Herceptin Hylecta
Generic: TRASTUZUMAB AND HYALURONIDASE-OYSK
Basic Information
Manufacturer
Genentech, Inc.
Product Type
HUMAN PRESCRIPTION DRUG
Route of Administration
SUBCUTANEOUS
FDA Set ID
ebf30894-41cf-480c-8bc3-56f592a13813
Indications & Usage
1 INDICATIONS AND USAGE 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 ) 1.1 Adjuvant 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) ] .
1.2 Metastatic 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) ] .
( 1.1 , 1.2 ) Select patients for therapy based on an FDA-authorized companion diagnostic for trastuzumab.
( 1 , 2.2 ) 1.1 Adjuvant 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) ] .
1.2 Metastatic 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) ] .
Adverse Reactions
6 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.
6.1 Clinical 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 1.7 Rash , 26 < 1 26 - Nail Disorder , 14 - 14 < 1 Pruritus , 9 - 9 - Skin Discoloration 9 - 8 - Erythema 7 < 1 3 - GASTROINTESTINAL DISORDERS Nausea 49 1.3 49 1.3 Diarrhea , 34 2.7 37 2.7 Vomiting 23 1 23 1.7 Stomatitis 21 < 1 18 < 1 Abdominal Pain , 14 - 14 < 1 Dyspepsia 11 - 10 - GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Fatigue , 46 < 1 49 2 Edema , 14 - 15 - Pyrexia 13 1 12 < 1 Mucosal Inflammation 10 < 1 13 - Pain , 5 - 8 < 1 Injection Site Reaction , Injection Site Reaction includes terms for injection related reaction and injection site joint pain, bruising, dermatitis, discoloration, discomfort, erythema, extravasation, fibrosis, hematoma, hemorrhage, hypersensitivity, induration, inflammation, irritation, macule, mass, nodule, edema, pallor, paraesthesia, pruritus, rash, reaction, swelling, ulcer, vesicles and warmth.
10 - < 1 - BLOOD AND LYMPHATIC SYSTEM DISORDERS Neutropenia 44 30 47 34 Leukopenia , 11 5 16 8 Anemia , 12 < 1 14 1 Febrile Neutropenia 6 6 4 4 INFECTIONS AND INFESTATIONS Upper Respiratory Tract Infection , 24 1 27 < 1 Urinary Tract Infection , 4 - 8 < 1 MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS Myalgia 21 - 19 < 1 Arthralgia , 18 - 21 < 1 Back Pain 11 1 9 1 Pain in Extremity 10 - 9 < 1 Pain , 8 < 1 9 - Bone Pain 6 < 1 3.4 - NERVOUS SYSTEM DISORDERS Neuropathy Peripheral 20 - 15 - Headache 17 < 1 15 < 1 Dizziness 10 < 1 9 < 1 Dysgeusia 10 - 8 - INJURY, POISONING AND PROCEDURAL COMPLICATIONS Incision Site Complication 11 - 8 < 1 Pain 6 - 5 < 1 RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS Cough 12 < 1 8 - Dyspnea , 7 - 8 - Epistaxis 6 - 6 - Nasal Inflammation / Discomfort , 5 - 7 - VASCULAR DISORDERS Flushing 14 < 1 13 < 1 Hypertension 8 2.4 5 < 1 METABOLISM AND NUTRITION DISORDERS Decreased Appetite 20 < 1 20 < 1 INVESTIGATIONS Liver Function Analysis Abnormal , 6 1 9 1.7 CARDIAC DISORDERS Arrhythmia 5 - 5 < 1 IMMUNE SYSTEM DISORDERS Hypersensitivity , 7 1 7 1.3 SafeHER 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 follow-up was 23.7 months.
During the treatment period, the most common adverse reactions of any grade (occurring in ≥10% of patients) were ARRs (39%), diarrhea (21%), fatigue (21%), arthralgia (21%), nausea (15%), myalgia (14%), headache (13%), asthenia (12%), pain in extremity (11%), cough (11%), pyrexia (11%), hot flush (10%), and rash (10%).
The most common Grade ≥3 adverse reactions (occurring in >1% of patients) were neutropenia (4%), febrile neutropenia (2%), hypertension (2%), leukopenia (1%), and diarrhea (1%).
Adverse reactions that led to study drug discontinuation (≥0.5% of patients) were ejection fraction decreased (2%) and left ventricular dysfunction (1%).
