HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`Herceptin safely and effectively. See full prescribing information for
`Herceptin.
`
`HERCEPTIN® (trastuzumab) for injection, for intravenous use
`Initial U.S. Approval: 1998
`
`
`WARNING: CARDIOMYOPATHY, INFUSION REACTIONS,
`EMBRYO-FETAL TOXICITY, and PULMONARY TOXICITY
`
`See full prescribing information for complete boxed warning
`Cardiomyopathy: Herceptin 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 for
`cardiomyopathy. (2.3, 5.1)
`
`Infusion Reactions, Pulmonary Toxicity: Discontinue Herceptin for
`anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory
`distress syndrome. (5.2, 5.4)
`
`Embryo-Fetal Toxicity: Exposure to Herceptin 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. (5.3, 8.1, 8.3)
`
`-----------------------------RECENT MAJOR CHANGES-------------------------
`
`
`Dosage and Administration (2.1)
`04/2017
`Warnings and Precautions (5.3)
`03/2016
`---------------------------INDICATIONS AND USAGE----------------------------
`Herceptin is a HER2/neu receptor antagonist indicated for:
`• The treatment of HER2-overexpressing breast cancer. (1.1, 1.2)
`• The treatment of HER2-overexpressing metastatic gastric or
`gastroesophageal junction adenocarcinoma. (1.3)
`Select patients for therapy based on an FDA-approved companion diagnostic
`for Herceptin (1, 2.1).
`------------------------DOSAGE AND ADMINISTRATION----------------------
`For intravenous (IV) infusion only. Do not administer as an IV push or
`bolus. (2.2)
`Do not substitute Herceptin (trastuzumab) for or with ado-trastuzumab
`emtansine. (2.2)
`Perform HER2 testing using FDA-approved tests by laboratories with
`demonstrated proficiency. (1, 2.1)
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`WARNING −− CARDIOMYOPATHY, INFUSION REACTIONS,
`EMBRYO-FETAL TOXICITY, and PULMONARY TOXICITY
`1
`INDICATIONS AND USAGE
`1.1 Adjuvant Breast Cancer
`1.2 Metastatic Breast Cancer
`1.3 Metastatic Gastric Cancer
`2 DOSAGE AND ADMINISTRATION
`2.1
`Patient Selection
`2.2 Recommended Doses and Schedules
`2.3
`Important Dosing Considerations
`2.4
`Preparation for Administration
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Cardiomyopathy
`5.2
`Infusion Reactions
`5.3
`Embryo-Fetal Toxicity
`5.4
`Pulmonary Toxicity
`Exacerbation of Chemotherapy-Induced Neutropenia
`5.5
`6 ADVERSE REACTIONS
`6.1
`Clinical Trials Experience
`6.2
`Immunogenicity
`6.3
`Post-Marketing Experience
`7 DRUG INTERACTIONS
`
`Adjuvant Treatment of HER2-Overexpressing Breast Cancer (2.2)
`Administer at either:
`• Initial dose of 4 mg/kg over 90 minute IV infusion, then 2 mg/kg over
`30 minute IV infusion weekly for 12 weeks (with paclitaxel or docetaxel)
`or 18 weeks (with docetaxel/carboplatin). One week after the last weekly
`dose of Herceptin, administer 6 mg/kg as an IV infusion over 30−90
`minutes every three weeks to complete a total of 52 weeks of therapy, or
`• Initial dose of 8 mg/kg over 90 minutes IV infusion, then 6 mg/kg over
`30−90 minutes IV infusion every three weeks for 52 weeks.
`Metastatic HER2-Overexpressing Breast Cancer (2.2)
`• Initial dose of 4 mg/kg as a 90 minute IV infusion followed by subsequent
`weekly doses of 2 mg/kg as 30 minute IV infusions.
`Metastatic HER2-Overexpressing Gastric Cancer (2.2)
`• Initial dose of 8 mg/kg over 90 minutes IV infusion, followed by 6 mg/kg
`over 30 to 90 minutes IV infusion every 3 weeks.
`---------------------DOSAGE FORMS AND STRENGTHS----------------------
`• For Injection: 150 mg lyophilized powder in a single-dose vial for
`reconstitution
`• For Injection: 420 mg lyophilized powder in a multiple-dose vial for
`reconstitution
`------------------------------CONTRAINDICATIONS------------------------------
`• None. (4)
`-----------------------WARNINGS AND PRECAUTIONS------------------------
`• Exacerbation of Chemotherapy-Induced Neutropenia. (5.5, 6.1)
`------------------------------ADVERSE REACTIONS------------------------------
`Adjuvant Breast Cancer
`• Most common adverse reactions (≥ 5%) are headache, diarrhea, nausea, and
`chills. (6.1)
`Metastatic Breast Cancer
`• Most common adverse reactions (≥ 10%) are fever, chills, headache,
`infection, congestive heart failure, insomnia, cough, and rash. (6.1)
`Metastatic Gastric Cancer
`• Most common adverse reactions (≥ 10%) are neutropenia, diarrhea, fatigue,
`anemia, stomatitis, weight loss, upper respiratory tract infections, fever,
`thrombocytopenia, mucosal inflammation, nasopharyngitis, and dysgeusia.
`(6.1)
`To report SUSPECTED ADVERSE REACTIONS, contact Genentech at
`1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`----------------------USE IN SPECIFIC POPULATIONS----------------------
`Females and Males of Reproductive Potential: Verify the pregnancy status of
`females prior to initiation of Herceptin (8.3).
`
`See 17 for PATIENT COUNSELING INFORMATION.
`
`Revised: 04/2017
`
`
`
`8 USE IN SPECIFIC POPULATIONS
`8.1
`Pregnancy
`8.2
`Lactation
`8.3
`Females and Males of Reproductive Potential
`8.4
`Pediatric Use
`8.5 Geriatric Use
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`14.1 Adjuvant Breast Cancer
`14.2 Metastatic Breast Cancer
`14.3 Metastatic Gastric Cancer
`16 HOW SUPPLIED/STORAGE AND HANDLING
`16.1 How Supplied
`16.2 Stability and Storage
`17 PATIENT COUNSELING INFORMATION
`
`* Sections or subsections omitted from the full prescribing information are not
`listed.
`
`1
`
`
`
`1 of 38
`
`Celltrion, Inc. 1038
`Celltrion v. Genentech
`IPR2017-01122
`
`

