Metastatic HER2-Overexpressing Breast Cancer (2.1)
`• 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 (2.1)
`• 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----------------------
`• Multidose vial nominally containing 440 mg Herceptin as a lyophilized,
`sterile powder. (3)
`------------------------------CONTRAINDICATIONS------------------------------
`• None. (4)
`-----------------------WARNINGS AND PRECAUTIONS------------------------
`• Cardiomyopathy (5.1, 6.1)
`• Infusion Reactions (5.2, 6.1)
`• Exacerbation of Chemotherapy-Induced Neutropenia (5.3, 6.1)
`• Pulmonary Toxicity (5.4, 6.1)
`• HER2 testing should be performed using FDA-approved tests by
`laboratories with demonstrated proficiency. (5.5)
`• Embryo-fetal Toxicity (5.6, 8.1)
`
` ------------------------------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)
`----------------------USE IN SPECIFIC POPULATIONS----------------------
`Nursing Mothers: Discontinue nursing or discontinue Herceptin. (8.3)
`
`To report SUSPECTED ADVERSE REACTIONS, contact Genentech at
`1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`
`See 17 for PATIENT COUNSELING INFORMATION.
`Revised: 10/ 2010
`
`
`
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`13.2 Animal Toxicology and/or Pharmacology
`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.
`
` *
`
`1.14.1.3 Final Labeling Text
`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)
`Intravenous Infusion
`Initial U.S. Approval: 1998
`
`
`WARNING: CARDIOMYOPATHY, INFUSION REACTIONS, and
`PULMONARY TOXICITY
`
`See full prescribing information for complete boxed warning
`Cardiomyopathy: Herceptin can result in sub-clinical 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. (5.1, 2.2)
`
`Infusion reactions, Pulmonary toxicity: Discontinue Herceptin for
`anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory
`distress syndrome. (5.2, 5.4)
`
`-----------------------------RECENT MAJOR CHANGES-------------------------
`Indications and Usage, Metastatic Gastric Cancer (1.3)
`10/2010
`Dosage and Administration (2.1)
`10/2010
`---------------------------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)
`------------------------DOSAGE AND ADMINISTRATION----------------------
`For intravenous (IV) infusion only. Do not administer as an IV push or
`bolus (5.2).
`Adjuvant Treatment of HER2-Overexpressing Breast Cancer (2.1)
` 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 52 weeks, 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.
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`WARNING − CARDIOMYOPATHY, INFUSION REACTIONS,
`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 Recommended Doses and Schedules
`2.2 Dose Modifications
`2.3
`Preparation for Administration
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Cardiomyopathy
`5.2
`Infusion Reactions
`5.3
`Exacerbation of Chemotherapy-Induced Neutropenia
`5.4
`Pulmonary Toxicity
`5.5 HER2 Testing
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`6.2
`Immunogenicity
`6.3
`Post-Marketing Experience
`7 DRUG INTERACTIONS
`8 USE IN SPECIFIC POPULATIONS
`8.1
`Pregnancy
`8.3 Nursing Mothers
`8.4
`Pediatric Use
`8.5 Geriatric Use
`
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`FULL PRESCRIBING INFORMATION
`
`WARNING: CARDIOMYOPATHY, INFUSION REACTIONS, 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
`withold Herceptin in patients with metastatic disease for clinically significant decrease in left
`ventricular function. [see Warnings and Precautions (5.1) and Dosage and Administration (2.2)]
`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)]
`
` 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
`• with docetaxel and carboplatin
`as a single agent following multi-modality anthracycline based therapy.
`•
`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.
`3 Metastatic Gastric Cancer
`1.
`Herceptin is indicated, in combination with cisplatin and capecitabine or 5-fluorouracil, for the
`
`eatment of patients with HER2 overexpressing metastatic gastric or gastroesophageal junction
`tr
`
`adenocarcinoma, who have not received prior treatment for metastatic disease.
`2
`DOSAGE AND ADMINISTRATION
`2.1 Recommended Doses and Schedules
`Do not administer as an intravenous push or bolus. Do not mix Herceptin with other drugs.
