Herceptin Hylecta

WARNING: CARDIOMYOPATHY, EMBRYO-FETAL TOXICITY, and PULMONARY TOXICITY WARNING: CARDIOMYOPATHY, EMBRYO-FETAL TOXICITY, and PULMONARY TOXICITY See full prescribing information for complete boxed warning. Cardiomyopathy: HERCEPTIN HYLECTA can result in subclinical and clinical cardiac failure manifesting as CHF, and decreased LVEF, with greatest risk when administered concurrently with anthracyclines. Evaluate cardiac function prior to and during treatment. Discontinue HERCEPTIN HYLECTA for cardiomyopathy. ( 2.4 , 5.1 ) Pulmonary Toxicity: Discontinue HERCEPTIN HYLECTA for anaphylaxis, angioedema, interstitial pneumonitis or acute respiratory distress syndrome. ( 5.3 ) Embryo-Fetal Toxicity: Exposure to HERCEPTIN HYLECTA during pregnancy can result in oligohydramnios, in some cases complicated by pulmonary hypoplasia and neonatal death. Advise patients of these risks and the need for effective contraception. ( 5.2 , 8.1 , 8.3 ) Cardiomyopathy HERCEPTIN HYLECTA administration can result in sub - clinical and clinical cardiac failure. The incidence and severity was highest in patients receiving HERCEPTIN HYLECTA with anthracycline - containing chemotherapy regimens. Evaluate left ventricular function in all patients prior to and during treatment with HERCEPTIN HYLECTA. Discontinue HERCEPTIN HYLECTA treatment in patients receiving adjuvant therapy and withhold HERCEPTIN HYLECTA in patients with metastatic disease for clinically significant decrease in left ventricular function [see Dosage and Administration (2.4) and Warnings and Precautions (5.1) ]. Pulmonary Toxicity HERCEPTIN HYLECTA administration can result in serious and fatal pulmonary toxicity. Symptoms usually occur during or within 24 hours of HERCEPTIN HYLECTA administration. Discontinue HERCEPTIN HYLECTA for anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome [see Warnings and Precautions (5.3 , 5.5) ] . Monitor patients until symptoms completely resolve. Embryo-Fetal Toxicity Exposure to HERCEPTIN HYLECTA during pregnancy can result in oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death. Advise patients of these risks and the need for effective contraception [see Warnings and Precautions (5.2) and Use in Specific Populations (8.1 , 8.3) ].

5 WARNINGS AND PRECAUTIONS 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 ) 5.1 Cardiomyopathy 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. 5.2 Embryo-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 status of females of reproductive potential prior to the initiation of HERCEPTIN HYLECTA. Advise pregnant women and females of reproductive potential that exposure to HERCEPTIN HYLECTA 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 HERCEPTIN HYLECTA [see Use in Specific Populations (8.1 , 8.3) and Clinical Pharmacology (12.3) ]. 5.3 Pulmonary Toxicity HERCEPTIN HYLECTA 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. 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. 5.4 Exacerbation of Chemotherapy-Induced Neutropenia HERCEPTIN HYLECTA may exacerbate chemotherapy-induced neutropenia. In randomized, controlled clinical trials with intravenous trastuzumab, the per-patient incidences of NCI-CTC Grade 3–4 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) ]. 5.5 Hypersensitivity and Administration-Related Reactions Severe administration-related reactions (ARRs), including hypersensitivity and anaphylaxis, have been reported with HERCEPTIN HYLECTA . Patients experiencing dyspnea at rest due to complications of advanced malignancy and comorbidities may be at increased risk of a severe or of a fatal ARR. In the HannaH and SafeHER trials, 9% and 4.2% of patients experienced Grade 1-4 hypersensitivity and anaphylaxis, respectively. Grade 3-4 hypersensitivity and anaphylactic reactions occurred in 1% and <1% of the patients treated with HERCEPTIN HYLECTA, respectively. In the SafeHER trial, 2 patients required permanent treatment discontinuation with HERCEPTIN HYLECTA (1 patient due to a hypersensitivity reaction and 1 patient due to anaphylaxis). Serious and fatal reactions have been reported after treatment with intravenous trastuzumab products. Closely monitor patients for systemic hypersensitivity reactions, especially during the first administration. Permanently discontinue HERCEPTIN HYLECTA in patients who experience anaphylaxis or severe hypersensitivity reactions. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use. For patients experiencing reversible Grade 1 or 2 hypersensitivity reactions, consider pre-medication with an analgesic, antipyretic, or an antihistamine prior to readministration of HERCEPTIN HYLECTA [see Adverse Reactions (6.1) ].