`

`
`
`FULL PRESCRIBING INFORMATION
`WARNING: CARDIOMYOPATHY, INFUSION REACTIONS, EMBRYO-FETAL
`TOXICITY, and PULMONARY TOXICITY
`Cardiomyopathy
` Herceptin administration can result in sub-clinical and clinical cardiac failure. The
`incidence and severity was highest in patients receiving Herceptin with
`anthracycline-containing chemotherapy regimens.
` Evaluate left ventricular function in all patients prior to and during treatment with
`Herceptin. Discontinue Herceptin treatment in patients receiving adjuvant therapy and
`withhold Herceptin in patients with metastatic disease for clinically significant decrease in left
`ventricular function [see Dosage and Administration (2.3) and Warnings and Precautions (5.1)].
`Infusion Reactions; Pulmonary Toxicity
` Herceptin administration can result in serious and fatal infusion reactions and pulmonary
`toxicity. Symptoms usually occur during or within 24 hours of Herceptin administration.
`Interrupt Herceptin infusion for dyspnea or clinically significant hypotension. Monitor
`patients until symptoms completely resolve. Discontinue Herceptin for anaphylaxis,
`angioedema, interstitial pneumonitis, or acute respiratory distress syndrome [see Warnings
`and Precautions (5.2, 5.4)].
`Embryo-Fetal Toxicity
` Exposure to Herceptin 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 (5.3) and Use in Specific Populations (8.1, 8.3)].
`
`1 INDICATIONS AND USAGE
`1.1 Adjuvant Breast Cancer
` Herceptin is indicated for adjuvant treatment of HER2 overexpressing node positive or node
`negative (ER/PR negative or with one high risk feature [see Clinical Studies (14.1)]) breast cancer
`as part of a treatment regimen consisting of doxorubicin, cyclophosphamide, and either
`•
`paclitaxel or docetaxel
`as part of a treatment regimen with docetaxel and carboplatin
`•
`as a single agent following multi-modality anthracycline based therapy.
`•
` Select patients for therapy based on an FDA-approved companion diagnostic for Herceptin [see
`Dosage and Administration (2.1)].
`1.2 Metastatic Breast Cancer
` Herceptin is indicated:
`In combination with paclitaxel for first-line treatment of HER2-overexpressing metastatic
`•
`breast cancer
`• As a single agent for treatment of HER2-overexpressing breast cancer in patients who have
`received one or more chemotherapy regimens for metastatic disease.
` Select patients for therapy based on an FDA-approved companion diagnostic for Herceptin [see
`Dosage and Administration (2.1)].
`1.3 Metastatic Gastric Cancer
` Herceptin is indicated, in combination with cisplatin and capecitabine or 5-fluorouracil, for the
`treatment of patients with HER2-overexpressing metastatic gastric or gastroesophageal junction
`adenocarcinoma who have not received prior treatment for metastatic disease.
`
`1
`
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`26
`27
`28
`29
`30
`31
`32
`33
`34
`
`35
`36
`37
`38
`39
`40
`41
`42
`
`43
`44
`45
`46
`
`2
`
`
`
`2 of 38
`
`Celltrion, Inc. 1038
`Celltrion v. Genentech
`IPR2017-01122
`
`