The incidence of ARRs was 39%, with Grade ≥3 ARRs reported in 1% of patients treated with HERCEPTIN HYLECTA.
The most frequently reported Grade ≥3 ARRs were dyspnea (<1%), cough (<1%), erythema (<1%), rash (<1%), and drug hypersensitivity (<1%).
ISRs were reported in 20% of patients treated with HERCEPTIN HYLECTA.
The most common ISRs were injection-site erythema (7%) and injection-site pain (6%).
All ISRs were Grade 1 or 2, except for one (<1%) Grade 3 injection site discomfort.
The data in Table 4 were obtained from the SafeHER trial for adverse reactions that occurred in ≥5% of the patients treated with HERCEPTIN HYLECTA.
Table 4 Adverse Reactions Contains grouped terms (≥ 5% Incidence) Reported in SafeHER Adverse Reactions , Includes adverse reactions reported throughout study treatment and follow-up.
HERCEPTIN HYLECTA 600 mg (once every 3 weeks) n=1864 All Grades % Grades 3 to 5 % GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Fatigue 33 < 1 Injection Site Reaction , ISR includes injection related reaction and injection site joint pain, bruising, dermatitis, discoloration, discomfort, erythema, extravasation, fibrosis, hematoma, hemorrhage, hypersensitivity, induration, inflammation, irritation, macule, mass, nodule, edema, pallor, paresthesia, pruritus, rash, reaction, swelling, ulcer, vesicles and warmth.
20 < 1 Edema 12 < 1 Pyrexia 11 < 1 Pain 8 < 1 Mucosal Inflammation 6 < 1 MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS Arthralgia 21 < 1 Myalgia 17 < 1 Pain in Extremity 11 < 1 Back Pain 8 < 1 Pain 7 < 1 GASTROINTESTINAL DISORDERS Diarrhea 21 1 Nausea 15 < 1 Abdominal Pain 10 < 1 Constipation 9 < 1 Stomatitis 8 < 1 Vomiting 7 < 1 SKIN AND SUBCUTANEOUS TISSUE DISORDERS Rash 17 < 1 Nail Disorder 10 < 1 Alopecia 9 < 1 Erythema 9 < 1 Pruritus 6 - INFECTIONS AND INFESTATIONS Upper Respiratory Tract Infection 19 < 1 Urinary Tract Infection 6 < 1 Viral Infection 5 - NERVOUS SYSTEM DISORDERS Neuropathy Peripheral 14 < 1 Headache 13 < 1 Dizziness 6 < 1 Paresthesia 6 < 1 RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS Cough 11 < 1 Dyspnea 8 < 1 Epistaxis 6 - Nasal Inflammation/Discomfort 6 - VASCULAR DISORDERS Flushing 12 < 1 Hypertension 8 2 BLOOD AND LYMPHATIC SYSTEM DISORDERS Anemia 8 < 1 Neutropenia 6 4 PSYCHIATRIC DISORDERS Insomnia 7 < 1 Metastatic Breast Cancer (based on intravenous trastuzumab) The data below reflect exposure to intravenous trastuzumab 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 one single-arm study (H0649g; n=222) in patients with metastatic breast cancer.
Data in Table 5 are based on H0648g and H0649g.
Among the 464 patients treated in H0648g, the median age was 52 years (range: 25–77 years).
Eighty-nine percent were white, 5% black, 1% Asian, and 5% other racial/ethnic groups.
All patients received 4 mg/kg initial dose of intravenous trastuzumab followed by 2 mg/kg weekly.
The percentages of patients who received intravenous trastuzumab treatment for ≥ 6 months and ≥ 12 months were 58% and 9%, respectively.
Among the 352 patients treated in single agent studies (213 patients from H0649g), the median age was 50 years (range 28–86 years), 86% were white, 3% were black, 3% were Asian, and 8% in other racial/ethnic groups.
Most of the patients received 4 mg/kg initial dose of intravenous trastuzumab followed by 2 mg/kg weekly.
The percentages of patients who received intravenous trastuzumab treatment for ≥ 6 months and ≥ 12 months were 31% and 16%, respectively.