<table width="85%" ID="t1"><caption>Table 1 Incidence of Congestive Heart Failure in Adjuvant Breast Cancer Studies</caption><col width="18%" align="left" valign="top"/><col width="28%" align="left" valign="top"/><col width="27%" align="center" valign="top"/><col width="27%" align="center" valign="top"/><thead><tr><th styleCode="Lrule" colspan="2"/><th styleCode="Botrule Rrule" colspan="2" align="center">Incidence of Congestive Heart Failure % (n)</th></tr><tr><th styleCode="Lrule" align="center" valign="bottom">Study</th><th align="center" valign="bottom">Regimen</th><th valign="bottom">Intravenous Trastuzumab</th><th styleCode="Rrule" valign="bottom">Control</th></tr></thead><tbody><tr><td styleCode="Lrule">NSABP B31 &amp; NCCTG N9831<content styleCode="italics"><footnote>Median follow-up duration for studies NSABP B31 and NCCTG N9831 combined was 8.3 years in the AC&#x2192; paclitaxel+Herceptin arm.</footnote></content></td><td>AC<content styleCode="italics"><footnote ID="t1f2">Anthracycline (doxorubicin) and cyclophosphamide.</footnote></content>&#x2192;paclitaxel + intravenous trastuzumab</td><td>3.2% (64/2000) <content styleCode="italics"><footnote>Includes 1 patient with fatal cardiomyopathy and 1 patient with sudden death without documented etiology.</footnote></content></td><td styleCode="Rrule">1.3% (21/1655)</td></tr><tr><td styleCode="Lrule">HERA<content styleCode="italics"><footnote>Includes NYHA II-IV and cardiac death at 12.6 months median duration of follow-up in the one-year intravenous trastuzumab arm.</footnote></content></td><td>Chemotherapy &#x2192; intravenous trastuzumab</td><td>2% (30/1678)</td><td styleCode="Rrule">0.3% (5/1708)</td></tr><tr><td styleCode="Lrule">BCIRG006</td><td>AC<content styleCode="italics"><footnoteRef IDREF="t1f2"/></content>&#x2192;docetaxel + intravenous trastuzumab</td><td>2% (20/1068)</td><td styleCode="Rrule">0.3% (3/1050)</td></tr><tr><td styleCode="Lrule">BCIRG006</td><td>Docetaxel + carboplatin + intravenous trastuzumab</td><td>0.4% (4/1056)</td><td styleCode="Rrule">0.3% (3/1050)</td></tr></tbody></table>

<table width="85%"><caption>Table 2 Incidence of Cardiac Dysfunction<footnote>Congestive heart failure or significant asymptomatic decrease in LVEF.</footnote> in Metastatic Breast Cancer Studies</caption><col width="15%" align="left" valign="top"/><col width="25%" align="left" valign="middle"/><col width="15%" align="center" valign="middle"/><col width="15%" align="center" valign="middle"/><col width="15%" align="center" valign="middle"/><col width="15%" align="center" valign="middle"/><thead><tr><th styleCode="Lrule" colspan="2"/><th styleCode="Rrule" colspan="4" align="center">Incidence</th></tr><tr><th styleCode="Lrule" colspan="2"/><th styleCode="Botrule" colspan="2">NYHA I&#x2013;IV</th><th styleCode="Botrule Rrule" colspan="2">NYHA III&#x2013;IV </th></tr><tr><th styleCode="Lrule" align="center" valign="bottom">Study</th><th align="center" valign="bottom">Event</th><th valign="bottom">Intravenous Trastuzumab</th><th valign="bottom">Control</th><th valign="bottom">Intravenous Trastuzumab</th><th styleCode="Rrule" valign="bottom">Control</th></tr></thead><tbody><tr><td styleCode="Lrule">H0648g (AC)<content styleCode="italics"><footnote>Anthracycline (doxorubicin or epirubicin) and cyclophosphamide.</footnote></content></td><td>Cardiac Dysfunction</td><td>28%</td><td>7%</td><td>19%</td><td styleCode="Rrule">3%</td></tr><tr><td styleCode="Lrule">H0648g (paclitaxel)</td><td>Cardiac Dysfunction</td><td>11%</td><td>1%</td><td>4%</td><td styleCode="Rrule">1%</td></tr><tr><td styleCode="Lrule">H0649g</td><td>Cardiac Dysfunction<content styleCode="italics"><footnote>Includes 1 patient with fatal cardiomyopathy.</footnote></content></td><td>7%</td><td>N/A</td><td>5%</td><td styleCode="Rrule">N/A</td></tr></tbody></table>

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.

