction has not been studied. Patients who receive anthracycline after stopping HERCEPTIN HYLECTA 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 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.
HERCEPTIN HYLECTA 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 , 17% (323/1864) reported a cardiac disorder during the treatment period. Decreased ejection fraction, reported in 4.5% (84/1864) of the patients was the most frequently reported cardiac disorder.
Congestive cardiac failure was reported in <1% (10/1864) of patients and <1% (4/1864) of patients reported cardiac failure during the treatment period. One patient reported congestive cardiac failure during the follow-up period. Six percent (111/1864) of the patients treated with HERCEPTIN HYLECTA had an LVEF <50% with a decrease of ≥10 points in LVEF from baseline. Trastuzumab (intravenous formulation): 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. Table 1 Incidence of Congestive Heart Failure in Adjuvant Breast Cancer Studies Incidence of Congestive Heart Failure % (n) Study Regimen Intravenous Trastuzumab Control NSABP B31 & NCCTG N9831 Median follow-up duration for studies NSABP B31 and NCCTG N9831 combined was 8.3 years in the AC→ paclitaxel+Herceptin arm.
AC Anthracycline (doxorubicin) and cyclophosphamide. →paclitaxel + intravenous 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 intravenous trastuzumab arm. Chemotherapy → intravenous trastuzumab 2% (30/1678) 0.3% (5/1708) BCIRG006 AC →docetaxel + intravenous trastuzumab 2% (20/1068) 0.3% (3/1050) BCIRG006 Docetaxel + carboplatin + intravenous trastuzumab 0.4% (4/1056) 0.3% (3/1050) 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%.
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 Intravenous Trastuzumab Control Intravenous 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 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.
5.2Embryo-Fetal Toxicity
HERCEPTIN HYLECTA 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 sta
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Interactions
Anthracyclines Patients who receive anthracycline after stopping HERCEPTIN HYLECTA may be at increased risk of cardiac dysfunction because of HERCEPTIN HYLECTA's estimated long washout period [see Clinical Pharmacology (12.3) ] . If possible, avoid anthracycline-based therapy for up to 7 months after stopping HERCEPTIN HYLECTA. If anthracyclines are used, closely monitor the patient's cardiac function.
Pregnancy and breastfeeding
8.1Pregnancy 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. Risk Summary 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 [see Data ].
Apprise the patient of the potential risks to a fetus. There are clinical considerations if HERCEPTIN HYLECTA is used in a pregnant woman or if a patient becomes pregnant within 7 months following the last dose of HERCEPTIN HYLECTA [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 HERCEPTIN HYLECTA 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 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 use of trastuzumab was stopped. In reported cases where Herceptin therapy was resumed after amniotic index improved, oligohydramnios recurred.
Animal Data HERCEPTIN HYLECTA for subcutaneous injection contains trastuzumab and hyaluronidase [see Description (11) ] . Trastuzumab : In studies where intravenous 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. Hyaluronidase: In an embryo-fetal study, mice have been dosed daily by subcutaneous injection during the period of organogenesis with hyaluronidase (recombinant human) at dose levels up to 2,200,000 U/kg, which is >7,200 times higher than the human dose.
The study found no evidence of teratogenicity. Reduced fetal weight and increased numbers of fetal resorptions were observed, with no effects found at a daily dose of 360,000 U/kg, which is >1,200 times higher than the human dose. In a peri-and post-natal reproduction study, mice have been dosed daily by subcutaneous injection, with hyaluronidase (recombinant human) from implantation through lactation and weaning at dose levels up to 1,100,000 U/kg, which is >3,600 times higher than the human dose.
The study found no adverse effects on sexual maturation, learning and memory or fertility of the offspring.
Adverse reactions
The following adverse reactions are discussed in greater detail in other sections of the label: Cardiomyopathy [see Warnings and Precautions (5.1) ] Embryo-Fetal Toxicity [see Warnings and Precautions (5.2) ] Pulmonary Toxicity [see Warnings and Precautions (5.3) ] Exacerbation of Chemotherapy-Induced Neutropenia [see Warnings and Precautions (5.4) ] Hypersensitivity and Administration-Related Reactions [see Warnings and Precautions (5.5) ] Adjuvant Breast Cancer Most common adverse reactions (≥10%) for HERCEPTIN HYLECTA are fatigue, arthralgia, diarrhea, injection site reaction, upper respiratory tract infection, rash, myalgia, nausea, headache, edema, flushing, pyrexia, cough, and pain in extremity.
( 6.1 ) Metastatic Breast Cancer (based on intravenous trastuzumab) Most common adverse reactions (≥10%) are fever, chills, headache, infection, congestive heart failure, insomnia, cough, and rash. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Genentech at 1-888-835-2555 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 safety of HERCEPTIN HYLECTA administered subcutaneously has been established in the HannaH and SafeHER studies conducted in patients with HER2 overexpressing breast cancer.