Table 5 Adverse Reactions ( ≥ 5%) in the Intravenous Trastuzumab Arm (H0648g and H0649g) Intravenous trastuzumab Data for Herceptin single agent were from 4 studies, including 213 patients from H0649g.
n = 352 % Intravenous trastuzumab + Paclitaxel n = 91 % Paclitaxel n = 95 % Intravenous trastuzumab + AC Anthracycline (doxorubicin or epirubicin) and cyclophosphamide.
n = 143 % AC n = 135 % General Pain 47 61 62 57 42 Asthenia 42 62 57 54 55 Fever 36 49 23 56 34 Chills 32 41 4 35 11 Headache 26 36 28 44 31 Abdominal pain 22 34 22 23 18 Back pain 22 34 30 27 15 Infection 20 47 27 47 31 Flu syndrome 10 12 5 12 6 Accidental injury 6 13 3 9 4 Allergic reaction 3 8 2 4 2 Gastrointestinal Nausea 33 51 9 76 77 Diarrhea 25 45 29 45 26 Vomiting 23 37 28 53 49 Anorexia 14 24 16 31 26 Nausea and vomiting 8 14 11 18 9 Respiratory Cough increased 26 41 22 43 29 Dyspnea 22 27 26 42 25 Rhinitis 14 22 5 22 16 Pharyngitis 12 22 14 30 18 Sinusitis 9 21 7 13 6 Skin Rash 18 38 18 27 17 Herpes simplex 2 12 3 7 9 Acne 2 11 3 3 < 1 Nervous Insomnia 14 25 13 29 15 Dizziness 13 22 24 24 18 Paresthesia 9 48 39 17 11 Depression 6 12 13 20 12 Peripheral neuritis 2 23 16 2 2 Neuropathy 1 13 5 4 4 Metabolic Peripheral edema 10 22 20 20 17 Edema 8 10 8 11 5 Cardiovascular Congestive heart failure 7 11 1 28 7 Tachycardia 5 12 4 10 5 Musculoskeletal Bone pain 7 24 18 7 7 Arthralgia 6 37 21 8 9 Urogenital Urinary tract infection 5 18 14 13 7 Blood and Lymphatic Anemia 4 14 9 36 26 Leukopenia 3 24 17 52 34 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of trastuzumab.
Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Administration-related reaction [see Warnings and Precautions (5.5) ] Oligohydramnios or oligohydramnios sequence, including pulmonary hypoplasia, skeletal abnormalities, and neonatal death [see Warnings and Precautions (5.2) ] Glomerulopathy [see Adverse Reactions (6.1) ] Immune thrombocytopenia Tumor lysis syndrome (TLS): Cases of possible TLS have been reported in patients treated with trastuzumab.
Patients with significant tumor burden (e.g.
bulky metastases) may be at a higher risk.
Patients could present with hyperuricemia, hyperphosphatemia, and acute renal failure which may represent possible TLS.
Providers should consider additional monitoring and/or treatment as clinically indicated.
( 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.
6.1 Clinical 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 1.7 Rash , 26 < 1 26 - Nail Disorder , 14 - 14 < 1 Pruritus , 9 - 9 - Skin Discoloration 9 - 8 - Erythema 7 < 1 3 - GASTROINTESTINAL DISORDERS Nausea 49 1.3 49 1.3 Diarrhea , 34 2.7 37 2.7 Vomiting 23 1 23 1.7 Stomatitis 21 < 1 18 < 1 Abdominal Pain , 14 - 14 < 1 Dyspepsia 11 - 10 - GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Fatigue , 46 < 1 49 2 Edema , 14 - 15 - Pyrexia 13 1 12 < 1 Mucosal Inflammation 10 < 1 13 - Pain , 5 - 8 < 1 Injection Site Reaction , Injection Site Reaction includes terms for injection related reaction and injection site joint pain, bruising, dermatitis, discoloration, discomfort, erythema, extravasation, fibrosis, hematoma, hemorrhage, hypersensitivity, induration, inflammation, irritation, macule, mass, nodule, edema, pallor, paraesthesia, pruritus, rash, reaction, swelling, ulcer, vesicles and warmth.