`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:
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`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 Dose Modifications (2.2)]
`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.
`tastatic 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 Dose Modifications (2.2)].
`
`2.2 Dose Modifications
`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.
`2.3 Preparation for Administration
`Reconstitution
` Reconstitute each 440 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 multi-dose solution
`containing 21 mg/mL 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:
`
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`• 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.
`• 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.
`• Store reconstituted Herceptin at 2−8○C; discard unused Herceptin after 28 days. If Herceptin
`is reconstituted with SWFI without preservative, use immediately and discard any unused
`portion.
`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.
`3 DOSAGE FORMS AND STRENGTHS
` 440 mg lyophilized powder per multi-use 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 (2.2)]. The safety of continuation or resumption of
`Herceptin in patients with Herceptin-induced left ventricular cardiac dysfunction has not been
`studied.
`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 (2.2)]
`• LVEF measurements every 6 months for at least 2 years following completion of Herceptin as
`a component of adjuvant therapy.
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`
`In Study 1, 16% (136/844) of patients discontinued Herceptin due to clinical evidence of myocardial
`dysfunction or significant decline in LVEF. In Study 3, the number of patients who discontinued
`Herceptin due to cardiac toxicity was 2.6% (44/1678). In Study 4, a total of 2.9% (31/1056) patients
`in the TCH arm (1.5% during the chemotherapy phase and 1.4% during the monotherapy phase) and
`5.7% (61/1068) 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 32 patients receiving adjuvant chemotherapy (Studies 1 and 2) who developed congestive
`heart failure, one patient died of cardiomyopathy and all other patients were receiving cardiac
`medication at last follow-up. Approximately half of the surviving patients had recovery to a normal
`LVEF (defined as ≥ 50%) on continuing medical management at the time of last follow-up.
`Incidence of congestive heart failure 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.
`
`
`Table 1
`Incidence of Congestive Heart Failure in Adjuvant Breast Cancer Studies
`
`
`
`Incidence of CHF
`
`Regimen
`Study
`ACb→Paclitaxel+Herceptin
`1 & 2a
`Chemo → Herceptin
`3
`ACb→Docetaxel+Herceptin
`4
`Docetaxel+Carbo+Herceptin
`4
` a Includes 1 patient with fatal cardiomyopathy.
` b Anthracycline (doxorubicin) and cyclophosphamide
`
`Herceptin
`2% (32/1677)
`2% (30/1678)
`2% (20/1068)
`0.4% (4/1056)
`
`Control
`0.4% (7/1600)
`0.3% (5/1708)
`0.3% (3/1050)
`0.3% (3/1050)
`
`Table 2
`Incidence of Cardiac Dysfunctiona in Metastatic Breast Cancer Studies
`Incidence
`
`Study
`
`Event
`
`NYHA I−IV
`Herceptin
`Control
`
`NYHA III−IV
`Herceptin
`Control
`
`150
`
`
`
`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.
`
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`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.
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`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 postmarketing 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.
`
`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 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)]
`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 HER2 Testing
` Detection of HER2 protein overexpression is necessary for selection of patients appropriate for
`Herceptin therapy because these are the only patients studied and for whom benefit has been shown.
`Due to differences in tumor histopathology, use FDA-approved tests for the specific tumor type
`(breast or gastric/gastroesophageal adenocarcinoma) to assess HER2 protein overexpression and
`HER2 gene amplification. Tests should be performed by laboratories with demonstrated proficiency
`in the specific technology being utilized. 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.
` Several FDA-approved commercial assays are available to aid in the selection of breast cancer and
`metastatic gastric cancer patients for Herceptin therapy. Users should refer to the package inserts of
`specific assay kits for information on the Intended Use, and the validation and performance of each
`
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`assay. Limitations in assay precision make it inadvisable to rely on a single method to rule out
`potential Herceptin benefit.
` Treatment outcomes for adjuvant breast cancer (Studies 2 and 3) and for metastatic breast cancer
`(Study 5) as a function of IHC and FISH testing are provided in Tables 8 and 10.