<table width="85%" ID="t3"><caption>Table 3 Adverse Reactions<footnote ID="t3f1">Contains grouped terms</footnote> (&#x2265; 5% Incidence) Reported in HannaH</caption><col width="24%" align="left" valign="middle"/><col width="19%" align="center" valign="middle"/><col width="19%" align="center" valign="middle"/><col width="19%" align="center" valign="middle"/><col width="19%" align="center" valign="middle"/><thead><tr styleCode="Botrule"><th styleCode="Lrule Rrule" align="center" valign="top">Adverse Reactions</th><th styleCode="Rrule" colspan="2" valign="top">HERCEPTIN HYLECTA 600 mg n=297</th><th styleCode="Rrule" colspan="2" valign="top">Intravenous Trastuzumab (loading dose: 8 mg/kg; maintenance dose: 6 mg/kg) n=298</th></tr><tr><th styleCode="Lrule Rrule"/><th styleCode="Rrule">All Grades %</th><th styleCode="Rrule">Grades 3 to 5 %</th><th styleCode="Rrule">All Grades %</th><th styleCode="Rrule">Grades 3 to 5 %</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5"><content styleCode="bold">SKIN AND SUBCUTANEOUS TISSUE DISORDERS</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Alopecia<content styleCode="italics"><footnoteRef IDREF="t3f1"/>^,<footnote ID="t3f2">The HannaH trial was not designed to demonstrate a statistically significant difference in adverse reaction rates between HERCEPTIN HYLECTA and intravenous trastuzumab. </footnote></content></td><td styleCode="Rrule">63</td><td styleCode="Rrule">1.3</td><td styleCode="Rrule">63</td><td styleCode="Rrule">1.7</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Rash<content styleCode="italics"><footnoteRef IDREF="t3f1"/>^,<footnoteRef IDREF="t3f2"/></content></td><td styleCode="Rrule">26</td><td styleCode="Rrule">&lt; 1</td><td styleCode="Rrule">26</td><td styleCode="Rrule">-</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Nail Disorder<content styleCode="italics"><footnoteRef IDREF="t3f1"/>^,<footnoteRef IDREF="t3f2"/></content></td><td styleCode="Rrule">14</td><td styleCode="Rrule">-</td><td styleCode="Rrule">14</td><td styleCode="Rrule">&lt; 1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Pruritus<content styleCode="italics"><footnoteRef IDREF="t3f1"/>^,<footnoteRef IDREF="t3f2"/></content></td><td styleCode="Rrule">9</td><td styleCode="Rrule">-</td><td styleCode="Rrule">9</td><td styleCode="Rrule">-</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Skin Discoloration<content styleCode="italics"><footnoteRef IDREF="t3f1"/></content></td><td styleCode="Rrule">9</td><td styleCode="Rrule">-</td><td styleCode="Rrule">8</td><td styleCode="Rrule">-</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Erythema<content styleCode="italics"><footnoteRef IDREF="t3f1"/></content></td><td styleCode="Rrule">7</td><td styleCode="Rrule">&lt; 1</td><td styleCode="Rrule">3</td><td styleCode="Rrule">-</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5"><content styleCode="bold">GASTROINTESTINAL DISORDERS</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Nausea</td><td styleCode="Rrule">49</td><td styleCode="Rrule">1.3</td><td styleCode="Rrule">49</td><td styleCode="Rrule">1.3</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Diarrhea<content styleCode="italics"><footnoteRef IDREF="t3f1"/>^,<footnoteRef IDREF="t3f2"/></content></td><td styleCode="Rrule">34</td><td styleCode="Rrule">2.7</td><td styleCode="Rrule">37</td><td styleCode="Rrule">2.7</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Vomiting<content styleCode="italics"><footnoteRef IDREF="t3f2"/></content></td><td styleCode="Rrule">23</td><td styleCode="Rrule">1</td><td styleCode="Rrule">23</td><td styleCode="Rrule">1.7</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Stomatitis<content styleCode="italics"><footnoteRef IDREF="t3f1"/></content></td><td styleCode="Rrule">21</td><td styleCode="Rrule">&lt; 1</td><td styleCode="Rrule">18</td><td styleCode="Rrule">&lt; 1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Abdominal Pain<content styleCode="italics"><footnoteRef IDREF="t3f1"/>^,<footnoteRef IDREF="t3f2"/></content></td><td styleCode="Rrule">14</td><td styleCode="Rrule">-</td><td styleCode="Rrule">14</td><td styleCode="Rrule">&lt; 1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Dyspepsia</td><td styleCode="Rrule">11</td><td styleCode="Rrule">-</td><td styleCode="Rrule">10</td><td styleCode="Rrule">-</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5"><content styleCode="bold">GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Fatigue<content styleCode="italics"><footnoteRef IDREF="t3f1"/>^,<footnoteRef IDREF="t3f2"/></content></td><td styleCode="Rrule">46</td><td styleCode="Rrule">&lt; 1</td><td styleCode="Rrule">49</td><td styleCode="Rrule">2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Edema<content styleCode="italics"><footnoteRef IDREF="t3f1"/>^,<footnoteRef IDREF="t3f2"/></content></td><td styleCode="Rrule">14</td><td styleCode="Rrule">-</td><td styleCode="Rrule">15</td><td styleCode="Rrule">-</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Pyrexia<content styleCode="italics"><footnoteRef IDREF="t3f1"/></content></td><td styleCode="Rrule">13</td><td styleCode="Rrule">1</td><td styleCode="Rrule">12</td><td styleCode="Rrule">&lt; 1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Mucosal Inflammation<content styleCode="italics"><footnoteRef IDREF="t3f2"/></content></td><td styleCode="Rrule">10</td><td styleCode="Rrule">&lt; 1</td><td styleCode="Rrule">13</td><td