`

`
`
` Select patients for therapy based on an FDA-approved companion diagnostic for Herceptin [see
`Dosage and Administration (2.1)].
`
`2 DOSAGE AND ADMINISTRATION
`2.1 Patient Selection
`Select patients based on HER2 protein overexpression or HER2 gene amplification in tumor
`specimens [see Indications and Usage (1) and Clinical Studies (14)]. Assessment of HER2 protein
`overexpression and HER2 gene amplification should be performed using FDA-approved tests
`specific for breast or gastric cancers by laboratories with demonstrated proficiency. Information on
`the FDA-approved tests for the detection of HER2 protein overexpression and HER2 gene
`amplification is available at: http://www.fda.gov/CompanionDiagnostics.
` Assessment of HER2 protein overexpression and HER2 gene amplification in metastatic gastric
`cancer should be performed using FDA-approved tests specifically for gastric cancers due to
`differences in gastric vs. breast histopathology, including incomplete membrane staining and more
`frequent heterogeneous expression of HER2 seen in gastric cancers.
`Improper assay performance, including use of suboptimally fixed tissue, failure to utilize
`specified reagents, deviation from specific assay instructions, and failure to include appropriate
`controls for assay validation, can lead to unreliable results.
`2.2 Recommended Doses and Schedules
`• Do not administer as an intravenous push or bolus. Do not mix Herceptin with other
`drugs.
`• Do not substitute Herceptin (trastuzumab) for or with ado-trastuzumab emtansine.
`Adjuvant Treatment, Breast Cancer
`Administer according to one of the following doses and schedules for a total of 52 weeks of
`Herceptin therapy:
` During and following paclitaxel, docetaxel, or docetaxel/carboplatin:
`Initial dose of 4 mg/kg as an intravenous infusion over 90 minutes then at 2 mg/kg as an
`•
`intravenous infusion over 30 minutes weekly during chemotherapy for the first 12 weeks
`(paclitaxel or docetaxel) or 18 weeks (docetaxel/carboplatin).
`• One week following the last weekly dose of Herceptin, administer Herceptin at 6 mg/kg as an
`intravenous infusion over 30−90 minutes every three weeks.
`As a single agent within three weeks following completion of multi-modality,
`anthracycline-based chemotherapy regimens:
`Initial dose at 8 mg/kg as an intravenous infusion over 90 minutes
`•
`• Subsequent doses at 6 mg/kg as an intravenous infusion over 30−90 minutes every
`three weeks [see Dosage and Administration (2.3)].
`• Extending adjuvant treatment beyond one year is not recommended [see Adverse Reactions
`(6.1)].
`Metastatic Treatment, Breast Cancer
`• Administer Herceptin, alone or in combination with paclitaxel, at an initial dose of 4 mg/kg as
`a 90-minute intravenous infusion followed by subsequent once weekly doses of 2 mg/kg as
`30-minute intravenous infusions until disease progression.
`Metastatic Gastric Cancer
`• Administer Herceptin at an initial dose of 8 mg/kg as a 90-minute intravenous infusion
`followed by subsequent doses of 6 mg/kg as an intravenous infusion over 30–90 minutes every
`three weeks until disease progression [see Dosage and Administration (2.3)].
`
`47
`48
`49
`50
`
`51
`52
`53
`54
`55
`56
`57
`58
`59
`60
`61
`62
`63
`64
`
`65
`66
`67
`68
`69
`70
`71
`72
`73
`74
`75
`76
`77
`78
`79
`80
`81
`82
`83
`84
`85
`86
`87
`88
`89
`90
`91
`92
`
`3
`
`
`
`3 of 38
`
`Celltrion, Inc. 1038
`Celltrion v. Genentech
`IPR2017-01122
`
`