The safety of intravenous trastuzumab has been established in studies H0648g and H0649g conducted in patients with HER2 overexpressing metastatic breast cancer. Adjuvant Breast Cancer HannaH HannaH was a randomized, open-label study to compare the pharmacokinetics, efficacy, and safety of HERCEPTIN HYLECTA compared to intravenous trastuzumab in women with HER2-positive breast cancer. Patients randomized to the HERCEPTIN HYLECTA arm received a dose of 600 mg HERCEPTIN HYLECTA every 3 weeks throughout the treatment phase.
Patients were treated for 8 cycles in combination with chemotherapy (docetaxel followed by 5FU, epirubicin and cyclophosphamide), then underwent surgery, and continued HERCEPTIN HYLECTA to complete 18 cycles of therapy. The median age of patients was 50 (range: 25-81 years), all patients were female, and a majority of patients were white (67%). The median number of HERCEPTIN HYLECTA cycles received was 18 (range 1-18).
The most common adverse reactions of any grade (occurring in ≥10% of patients) with HERCEPTIN HYLECTA were alopecia (63%), nausea (49%), ARRs (48%), neutropenia (44%), diarrhea (34%), asthenia (25%), fatigue (24%), vomiting (23%), myalgia (21%), decreased appetite (20%), stomatitis (19%), arthralgia (18%), headache (17%), rash (16%), constipation (14%), radiation skin injury (14%), pyrexia (12%), cough (12%), anemia (11%), dyspnea (11%), incision site pain (11%), peripheral sensory neuropathy (11%), leukopenia (10%), mucosal inflammation (10%), hot flush (10%), upper respiratory tract infection (10%).
The most common Grade ≥3 adverse reactions (occurring in >1% of patients) in the HERCEPTIN HYLECTA arm were neutropenia (30%), febrile neutropenia (6%), leukopenia (4%), diarrhea (3%), hypertension (2%), irregular menstruation (2%), alopecia (1%), nausea (1%), granulocytopenia (1%), vomiting (1%), amenorrhea (1%), and cellulitis (1%). Adverse reactions leading to interruption of any study drug in the HERCEPTIN HYLECTA arm occurred in 34% of patients; 31% of patients had these events during the neoadjuvant phase of the study with concurrent chemotherapy and 9% of patients had these events during the adjuvant phase.
Overall, the most common (≥ 1%) were neutropenia (21%), leukopenia (2.4%), ALT increase (1.7%), pyrexia (1.7%), anemia (1%), bronchitis (1%), and left ventricular dysfunction (1%). Adverse reactions that led to discontinuation of any study drug in the HERCEPTIN HYLECTA arm (>1 patient) were left ventricular dysfunction (2%). The incidence of ARRs in the HERCEPTIN HYLECTA arm was 48% and was 37% in the intravenous trastuzumab arm.
Five (2%) patients in the HERCEPTIN HYLECTA arm experienced a Grade 3 ARR. Three of the events in the HERCEPTIN HYLECTA arm occurred on the day of study drug administration when docetaxel treatment was administered concurrently. The most commonly reported ARRs in the HERCEPTIN HYLECTA arm (≥5% of patients) were rash, pruritus, erythema, cough and dyspnea. Grade 1 and 2 injection-site reactions (ISRs) occurred in 10% of patients in the HERCEPTIN HYLECTA arm.
The most common ISRs were injection-site pain and injection-site erythema. The data in Table 3 were obtained from the HannaH trial for adverse reactions that occurred in ≥ 5% of the patients treated with HERCEPTIN HYLECTA. Table 3 Adverse Reactions Contains grouped terms (≥ 5% Incidence) Reported in HannaH Adverse Reactions HERCEPTIN HYLECTA 600 mg n=297 Intravenous Trastuzumab (loading dose: 8 mg/kg; maintenance dose: 6 mg/kg) n=298 All Grades % Grades 3 to 5 % All Grades % Grades 3 to 5 % SKIN AND SUBCUTANEOUS TISSUE DISORDERS Alopecia , The HannaH trial was not designed to demonstrate a statistically significant difference in adverse reaction rates between HERCEPTIN HYLECTA and intravenous trastuzumab. 63 1.3 63
SafeHER was a prospective, two-cohort, non-randomized, multi-center, multinational, open-label study to assess the safety of HERCEPTIN HYLECTA in patients with operable HER2-positive breast cancer. In SafeHER, 1864 patients were enrolled and treated with 600 mg of HERCEPTIN HYLECTA administered subcutaneously once every three weeks for 18 cycles. The median age of patients was 54 (range: 20-88 years), 99.8% were female, and a majority were white (76%).
A majority of the patients received HERCEPTIN HYLECTA concurrently with a chemotherapy regimen (58%). The median number of HERCEPTIN HYLECTA cycles administered was 18 and the median duration of HERCEPTIN HYLECTA exposure was 11.8 months. The median duration of
Our copy of this section ends here. The full text is in the official label at the FDA. Open Drugs@FDA
Composition
Active ingredients
TRASTUZUMAB AND HYALURONIDASE-OYSK 600MG
Official product information
Drugs@FDA lists the approved labels, letters and reviews for application BLA761106.
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.
