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)]

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* (≥ 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 %
* Contains grouped terms † The HannaH trial was not designed to demonstrate a statistically significant difference in adverse reaction rates between HERCEPTIN HYLECTA and intravenous trastuzumab. ‡ 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.
SKIN AND SUBCUTANEOUS TISSUE DISORDERS
Alopecia*,†	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*,‡	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* (≥ 5% Incidence) Reported in SafeHER
Adverse Reactions *,†	HERCEPTIN HYLECTA 600 mg (once every 3 weeks) n=1864
Adverse Reactions *,†	All Grades %	Grades 3 to 5 %
* Contains grouped terms † Includes adverse reactions reported throughout study treatment and follow-up. ‡ 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.
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS
Fatigue*	33	< 1
Injection Site Reaction*,‡	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 * n = 352 %	Intravenous trastuzumab + Paclitaxel n = 91 %	Paclitaxel n = 95 %	Intravenous trastuzumab + AC† n = 143 %	AC† n = 135 %
* Data for Herceptin single agent were from 4 studies, including 213 patients from H0649g. † Anthracycline (doxorubicin or epirubicin) and cyclophosphamide.
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.