`

`93
`94
`95
`96
`97
`98
`99
`100
`101
`102
`103
`104
`105
`106
`107
`108
`109
`110
`111
`112
`113
`114
`115
`116
`117
`118
`119
`120
`
`121
`122
`123
`
`124
`125
`126
`127
`128
`129
`130
`131
`132
`133
`134
`135
`136
`137
`138
`
`
`
`2.3 Important Dosing Considerations
`If the patient has missed a dose of Herceptin by one week or less, then the usual maintenance dose
`(weekly schedule: 2 mg/kg; three-weekly schedule: 6 mg/kg) should be administered as soon as
`possible. Do not wait until the next planned cycle. Subsequent Herceptin maintenance doses should
`be administered 7 days or 21 days later according to the weekly or three-weekly schedules,
`respectively.
`If the patient has missed a dose of Herceptin by more than one week, a re-loading dose of
`Herceptin should be administered over approximately 90 minutes (weekly schedule: 4 mg/kg; three-
`weekly schedule: 8 mg/kg) as soon as possible. Subsequent Herceptin maintenance doses (weekly
`schedule: 2 mg/kg; three-weekly schedule 6 mg/kg) should be administered 7 days or 21 days later
`according to the weekly or three-weekly schedules, respectively.
`Infusion Reactions
`[See Boxed Warning, Warnings and Precautions (5.2)]
`• Decrease the rate of infusion for mild or moderate infusion reactions
`Interrupt the infusion in patients with dyspnea or clinically significant hypotension
`•
`• Discontinue Herceptin for severe or life-threatening infusion reactions.
`Cardiomyopathy
`[See Boxed Warning, Warnings and Precautions (5.1)]
` Assess left ventricular ejection fraction (LVEF) prior to initiation of Herceptin and at regular
`intervals during treatment. Withhold Herceptin dosing for at least 4 weeks for either of the
`following:
` ≥ 16% absolute decrease in LVEF from pre-treatment values
`•
`• LVEF below institutional limits of normal and ≥ 10% absolute decrease in LVEF from
`pretreatment values.
` Herceptin may be resumed if, within 4−8 weeks, the LVEF returns to normal limits and the
`absolute decrease from baseline is ≤ 15%.
` Permanently discontinue Herceptin for a persistent (> 8 weeks) LVEF decline or for suspension of
`Herceptin dosing on more than 3 occasions for cardiomyopathy.
`2.4 Preparation for Administration
` To prevent medication errors, it is important to check the vial labels to ensure that the drug being
`prepared and administered is Herceptin (trastuzumab) and not ado-trastuzumab emtansine.
`420 mg Multiple-dose vial
`Reconstitution
` Reconstitute each 420 mg vial of Herceptin with 20 mL of Bacteriostatic Water for Injection
`(BWFI), USP, containing 1.1% benzyl alcohol as a preservative to yield a multiple-dose solution
`containing 21 mg/mL trastuzumab that delivers 20 mL (420 mg trastuzumab). In patients with
`known hypersensitivity to benzyl alcohol, reconstitute with 20 mL of Sterile Water for Injection
`(SWFI) without preservative to yield a single use solution.
` Use appropriate aseptic technique when performing the following reconstitution steps:
`• Using a sterile syringe, slowly inject the 20 mL of diluent into the vial containing the
`lyophilized cake of Herceptin. The stream of diluent should be directed into the lyophilized
`cake. The reconstituted vial yields a solution for multiple-dose use, containing 21 mg/mL
`trastuzumab.
`• Swirl the vial gently to aid reconstitution. DO NOT SHAKE.
`• Slight foaming of the product may be present upon reconstitution. Allow the vial to stand
`undisturbed for approximately 5 minutes.
`
`4
`
`
`
`4 of 38
`
`Celltrion, Inc. 1038
`Celltrion v. Genentech
`IPR2017-01122
`
`