styleCode="Rrule">-</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Pain<content styleCode="italics"><footnoteRef IDREF="t3f1"/>^,<footnoteRef IDREF="t3f2"/></content></td><td styleCode="Rrule">5</td><td styleCode="Rrule">-</td><td styleCode="Rrule">8</td><td styleCode="Rrule">&lt; 1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Injection Site Reaction<content styleCode="italics"><footnoteRef IDREF="t3f1"/>^,<footnote>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. </footnote></content></td><td styleCode="Rrule">10</td><td styleCode="Rrule">-</td><td styleCode="Rrule">&lt; 1</td><td styleCode="Rrule">-</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5"><content styleCode="bold">BLOOD AND LYMPHATIC SYSTEM DISORDERS </content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Neutropenia<content styleCode="italics"><footnoteRef IDREF="t3f2"/></content></td><td styleCode="Rrule">44</td><td styleCode="Rrule">30</td><td styleCode="Rrule">47</td><td styleCode="Rrule">34</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Leukopenia<content styleCode="italics"><footnoteRef IDREF="t3f1"/>^,<footnoteRef IDREF="t3f2"/></content></td><td styleCode="Rrule">11</td><td styleCode="Rrule">5</td><td styleCode="Rrule">16</td><td styleCode="Rrule">8</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Anemia<content styleCode="italics"><footnoteRef IDREF="t3f1"/>^,<footnoteRef IDREF="t3f2"/></content></td><td styleCode="Rrule">12</td><td styleCode="Rrule">&lt; 1</td><td styleCode="Rrule">14</td><td styleCode="Rrule">1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Febrile Neutropenia<content styleCode="italics"><footnoteRef IDREF="t3f1"/></content></td><td styleCode="Rrule">6</td><td styleCode="Rrule">6</td><td styleCode="Rrule">4</td><td styleCode="Rrule">4</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5"><content styleCode="bold">INFECTIONS AND INFESTATIONS</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Upper Respiratory Tract Infection<content styleCode="italics"><footnoteRef IDREF="t3f1"/>^,<footnoteRef IDREF="t3f2"/></content></td><td styleCode="Rrule">24</td><td styleCode="Rrule">1</td><td styleCode="Rrule">27</td><td styleCode="Rrule">&lt; 1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Urinary Tract Infection<content styleCode="italics"><footnoteRef IDREF="t3f1"/>^,<footnoteRef IDREF="t3f2"/></content></td><td styleCode="Rrule">4</td><td styleCode="Rrule">-</td><td styleCode="Rrule">8</td><td styleCode="Rrule">&lt; 1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5"><content styleCode="bold">MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Myalgia<content styleCode="italics"><footnoteRef IDREF="t3f1"/></content></td><td styleCode="Rrule">21</td><td styleCode="Rrule">-</td><td styleCode="Rrule">19</td><td styleCode="Rrule">&lt; 1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Arthralgia<content styleCode="italics"><footnoteRef IDREF="t3f1"/>^,<footnoteRef IDREF="t3f2"/></content></td><td styleCode="Rrule">18</td><td styleCode="Rrule">-</td><td styleCode="Rrule">21</td><td styleCode="Rrule">&lt; 1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Back Pain<content styleCode="italics"><footnoteRef IDREF="t3f1"/></content></td><td styleCode="Rrule">11</td><td styleCode="Rrule">1</td><td styleCode="Rrule">9</td><td styleCode="Rrule">1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Pain in Extremity</td><td styleCode="Rrule">10</td><td styleCode="Rrule">-</td><td styleCode="Rrule">9</td><td styleCode="Rrule">&lt; 1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Pain<content styleCode="italics"><footnoteRef IDREF="t3f1"/>^,<footnoteRef IDREF="t3f2"/></content></td><td styleCode="Rrule">8</td><td styleCode="Rrule">&lt; 1</td><td styleCode="Rrule">9</td><td styleCode="Rrule">-</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Bone Pain</td><td styleCode="Rrule">6</td><td styleCode="Rrule">&lt; 1</td><td styleCode="Rrule">3.4</td><td styleCode="Rrule">-</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5"><content styleCode="bold">NERVOUS SYSTEM DISORDERS</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Neuropathy Peripheral<content styleCode="italics"><footnoteRef IDREF="t3f1"/></content></td><td styleCode="Rrule">20</td><td styleCode="Rrule">-</td><td styleCode="Rrule">15</td><td styleCode="Rrule">-</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Headache<content styleCode="italics"><footnoteRef IDREF="t3f1"/></content></td><td styleCode="Rrule">17</td><td styleCode="Rrule">&lt; 1</td><td styleCode="Rrule">15</td><td styleCode="Rrule">&lt; 1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Dizziness<content styleCode="italics"><footnoteRef IDREF="t3f1"/></content></td><td styleCode="Rrule">10</td><td styleCode="Rrule">&lt; 1</td><td styleCode="Rrule">9</td><td styleCode="Rrule">&lt; 1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Dysgeusia<content styleCode="italics"><footnoteRef IDREF="t3f1"/></content></td><td styleCode="Rrule">10</td><td styleCode="Rrule">-</td><td styleCode="Rrule">8</td><td styleCode="Rrule">-</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5"><content styleCode="bold">INJURY, POISONING AND PROCEDURAL COMPLICATIONS</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Incision Site Complication<content styleCode="italics"><footnoteRef IDREF="t3f1"/></content></td><td styleCode="Rrule">11</td><td styleCode="Rrule">-</td><td styleCode="Rrule">8</td><td