` 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. Study 7 demonstrated that gene
`amplification and protein overexpression were not as well correlated as with breast cancer.
`Treatment outcomes for metastatic gastric cancer (Study 7), based on HER2 gene amplification
`(FISH) and HER2 protein overexpression (IHC) test results are provided in Table 12.
`5.6 Embryo-Fetal Toxicity
` Herceptin can cause fetal harm when administered to a pregnant woman. Post-marketing case
`reports suggest that Herceptin use during pregnancy increases the risk of oligohydramnios during the
`second and third trimesters. If Herceptin is used during pregnancy or if a woman becomes pregnant
`while taking Herceptin, she should be apprised of the potential hazard to a fetus. [see Use in Specific
`Populations (8.1)].
`
` 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)]
`•
`• Exacerbation of chemotherapy-induced neutropenia [see Warnings and Precautions (5.3)]
`• Pulmonary toxicity [see Warnings and Precautions (5.4)]
`
`
` 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
`left ventricular cardiac function, severe infusion reactions, and pulmonary toxicity [see Dosage and
`Administration (2.2)].
` In the metastatic gastric cancer setting, the most common adverse reactions (> 10%) that were
`> 5% difference) in the Herceptin arm as compared to the chemotherapy alone arm were
`increased (
`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 Herceptin across three randomized, open-label studies,
`Studies 1, 2, and 3, with (n= 3355) or without (n= 3308) trastuzumab in the adjuvant treatment of
`breast cancer.
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` 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 Study 3, the median age was 49 years (range: 21 to 80 years),
`83% of patients were Caucasian, and 13% were Asian.
`
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`Table 3
`Adverse Reactions for Study 3, All Gradesa:
`
`1 Year Herceptin
`Observation
`Adverse Reaction
`(n= 1678)
`(n=1708)
`
`Cardiac
`64 (4%)
`Hypertension
`60 (4%)
`Dizziness
`58 (3.5%)
`Ejection Fraction Decreased
`48 (3%)
`Palpitations
`Cardiac Arrhythmiasb
`40 (3%)
`30 (2%)
`Cardiac Failure Congestive
`9 (0.5%)
`Cardiac Failure
`5 (0.3%)
`Cardiac Disorder
`4 (0.2%)
`Ventricular Dysfunction
`Respiratory Thoracic Mediastinal Disorders
`Cough
`81 (5%)
`Influenza
`70 (4%)
`Dyspnea
`57 (3%)
`URI
`46 (3%)
`Rhinitis
`36 (2%)
`Pharyngolaryngeal Pain
`32 (2%)
`Sinusitis
`26 (2%)
`Epistaxis
`25 (2%)
`Pulmonary Hypertension
`4 (0.2%)
`Interstitial Pneumonitis
`4 (0.2%)
`Gastrointestinal Disorders
`123 (7%)
`Diarrhea
`108 (6%)
`Nausea
`58 (3.5%)
`Vomiting
`33 (2%)
`Constipation
`30 (2%)
`Dyspepsia
`29 (2%)
`Upper Abdominal Pain
`Musculoskeletal & Connective Tissue Disorders
`Arthralgia
`137 (8%)
`Back Pain
`91 (5%)
`Myalgia
`63 (4%)
`Bone Pain
`49 (3%)
`Muscle Spasm
`46 (3%)
`Nervous System Disorders
`Headache
`Paraesthesia
`Skin & Subcutaneous Tissue Disorders
`Rash
`Nail Disorders
`Pruritis
`
`70 (4%)
`43 (2%)
`40 (2%)
`
`162 (10%)
`29 (2%)
`
`35 (2%)
`29 (2%)
`11 (0.6%)
`12 (0.7%)
`17 (1%)
`5 (0.3%)
`4 (0.2%)
`0 (0%)
`0 (0%)
`
`34 (2%)
`9 (0.5%)
`26 (2%)
`20 (1%)
`6 (0.4%)
`8 (0.5%)
`5 (0.3%)
`1 (0.06%)
`0 (0%)
`0 (0%)