10 - < 1 - BLOOD AND LYMPHATIC SYSTEM DISORDERS Neutropenia 44 30 47 34 Leukopenia , 11 5 16 8 Anemia , 12 < 1 14 1 Febrile Neutropenia 6 6 4 4 INFECTIONS AND INFESTATIONS Upper Respiratory Tract Infection , 24 1 27 < 1 Urinary Tract Infection , 4 - 8 < 1 MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS Myalgia 21 - 19 < 1 Arthralgia , 18 - 21 < 1 Back Pain 11 1 9 1 Pain in Extremity 10 - 9 < 1 Pain , 8 < 1 9 - Bone Pain 6 < 1 3.4 - NERVOUS SYSTEM DISORDERS Neuropathy Peripheral 20 - 15 - Headache 17 < 1 15 < 1 Dizziness 10 < 1 9 < 1 Dysgeusia 10 - 8 - INJURY, POISONING AND PROCEDURAL COMPLICATIONS Incision Site Complication 11 - 8 < 1 Pain 6 - 5 < 1 RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS Cough 12 < 1 8 - Dyspnea , 7 - 8 - Epistaxis 6 - 6 - Nasal Inflammation / Discomfort , 5 - 7 - VASCULAR DISORDERS Flushing 14 < 1 13 < 1 Hypertension 8 2.4 5 < 1 METABOLISM AND NUTRITION DISORDERS Decreased Appetite 20 < 1 20 < 1 INVESTIGATIONS Liver Function Analysis Abnormal , 6 1 9 1.7 CARDIAC DISORDERS Arrhythmia 5 - 5 < 1 IMMUNE SYSTEM DISORDERS Hypersensitivity , 7 1 7 1.3 SafeHER 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 follow-up was 23.7 months.
During the treatment period, the most common adverse reactions of any grade (occurring in ≥10% of patients) were ARRs (39%), diarrhea (21%), fatigue (21%), arthralgia (21%), nausea (15%), myalgia (14%), headache (13%), asthenia (12%), pain in extremity (11%), cough (11%), pyrexia (11%), hot flush (10%), and rash (10%).
The most common Grade ≥3 adverse reactions (occurring in >1% of patients) were neutropenia (4%), febrile neutropenia (2%), hypertension (2%), leukopenia (1%), and diarrhea (1%).
Adverse reactions that led to study drug discontinuation (≥0.5% of patients) were ejection fraction decreased (2%) and left ventricular dysfunction (1%).
The incidence of ARRs was 39%, with Grade ≥3 ARRs reported in 1% of patients treated with HERCEPTIN HYLECTA.
The most frequently reported Grade ≥3 ARRs were dyspnea (<1%), cough (<1%), erythema (<1%), rash (<1%), and drug hypersensitivity (<1%).
ISRs were reported in 20% of patients treated with HERCEPTIN HYLECTA.
The most common ISRs were injection-site erythema (7%) and injection-site pain (6%).
All ISRs were Grade 1 or 2, except for one (<1%) Grade 3 injection site discomfort.
The data in Table 4 were obtained from the SafeHER trial for adverse reactions that occurred in ≥5% of the patients treated with HERCEPTIN HYLECTA.
Table 4 Adverse Reactions Contains grouped terms (≥ 5% Incidence) Reported in SafeHER Adverse Reactions , Includes adverse reactions reported throughout study treatment and follow-up.
HERCEPTIN HYLECTA 600 mg (once every 3 weeks) n=1864 All Grades % Grades 3 to 5 % GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Fatigue 33 < 1 Injection Site Reaction , ISR includes injection related reaction and injection site joint pain, bruising, dermatitis, discoloration, discomfort, erythema, extravasation, fibrosis, hematoma, hemorrhage, hypersensitivity, induration, inflammation, irritation, macule, mass, nodule, edema, pallor, paresthesia, pruritus, rash, reaction, swelling, ulcer, vesicles and warmth.
20 < 1 Edema 12 < 1 Pyrexia 11 < 1 Pain 8 < 1 Mucosal Inflammation 6 < 1 MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS Arthralgia 21 < 1 Myalgia 17 < 1 Pain in Extremity 11 < 1 Back Pain 8 < 1 Pain 7 < 1 GASTROINTESTINAL DISORDERS Diarrhea 21 1 Nausea 15 < 1 Abdominal Pain 10 < 1 Constipation 9 < 1 Stomatitis 8 < 1 Vomiting 7 < 1 SKIN AND SUBCUTANEOUS TISSUE DISORDERS Rash 17 < 1 Nail Disorder 10 < 1 Alopecia 9 < 1 Erythema 9 < 1 Pruritus 6 - INFECTIONS AND INFESTATIONS Upper Respiratory Tract Infection 19 < 1 Urinary Tract Infection 6 < 1 Viral Infection 5 - NERVOUS SYSTEM DISORDERS Neuropathy Peripheral 14 < 1 Headache 13 < 1 Dizziness 6 < 1 Paresthesia 6 < 1 RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS Cough 11 < 1 Dyspnea 8 < 1 Epistaxis 6 - Nasal Inflammation/Discomfort 6 - VASCULAR DISORDERS Flushing 12 < 1 Hypertension 8 2 BLOOD AND LYMPHATIC SYSTEM DISORDERS Anemia 8 < 1 Neutropenia 6 4 PSYCHIATRIC DISORDERS Insomnia 7 < 1 Metastatic Breast Cancer (based on intravenous trastuzumab) The data below reflect exposure to intravenous trastuzumab 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 one single-arm study (H0649g; n=222) in patients with metastatic breast cancer.