styleCode="Rrule">&lt; 1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Pain<content styleCode="italics"><footnoteRef IDREF="t3f1"/></content></td><td styleCode="Rrule">6</td><td styleCode="Rrule">-</td><td styleCode="Rrule">5</td><td styleCode="Rrule">&lt; 1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5"><content styleCode="bold">RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Cough<content styleCode="italics"><footnoteRef IDREF="t3f1"/></content></td><td styleCode="Rrule">12</td><td styleCode="Rrule">&lt; 1</td><td styleCode="Rrule">8</td><td styleCode="Rrule">-</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Dyspnea<content styleCode="italics"><footnoteRef IDREF="t3f1"/>^,<footnoteRef IDREF="t3f2"/></content></td><td styleCode="Rrule">7</td><td styleCode="Rrule">-</td><td styleCode="Rrule">8</td><td styleCode="Rrule">-</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Epistaxis</td><td styleCode="Rrule">6</td><td styleCode="Rrule">-</td><td styleCode="Rrule">6</td><td styleCode="Rrule">-</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Nasal Inflammation / Discomfort<content styleCode="italics"><footnoteRef IDREF="t3f1"/>^,<footnoteRef IDREF="t3f2"/></content></td><td styleCode="Rrule">5</td><td styleCode="Rrule">-</td><td styleCode="Rrule">7</td><td styleCode="Rrule">-</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5"><content styleCode="bold">VASCULAR DISORDERS</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Flushing<content styleCode="italics"><footnoteRef IDREF="t3f1"/></content></td><td styleCode="Rrule">14</td><td styleCode="Rrule">&lt; 1</td><td styleCode="Rrule">13</td><td styleCode="Rrule">&lt; 1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Hypertension<content styleCode="italics"><footnoteRef IDREF="t3f1"/></content></td><td styleCode="Rrule">8</td><td styleCode="Rrule">2.4</td><td styleCode="Rrule">5</td><td styleCode="Rrule">&lt; 1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5"><content styleCode="bold">METABOLISM AND NUTRITION DISORDERS</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Decreased Appetite</td><td styleCode="Rrule">20</td><td styleCode="Rrule">&lt; 1</td><td styleCode="Rrule">20</td><td styleCode="Rrule">&lt; 1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5"><content styleCode="bold">INVESTIGATIONS </content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Liver Function Analysis Abnormal<content styleCode="italics"><footnoteRef IDREF="t3f1"/>^,<footnoteRef IDREF="t3f2"/></content></td><td styleCode="Rrule">6</td><td styleCode="Rrule">1</td><td styleCode="Rrule">9</td><td styleCode="Rrule">1.7</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5"><content styleCode="bold">CARDIAC DISORDERS</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Arrhythmia<content styleCode="italics"><footnoteRef IDREF="t3f1"/><footnoteRef IDREF="t3f2"/></content></td><td styleCode="Rrule">5</td><td styleCode="Rrule">-</td><td styleCode="Rrule">5</td><td styleCode="Rrule">&lt; 1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5"><content styleCode="bold">IMMUNE SYSTEM DISORDERS</content></td></tr><tr><td styleCode="Lrule Rrule">Hypersensitivity<content styleCode="italics"><footnoteRef IDREF="t3f1"/>^,<footnoteRef IDREF="t3f2"/></content></td><td styleCode="Rrule">7</td><td styleCode="Rrule">1</td><td styleCode="Rrule">7</td><td styleCode="Rrule">1.3</td></tr></tbody></table>

<table width="85%" ID="t4"><caption>Table 4 Adverse Reactions<footnote ID="t4f1">Contains grouped terms</footnote> (&#x2265; 5% Incidence) Reported in SafeHER</caption><col width="44%" align="left" valign="middle"/><col width="28%" align="center" valign="middle"/><col width="28%" align="center" valign="middle"/><thead><tr><th styleCode="Lrule Rrule" rowspan="2" align="center">Adverse Reactions <content styleCode="italics"><footnoteRef IDREF="t4f1"/>^,<footnote>Includes adverse reactions reported throughout study treatment and follow-up.</footnote></content></th><th styleCode="Botrule Rrule" colspan="2">HERCEPTIN HYLECTA 600 mg (once every 3 weeks) n=1864</th></tr><tr><th styleCode="Rrule" align="center">All Grades %</th><th styleCode="Rrule">Grades 3 to 5 %</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Fatigue<content styleCode="italics"><footnoteRef IDREF="t4f1"/></content></td><td styleCode="Rrule">33</td><td styleCode="Rrule">&lt; 1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Injection Site Reaction<content styleCode="italics"><footnoteRef IDREF="t4f1"/>^,<footnote>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. </footnote></content></td><td styleCode="Rrule">20</td><td styleCode="Rrule">&lt; 1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Edema<content styleCode="italics"><footnoteRef IDREF="t4f1"/></content></td><td styleCode="Rrule">12</td><td styleCode="Rrule">&lt; 1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Pyrexia<content styleCode="italics"><footnoteRef IDREF="t4f1"/></content></td><td styleCode="Rrule">11</td><td styleCode="Rrule">&lt; 1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Pain<content styleCode="italics"><footnoteRef IDREF="t4f1"/></content></td><td styleCode="Rrule">8</td><td styleCode="Rrule">&lt; 1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Mucosal Inflammation</td><td styleCode="Rrule">6</td><td styleCode="Rrule">&lt; 1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Arthralgia<content styleCode="italics"><footnoteRef