`

`
`
`• Parenteral drug products should be inspected visually for particulate matter and discoloration
`prior to administration, whenever solution and container permit. Inspect visually for
`particulates and discoloration. The solution should be free of visible particulates, clear to
`slightly opalescent and colorless to pale yellow.
`• Store reconstituted Herceptin in the refrigerator at 2○C to 8○C (36°F to 46°F); discard unused
`Herceptin after 28 days. If Herceptin is reconstituted with SWFI without preservative, use
`immediately and discard any unused portion. Do not freeze.
`Dilution
`• Determine the dose (mg) of Herceptin [see Dosage and Administration (2.2)]. Calculate the
`volume of the 21 mg/mL reconstituted Herceptin solution needed, withdraw this amount from
`the vial and add it to an infusion bag containing 250 mL of 0.9% Sodium Chloride Injection,
`USP. DO NOT USE DEXTROSE (5%) SOLUTION.
`• Gently invert the bag to mix the solution.
`• The solution of Herceptin for infusion diluted in polyvinylchloride or polyethylene bags
`containing 0.9% Sodium Chloride Injection, USP, should be stored at 2°C to 8°C (36°F to
`46°F) for no more than 24 hours prior to use. Do not freeze.
`
`
`150 mg Single-dose vial
`Reconstitution
` Reconstitute each 150 mg vial of Herceptin with 7.4 mL of Sterile Water for Injection (SWFI)
`(not supplied) to yield a single-dose solution containing 21 mg/mL trastuzumab that delivers 7.15
`mL (150 mg trastuzumab).
` Use appropriate aseptic technique when performing the following reconstitution steps:
`• Using a sterile syringe, slowly inject 7.4 mL of SWFI (not supplied) into the vial containing
`the lyophilized 150 mg Herceptin, directing the diluent stream into the lyophilized cake. The
`reconstituted vial yields a solution for single-dose use, containing 21 mg/mL trastuzumab.
`• Swirl the vial gently to aid reconstitution. DO NOT SHAKE.
`• Slight foaming of the product may be present upon reconstitution. Allow the vial to stand
`undisturbed for approximately 5 minutes.
`• Parenteral drug products should be inspected visually for particulate matter and discoloration
`prior to administration, whenever solution and container permit. Inspect visually for
`particulates and discoloration. The solution should be free of visible particulates, clear to
`slightly opalescent and colorless to pale yellow.
`• Use the Herceptin solution immediately following reconstitution with SWFI, as it contains no
`preservative and is intended for single-dose only. If not used immediately, store the
`reconstituted Herceptin solution for up to 24 hours at 2○C to 8○C (36○F to 46○F); discard any
`unused Herceptin after 24 hours. Do not freeze.
`Dilution
`• Determine the dose (mg) of Herceptin [see Dosage and Administration (2.1)].
`• Calculate the volume of the 21 mg/mL reconstituted Herceptin solution needed.
`• Withdraw this amount from the vial and add it to an infusion bag containing 250 mL of
`0.9% Sodium Chloride Injection, USP. DO NOT USE DEXTROSE (5%) SOLUTION.
`• Gently invert the bag to mix the solution.
`• The solution of Herceptin for infusion diluted in polyvinylchloride or polyethylene bags
`containing 0.9% Sodium Chloride Injection, USP, should be stored at 2°C to 8°C (36°F to
`46°F) for no more than 24 hours prior to use. Discard after 24 hours. This storage time is
`additional to the time allowed for the reconstituted vials. Do not freeze.
`
`
`
`139
`140
`141
`142
`143
`144
`145
`146
`147
`148
`149
`150
`151
`152
`153
`154
`155
`156
`157
`158
`159
`160
`161
`162
`163
`164
`165
`166
`167
`168
`169
`170
`171
`172
`173
`174
`175
`176
`177
`178
`179
`180
`181
`182
`183
`184
`185
`186
`
`5
`
`
`
`5 of 38
`
`Celltrion, Inc. 1038
`Celltrion v. Genentech
`IPR2017-01122
`
`