Data in Table 5 are based on H0648g and H0649g.
Among the 464 patients treated in H0648g, the median age was 52 years (range: 25–77 years).
Eighty-nine percent were white, 5% black, 1% Asian, and 5% other racial/ethnic groups.
All patients received 4 mg/kg initial dose of intravenous trastuzumab followed by 2 mg/kg weekly.
The percentages of patients who received intravenous trastuzumab treatment for ≥ 6 months and ≥ 12 months were 58% and 9%, respectively.
Among the 352 patients treated in single agent studies (213 patients from H0649g), the median age was 50 years (range 28–86 years), 86% were white, 3% were black, 3% were Asian, and 8% in other racial/ethnic groups.
Most of the patients received 4 mg/kg initial dose of intravenous trastuzumab followed by 2 mg/kg weekly.
The percentages of patients who received intravenous trastuzumab treatment for ≥ 6 months and ≥ 12 months were 31% and 16%, respectively.
Table 5 Adverse Reactions ( ≥ 5%) in the Intravenous Trastuzumab Arm (H0648g and H0649g) Intravenous trastuzumab Data for Herceptin single agent were from 4 studies, including 213 patients from H0649g.
n = 352 % Intravenous trastuzumab + Paclitaxel n = 91 % Paclitaxel n = 95 % Intravenous trastuzumab + AC Anthracycline (doxorubicin or epirubicin) and cyclophosphamide.
n = 143 % AC n = 135 % General Pain 47 61 62 57 42 Asthenia 42 62 57 54 55 Fever 36 49 23 56 34 Chills 32 41 4 35 11 Headache 26 36 28 44 31 Abdominal pain 22 34 22 23 18 Back pain 22 34 30 27 15 Infection 20 47 27 47 31 Flu syndrome 10 12 5 12 6 Accidental injury 6 13 3 9 4 Allergic reaction 3 8 2 4 2 Gastrointestinal Nausea 33 51 9 76 77 Diarrhea 25 45 29 45 26 Vomiting 23 37 28 53 49 Anorexia 14 24 16 31 26 Nausea and vomiting 8 14 11 18 9 Respiratory Cough increased 26 41 22 43 29 Dyspnea 22 27 26 42 25 Rhinitis 14 22 5 22 16 Pharyngitis 12 22 14 30 18 Sinusitis 9 21 7 13 6 Skin Rash 18 38 18 27 17 Herpes simplex 2 12 3 7 9 Acne 2 11 3 3 < 1 Nervous Insomnia 14 25 13 29 15 Dizziness 13 22 24 24 18 Paresthesia 9 48 39 17 11 Depression 6 12 13 20 12 Peripheral neuritis 2 23 16 2 2 Neuropathy 1 13 5 4 4 Metabolic Peripheral edema 10 22 20 20 17 Edema 8 10 8 11 5 Cardiovascular Congestive heart failure 7 11 1 28 7 Tachycardia 5 12 4 10 5 Musculoskeletal Bone pain 7 24 18 7 7 Arthralgia 6 37 21 8 9 Urogenital Urinary tract infection 5 18 14 13 7 Blood and Lymphatic Anemia 4 14 9 36 26 Leukopenia 3 24 17 52 34 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of trastuzumab.
Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Administration-related reaction [see Warnings and Precautions (5.5) ] Oligohydramnios or oligohydramnios sequence, including pulmonary hypoplasia, skeletal abnormalities, and neonatal death [see Warnings and Precautions (5.2) ] Glomerulopathy [see Adverse Reactions (6.1) ] Immune thrombocytopenia Tumor lysis syndrome (TLS): Cases of possible TLS have been reported in patients treated with trastuzumab.
Patients with significant tumor burden (e.g.
bulky metastases) may be at a higher risk.
Patients could present with hyperuricemia, hyperphosphatemia, and acute renal failure which may represent possible TLS.
Providers should consider additional monitoring and/or treatment as clinically indicated.