IDREF="t4f1"/></content></td><td styleCode="Rrule">21</td><td styleCode="Rrule">&lt; 1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Myalgia<content styleCode="italics"><footnoteRef IDREF="t4f1"/></content></td><td styleCode="Rrule">17</td><td styleCode="Rrule">&lt; 1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Pain in Extremity</td><td styleCode="Rrule">11</td><td styleCode="Rrule">&lt; 1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Back Pain<content styleCode="italics"><footnoteRef IDREF="t4f1"/></content></td><td styleCode="Rrule">8</td><td styleCode="Rrule">&lt; 1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Pain<content styleCode="italics"><footnoteRef IDREF="t4f1"/></content></td><td styleCode="Rrule">7</td><td styleCode="Rrule">&lt; 1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">GASTROINTESTINAL DISORDERS </content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Diarrhea<content styleCode="italics"><footnoteRef IDREF="t4f1"/></content></td><td styleCode="Rrule">21</td><td styleCode="Rrule">1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Nausea</td><td styleCode="Rrule">15</td><td styleCode="Rrule">&lt; 1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Abdominal Pain<content styleCode="italics"><footnoteRef IDREF="t4f1"/></content></td><td styleCode="Rrule">10</td><td styleCode="Rrule">&lt; 1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Constipation</td><td styleCode="Rrule">9</td><td styleCode="Rrule">&lt; 1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Stomatitis<content styleCode="italics"><footnoteRef IDREF="t4f1"/></content></td><td styleCode="Rrule">8</td><td styleCode="Rrule">&lt; 1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Vomiting</td><td styleCode="Rrule">7</td><td styleCode="Rrule">&lt; 1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">SKIN AND SUBCUTANEOUS TISSUE DISORDERS</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Rash<content styleCode="italics"><footnoteRef IDREF="t4f1"/></content></td><td styleCode="Rrule">17</td><td styleCode="Rrule">&lt; 1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Nail Disorder<content styleCode="italics"><footnoteRef IDREF="t4f1"/></content></td><td styleCode="Rrule">10</td><td styleCode="Rrule">&lt; 1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Alopecia<content styleCode="italics"><footnoteRef IDREF="t4f1"/></content></td><td styleCode="Rrule">9</td><td styleCode="Rrule">&lt; 1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Erythema<content styleCode="italics"><footnoteRef IDREF="t4f1"/></content></td><td styleCode="Rrule">9</td><td styleCode="Rrule">&lt; 1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Pruritus<content styleCode="italics"><footnoteRef IDREF="t4f1"/></content></td><td styleCode="Rrule">6</td><td styleCode="Rrule">-</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">INFECTIONS AND INFESTATIONS </content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Upper Respiratory Tract Infection<content styleCode="italics"><footnoteRef IDREF="t4f1"/></content></td><td styleCode="Rrule">19</td><td styleCode="Rrule">&lt; 1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Urinary Tract Infection<content styleCode="italics"><footnoteRef IDREF="t4f1"/></content></td><td styleCode="Rrule">6</td><td styleCode="Rrule">&lt; 1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Viral Infection<content styleCode="italics"><footnoteRef IDREF="t4f1"/></content></td><td styleCode="Rrule">5</td><td styleCode="Rrule">-</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">NERVOUS SYSTEM DISORDERS</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Neuropathy Peripheral<content styleCode="italics"><footnoteRef IDREF="t4f1"/></content></td><td styleCode="Rrule">14</td><td styleCode="Rrule">&lt; 1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Headache<content styleCode="italics"><footnoteRef IDREF="t4f1"/></content></td><td styleCode="Rrule">13</td><td styleCode="Rrule">&lt; 1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Dizziness<content styleCode="italics"><footnoteRef IDREF="t4f1"/></content></td><td styleCode="Rrule">6</td><td styleCode="Rrule">&lt; 1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Paresthesia</td><td styleCode="Rrule">6</td><td styleCode="Rrule">&lt; 1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Cough<content styleCode="italics"><footnoteRef IDREF="t4f1"/></content></td><td styleCode="Rrule">11</td><td styleCode="Rrule">&lt; 1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Dyspnea<content styleCode="italics"><footnoteRef IDREF="t4f1"/></content></td><td styleCode="Rrule">8</td><td styleCode="Rrule">&lt; 1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Epistaxis</td><td styleCode="Rrule">6</td><td styleCode="Rrule">-</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Nasal Inflammation/Discomfort<content styleCode="italics"><footnoteRef IDREF="t4f1"/></content></td><td styleCode="Rrule">6</td><td styleCode="Rrule">-</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">VASCULAR DISORDERS</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Flushing<content styleCode="italics"><footnoteRef IDREF="t4f1"/></content></td><td styleCode="Rrule">12</td><td styleCode="Rrule">&lt; 1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Hypertension<content styleCode="italics"><footnoteRef IDREF="t4f1"/></content></td><td styleCode="Rrule">8</td><td styleCode="Rrule">2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">BLOOD AND LYMPHATIC SYSTEM DISORDERS</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Anemia<content styleCode="italics"><footnoteRef IDREF="t4f1"/></content></td><td styleCode="Rrule">8</td><td styleCode="Rrule">&lt; 1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Neutropenia</td><td styleCode="Rrule">6</td><td styleCode="Rrule">4</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">PSYCHIATRIC DISORDERS</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr><td styleCode="Lrule Rrule">Insomnia<content styleCode="italics"><footnoteRef IDREF="t4f1"/></content></td><td styleCode="Rrule">7</td><td styleCode="Rrule">&lt; 1</td></tr></tbody></table>