`

`187
`188
`189
`190
`191
`192
`193
`194
`
`195
`196
`197
`198
`199
`200
`201
`202
`203
`204
`205
`206
`207
`208
`209
`210
`211
`212
`213
`214
`215
`216
`217
`218
`219
`220
`221
`222
`223
`224
`225
`226
`227
`228
`229
`230
`231
`232
`233
`234
`
`
`
`3 DOSAGE FORMS AND STRENGTHS
`• For injection: 150 mg lyophilized powder in a single-dose vial
`• For injection: 420 mg lyophilized powder in a multiple-dose vial.
`
`4 CONTRAINDICATIONS
` None.
`
`5 WARNINGS AND PRECAUTIONS
`5.1 Cardiomyopathy
` Herceptin can cause left ventricular cardiac dysfunction, arrhythmias, hypertension, disabling
`cardiac failure, cardiomyopathy, and cardiac death [see Boxed Warning: Cardiomyopathy].
`Herceptin can also cause asymptomatic decline in left ventricular ejection fraction (LVEF).
` There is a 4−6 fold increase in the incidence of symptomatic myocardial dysfunction among
`patients receiving Herceptin as a single agent or in combination therapy compared with those not
`receiving Herceptin. The highest absolute incidence occurs when Herceptin is administered with an
`anthracycline.
` Withhold Herceptin 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 (2.3)]. The safety of continuation or resumption of
`Herceptin in patients with Herceptin-induced left ventricular cardiac dysfunction has not been
`studied.
` Patients who receive anthracycline after stopping Herceptin 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
`• LVEF measurements every 3 months during and upon completion of Herceptin
`• Repeat LVEF measurement at 4 week intervals if Herceptin is withheld for significant left
`ventricular cardiac dysfunction [see Dosage and Administration (2.3)]
`• LVEF measurements every 6 months for at least 2 years following completion of Herceptin as
`a component of adjuvant therapy.
`In Study 1, 15% (158/1031) of patients discontinued Herceptin 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 Study 3 (one-year Herceptin treatment), the number of patients who
`discontinued Herceptin due to cardiac toxicity at 12.6 months median duration of follow-up was
`2.6% (44/1678). In Study 4, 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 Herceptin due to cardiac toxicity.
` Among 64 patients receiving adjuvant chemotherapy (Studies 1 and 2) who developed congestive
`heart failure, one patient died of cardiomyopathy, one patient died suddenly without documented
`etiology, and 33 patients were receiving cardiac medication at last follow-up. Approximately 24%
`of the surviving patients had recovery to a normal LVEF (defined as ≥ 50%) and no symptoms on
`continuing medical management at the time of last follow-up. Incidence of congestive heart failure
`(CHF) is presented in Table 1. The safety of continuation or resumption of Herceptin in patients
`with Herceptin-induced left ventricular cardiac dysfunction has not been studied.
`
`
`6
`
`
`
`6 of 38
`
`Celltrion, Inc. 1038
`Celltrion v. Genentech
`IPR2017-01122
`
`

`

`
`
`
`
`Table 1
`Incidence of Congestive Heart Failure in Adjuvant Breast Cancer Studies
`
`Incidence of CHF
`
`Control
`Herceptin
`Regimen
`Study
`3.2% (64/2000)c
`ACb→Paclitaxel+Herceptin
`1 & 2a
`1.3% (21/1655)
`3d
`0.3% (5/1708)
`2% (30/1678)
`Chemo → Herceptin
`ACb→Docetaxel+Herceptin
`0.3% (3/1050)
`2% (20/1068)
`4
`0.3% (3/1050)
`0.4% (4/1056)
`Docetaxel+Carbo+Herceptin
`4
` a Median follow-up duration for studies 1 and 2 combined was 8.3 years in the AC→TH arm.
` b Anthracycline (doxorubicin) and cyclophosphamide.
` c Includes 1 patient with fatal cardiomyopathy and 1 patient with sudden death without documented
`etiology.
` d Includes NYHA II-IV and cardiac death at 12.6 months median duration of follow-up in the one-year
`Herceptin arm.
`
`
` In Study 3 (one-year Herceptin 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 Dysfunctiona in Metastatic Breast Cancer Studies
`Incidence
`
`Study
`
`Event
`
`NYHA I−IV
`Herceptin
`Control
`
`NYHA III−IV
`Herceptin
`Control
`
`Cardiac Dysfunction
`
`Cardiac Dysfunction
`
`28%
`
`11%
`
`7%
`
`1%
`
`19%
`
`4%
`
`5%
`
`3%
`
`1%
`
`N/A
`
`5
`(AC)b
`5
`(paclitaxel)
`Cardiac Dysfunctionc
`N/A
`7%
`6
` a Congestive heart failure or significant asymptomatic decrease in LVEF.
` b Anthracycline (doxorubicin or epirubicin) and cyclophosphamide.
` c Includes 1 patient with fatal cardiomyopathy.
`
`
`In Study 4, the incidence of NCI-CTC Grade 3/4 cardiac ischemia/infarction was higher in the
`
`Herceptin containing regimens (AC-TH: 0.3% (3/1068) and TCH: 0.2% (2/1056)) as compared to
`none in AC-T.
`5.2 Infusion Reactions
`
`Infusion reactions consist of a symptom complex characterized by fever and chills, and on
`occasion included nausea, vomiting, pain (in some cases at tumor sites), headache, dizziness,
`dyspnea, hypotension, rash, and asthenia [see Adverse Reactions (6.1)].
`
`In post-marketing reports, serious and fatal infusion reactions have been reported. Severe
`reactions, which include bronchospasm, anaphylaxis, angioedema, hypoxia, and severe hypotension,
`were usually reported during or immediately following the initial infusion. However, the onset and
`clinical course were variable, including progressive worsening, initial improvement followed by
`clinical deterioration, or delayed post-infusion events with rapid clinical deterioration. For fatal
`events, death occurred within hours to days following a serious infusion reaction.
`
`7
`
`235
`236
`237
`238
`239
`
`240
`241
`242
`243
`
`244
`245
`246
`247
`248
`249
`250
`251
`252
`253
`
`
`
`7 of 38
`
`Celltrion, Inc. 1038
`Celltrion v. Genentech
`IPR2017-01122
`
`