<table width="85%" ID="t5"><caption>Table 5 Adverse Reactions ( &#x2265; 5%) in the Intravenous Trastuzumab Arm (H0648g and H0649g)</caption><col width="25%" align="left" valign="top"/><col width="15%" align="center" valign="top"/><col width="15%" align="center" valign="top"/><col width="15%" align="center" valign="top"/><col width="15%" align="center" valign="top"/><col width="15%" align="center" valign="top"/><thead><tr><th styleCode="Lrule Rrule"/><th valign="bottom" styleCode="Rrule">Intravenous trastuzumab <footnote ID="foot5a">Data for Herceptin single agent were from 4 studies, including 213 patients from H0649g.</footnote> n = 352 %</th><th valign="bottom" styleCode="Rrule">Intravenous trastuzumab + Paclitaxel n = 91 %</th><th valign="bottom" styleCode="Rrule">Paclitaxel n = 95 %</th><th valign="bottom" styleCode="Rrule">Intravenous trastuzumab + AC<footnote ID="foot5b">Anthracycline (doxorubicin or epirubicin) and cyclophosphamide.</footnote> n = 143 %</th><th styleCode="Rrule" valign="bottom">AC<footnoteRef IDREF="foot5b"/> n = 135 %</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="6"><content styleCode="bold">General</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Pain</td><td styleCode="Rrule">47</td><td styleCode="Rrule">61</td><td styleCode="Rrule">62</td><td styleCode="Rrule">57</td><td styleCode="Rrule">42</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Asthenia</td><td styleCode="Rrule">42</td><td styleCode="Rrule">62</td><td styleCode="Rrule">57</td><td styleCode="Rrule">54</td><td styleCode="Rrule">55</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Fever</td><td styleCode="Rrule">36</td><td styleCode="Rrule">49</td><td styleCode="Rrule">23</td><td styleCode="Rrule">56</td><td styleCode="Rrule">34</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Chills</td><td styleCode="Rrule">32</td><td styleCode="Rrule">41</td><td styleCode="Rrule">4</td><td styleCode="Rrule">35</td><td styleCode="Rrule">11</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Headache</td><td styleCode="Rrule">26</td><td styleCode="Rrule">36</td><td styleCode="Rrule">28</td><td styleCode="Rrule">44</td><td styleCode="Rrule">31</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Abdominal pain</td><td styleCode="Rrule">22</td><td styleCode="Rrule">34</td><td styleCode="Rrule">22</td><td styleCode="Rrule">23</td><td styleCode="Rrule">18</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Back pain</td><td styleCode="Rrule">22</td><td styleCode="Rrule">34</td><td styleCode="Rrule">30</td><td styleCode="Rrule">27</td><td styleCode="Rrule">15</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Infection</td><td styleCode="Rrule">20</td><td styleCode="Rrule">47</td><td styleCode="Rrule">27</td><td styleCode="Rrule">47</td><td styleCode="Rrule">31</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Flu syndrome</td><td styleCode="Rrule">10</td><td styleCode="Rrule">12</td><td styleCode="Rrule">5</td><td styleCode="Rrule">12</td><td styleCode="Rrule">6</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Accidental injury</td><td styleCode="Rrule">6</td><td styleCode="Rrule">13</td><td styleCode="Rrule">3</td><td styleCode="Rrule">9</td><td styleCode="Rrule">4</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Allergic reaction</td><td styleCode="Rrule">3</td><td styleCode="Rrule">8</td><td styleCode="Rrule">2</td><td styleCode="Rrule">4</td><td styleCode="Rrule">2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="6"><content styleCode="bold">Gastrointestinal</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Nausea</td><td styleCode="Rrule">33</td><td styleCode="Rrule">51</td><td styleCode="Rrule">9</td><td styleCode="Rrule">76</td><td styleCode="Rrule">77</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Diarrhea</td><td styleCode="Rrule">25</td><td styleCode="Rrule">45</td><td styleCode="Rrule">29</td><td styleCode="Rrule">45</td><td styleCode="Rrule">26</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Vomiting</td><td styleCode="Rrule">23</td><td styleCode="Rrule">37</td><td styleCode="Rrule">28</td><td styleCode="Rrule">53</td><td styleCode="Rrule">49</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Anorexia</td><td styleCode="Rrule">14</td><td styleCode="Rrule">24</td><td styleCode="Rrule">16</td><td styleCode="Rrule">31</td><td styleCode="Rrule">26</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Nausea and vomiting</td><td styleCode="Rrule">8</td><td styleCode="Rrule">14</td><td styleCode="Rrule">11</td><td styleCode="Rrule">18</td><td styleCode="Rrule">9</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="6"><content styleCode="bold">Respiratory</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Cough