`

`
`
`Interrupt Herceptin infusion in all patients experiencing dyspnea, clinically significant
`
`hypotension, and intervention of medical therapy administered (which may include epinephrine,
`corticosteroids, diphenhydramine, bronchodilators, and oxygen). Patients should be evaluated and
`carefully monitored until complete resolution of signs and symptoms. Permanent discontinuation
`should be strongly considered in all patients with severe infusion reactions.
` There are no data regarding the most appropriate method of identification of patients who may
`safely be retreated with Herceptin after experiencing a severe infusion reaction. Prior to resumption
`of Herceptin infusion, the majority of patients who experienced a severe infusion reaction were
`pre-medicated with antihistamines and/or corticosteroids. While some patients tolerated Herceptin
`infusions, others had recurrent severe infusion reactions despite pre-medications.
`5.3 Embryo-Fetal Toxicity
` Herceptin can cause fetal harm when administered to a pregnant woman. In post-marketing
`reports, use of Herceptin 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. Advise pregnant women and females of reproductive potential that exposure to
`Herceptin 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 [see Use in Specific Populations (8.1, 8.3) and Clinical
`Pharmacology (12.3)].
`5.4 Pulmonary Toxicity
` Herceptin use 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. Such events can occur as sequelae of infusion reactions [see Warnings and
`Precautions (5.2)]. 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.
`5.5 Exacerbation of Chemotherapy-Induced Neutropenia
`
`In randomized, controlled clinical trials, the per-patient incidences of NCI-CTC Grade 3−4
`neutropenia and of febrile neutropenia were higher in patients receiving Herceptin in combination
`with myelosuppressive chemotherapy as compared to those who received chemotherapy alone. The
`incidence of septic death was similar among patients who received Herceptin and those who did not
`[see Adverse Reactions (6.1)].
`
`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)]
`Infusion Reactions [see Warnings and Precautions (5.2)]
`•
`• Embryo-Fetal Toxicity [see Warnings and Precautions (5.3)]
`• Pulmonary Toxicity [see Warnings and Precautions (5.4)]
`• Exacerbation of Chemotherapy-Induced Neutropenia [see Warnings and Precautions (5.5)]
`
`
` The most common adverse reactions in patients receiving Herceptin in the adjuvant and metastatic
`breast cancer setting are fever, nausea, vomiting, infusion reactions, diarrhea, infections, increased
`cough, headache, fatigue, dyspnea, rash, neutropenia, anemia, and myalgia. Adverse reactions
`requiring interruption or discontinuation of Herceptin treatment include CHF, significant decline in
`
`254
`255
`256
`257
`258
`259
`260
`261
`262
`263
`
`264
`265
`266
`267
`268
`269
`270
`271
`272
`273
`274
`
`275
`276
`277
`278
`279
`280
`281
`
`282
`283
`284
`285
`286
`287
`288
`289
`290
`291
`292
`293
`294
`295
`296
`297
`298
`299
`300
`
`8
`
`
`
`8 of 38
`
`Celltrion, Inc. 1038
`Celltrion v. Genentech
`IPR2017-01122
`
`

`

`
`
`301
`302
`303
`304
`305
`306
`307
`308
`309
`
`310
`311
`312
`313
`314
`315
`316
`317
`318
`319
`320
`321
`322
`323
`
`left ventricular cardiac function, severe infusion reactions, and pulmonary toxicity [see Dosage and
`Administration (2.3)].
` In the metastatic gastric cancer setting, the most common adverse reactions (≥ 10%) that were
`increased (≥ 5% difference) in the Herceptin arm as compared to the chemotherapy alone arm were
`neutropenia, diarrhea, fatigue, anemia, stomatitis, weight loss, upper respiratory tract infections,
`fever, thrombocytopenia, mucosal inflammation, nasopharyngitis, and dysgeusia. The most
`common adverse reactions which resulted in discontinuation of treatment on the Herceptin-
`containing arm in the absence of disease progression were infection, diarrhea, and febrile
`neutropenia.
`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.
`Adjuvant Breast Cancer Studies
` The data below reflect exposure to one-year Herceptin therapy across three randomized,
`open-label studies, Studies 1, 2, and 3, with (n = 3678) or without (n = 3363) trastuzumab in the
`adjuvant treatment of breast cancer.
` The data summarized in Table 3 below, from Study 3, reflect exposure to Herceptin in
`1678 patients; the median treatment duration was 51 weeks and median number of infusions was 18.
`Among the 3386 patients enrolled in the observation and one-year Herceptin arms of Study 3 at a
`median duration of follow-up of 12.6 months in the Herceptin arm, the median age was 49 years
`(range: 21 to 80 years), 83% of patients were Caucasian, and 13% were Asian.
`
`
`9
`
`
`
`9 of 38
`
`Celltrion, Inc. 1038
`Celltrion v. Genentech
`IPR2017-01122
`
`

`

`
`
`Table 3
`Adverse Reactions for Study 3a, All Gradesb
`
`One Year Herceptin
`Observation
`Adverse Reaction
`(n = 1678)
`(n = 1708)
`
`Cardiac
`64 (4%)
`Hypertension
`