increased</td><td styleCode="Rrule">26</td><td styleCode="Rrule">41</td><td styleCode="Rrule">22</td><td styleCode="Rrule">43</td><td styleCode="Rrule">29</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Dyspnea</td><td styleCode="Rrule">22</td><td styleCode="Rrule">27</td><td styleCode="Rrule">26</td><td styleCode="Rrule">42</td><td styleCode="Rrule">25</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Rhinitis</td><td styleCode="Rrule">14</td><td styleCode="Rrule">22</td><td styleCode="Rrule">5</td><td styleCode="Rrule">22</td><td styleCode="Rrule">16</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Pharyngitis</td><td styleCode="Rrule">12</td><td styleCode="Rrule">22</td><td styleCode="Rrule">14</td><td styleCode="Rrule">30</td><td styleCode="Rrule">18</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Sinusitis</td><td styleCode="Rrule">9</td><td styleCode="Rrule">21</td><td styleCode="Rrule">7</td><td styleCode="Rrule">13</td><td styleCode="Rrule">6</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="6"><content styleCode="bold">Skin</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Rash</td><td styleCode="Rrule">18</td><td styleCode="Rrule">38</td><td styleCode="Rrule">18</td><td styleCode="Rrule">27</td><td styleCode="Rrule">17</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Herpes simplex</td><td styleCode="Rrule">2</td><td styleCode="Rrule">12</td><td styleCode="Rrule">3</td><td styleCode="Rrule">7</td><td styleCode="Rrule">9</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Acne</td><td styleCode="Rrule">2</td><td styleCode="Rrule">11</td><td styleCode="Rrule">3</td><td styleCode="Rrule">3</td><td styleCode="Rrule">&lt; 1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="6"><content styleCode="bold">Nervous</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Insomnia</td><td styleCode="Rrule">14</td><td styleCode="Rrule">25</td><td styleCode="Rrule">13</td><td styleCode="Rrule">29</td><td styleCode="Rrule">15</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Dizziness</td><td styleCode="Rrule">13</td><td styleCode="Rrule">22</td><td styleCode="Rrule">24</td><td styleCode="Rrule">24</td><td styleCode="Rrule">18</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Paresthesia</td><td styleCode="Rrule">9</td><td styleCode="Rrule">48</td><td styleCode="Rrule">39</td><td styleCode="Rrule">17</td><td styleCode="Rrule">11</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Depression</td><td styleCode="Rrule">6</td><td styleCode="Rrule">12</td><td styleCode="Rrule">13</td><td styleCode="Rrule">20</td><td styleCode="Rrule">12</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Peripheral neuritis</td><td styleCode="Rrule">2</td><td styleCode="Rrule">23</td><td styleCode="Rrule">16</td><td styleCode="Rrule">2</td><td styleCode="Rrule">2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Neuropathy</td><td styleCode="Rrule">1</td><td styleCode="Rrule">13</td><td styleCode="Rrule">5</td><td styleCode="Rrule">4</td><td styleCode="Rrule">4</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="6"><content styleCode="bold">Metabolic</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Peripheral edema</td><td styleCode="Rrule">10</td><td styleCode="Rrule">22</td><td styleCode="Rrule">20</td><td styleCode="Rrule">20</td><td styleCode="Rrule">17</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Edema</td><td styleCode="Rrule">8</td><td styleCode="Rrule">10</td><td styleCode="Rrule">8</td><td styleCode="Rrule">11</td><td styleCode="Rrule">5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="6"><content styleCode="bold">Cardiovascular</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Congestive heart failure</td><td styleCode="Rrule">7</td><td styleCode="Rrule">11</td><td styleCode="Rrule">1</td><td styleCode="Rrule">28</td><td styleCode="Rrule">7</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Tachycardia</td><td styleCode="Rrule">5</td><td styleCode="Rrule">12</td><td styleCode="Rrule">4</td><td styleCode="Rrule">10</td><td styleCode="Rrule">5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="6"><content styleCode="bold"> Musculoskeletal</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Bone pain</td><td styleCode="Rrule">7</td><td styleCode="Rrule">24</td><td styleCode="Rrule">18</td><td styleCode="Rrule">7</td><td styleCode="Rrule">7</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Arthralgia</td><td styleCode="Rrule">6</td><td styleCode="Rrule">37</td><td styleCode="Rrule">21</td><td styleCode="Rrule">8</td><td styleCode="Rrule">9</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="6"><content styleCode="bold">Urogenital</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Urinary tract infection</td><td styleCode="Rrule">5</td><td styleCode="Rrule">18</td><td styleCode="Rrule">14</td><td styleCode="Rrule">13</td><td styleCode="Rrule">7</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="6"><content styleCode="bold">Blood and Lymphatic</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Anemia</td><td styleCode="Rrule">4</td><td styleCode="Rrule">14</td><td styleCode="Rrule">9</td><td styleCode="Rrule">36</td><td styleCode="Rrule">26</td></tr><tr><td styleCode="Lrule Rrule"> Leukopenia</td><td styleCode="Rrule">3</td><td styleCode="Rrule">24</td><td styleCode="Rrule">17</td><td styleCode="Rrule">52</td><td styleCode="Rrule">34</td></tr></tbody></table>