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`16 (1%)
`19 (1%)
`10 (0.6%)
`17 (1%)
`9 (0.5%)
`15 (1%)
`
`98 (6%)
`58 (3%)
`17 (1%)
`26 (2%)
`3 (0.2%)
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`49 (3%)
`11 (0.6%)
`
`10 (.6%)
`0 (0%)
`10 (0.6%)
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`Table 3 (cont’d)
`Adverse Reactions for Study 3, All Gradesa:
`1 Year Herceptin
`Observation
`(n= 1678)
`(n=1708)
`
`Adverse Reaction
`
`100 (6%)
`79 (5%)
`85 (5%)
`75 (4.5%)
`40 (2%)
`1 (.06%)
`
`135 (8%)
`39 (3%)
`
`6 (0.4%)
`37 (2%)
`0 (0%)
`30 (2%)
`3 (0.2%)
`0 (0%)
`
`43 (3%)
`13 (0.8%)
`
`General Disorders
`Pyrexia
`Edema Peripheral
`Chills
`Aesthenia
`Influenza-like Illness
`Sudden Death
`Infections
`Nasopharyngitis
`UTI
`Immune System Disorders
`1 (0.06%)
`10 (0.6%)
`Hypersensitivity
`0 (0%)
`4 (0.3%)
`Autoimmune Thyroiditis
` a The incidence of Grade 3/4 adverse reactions was <1% in both arms for
`each listed term.
` b Higher level grouping term.
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`
` The data from Studies 1 and 2 were obtained from 3206 patients, of whom 1635 received
`Herceptin; the median treatment duration was 50 weeks. The median age was 49 years (range:
`24−80); 84% of patients were White, 7% Black, 4% Hispanic, and 4% Asian.
`
`In Study 1, only Grade 3−5 adverse events, treatment-related Grade 2 events, and Grade 2−5
`dyspnea were collected during and for up to 3 months following protocol-specified treatment. The
`following non-cardiac adverse reactions of Grade 2−5 occurred at an incidence of at least 2% greater
`among patients randomized to Herceptin plus chemotherapy as compared to chemotherapy alone:
`arthralgia (31% vs. 28%), fatigue (28% vs. 22%), infection (22% vs. 14%), hot flashes (17% vs.
`15%), anemia (13% vs. 7%), dyspnea (12% vs. 4%), rash/desquamation (11% vs. 7%), neutropenia
`(7% vs. 5%), headache (6% vs. 4%), and insomnia (3.7% vs. 1.5%). The majority of these events
`were Grade 2 in severity.
`
`In Study 2, data collection was limited to the following investigator-attributed treatment-related
`adverse reactions NCI-CTC Grade 4 and 5 hematologic toxicities, Grade 3−5 non-hematologic
`toxicities, selected Grade 2−5 toxicities associated with taxanes (myalgia, arthralgias, nail changes,
`motor neuropathy, sensory neuropathy) and Grade 1−5 cardiac toxicities occurring during
`chemotherapy and/or Herceptin treatment. The following non-cardiac adverse reactions of
`Grade 2−5 occurred at an incidence of at least 2% greater among patients randomized to Herceptin
`plus chemotherapy as compared to chemotherapy alone: arthralgia (11% vs. 8.4%), myalgia (10%
`vs. 8%), nail changes (9% vs. 7%), and dyspnea (2.5% vs. 0.1%). The majority of these events were
`Grade 2 in severity.
` Safety data from Study 4 reflect exposure to Herceptin as part of an adjuvant treatment regimen
`from 2124 patients receiving at least one dose of study treatment [AC-TH: n = 1068; TCH: n = 1056].
`The overall median treatment duration was 54 weeks in both the AC-TH and TCH arms.
`The median number of infusions was 26 in the AC-TH arm and 30 in the TCH arm, including
`weekly infusions during the chemotherapy phase and every three week dosing in the monotherapy
`period. Among these patients, the median age was 49 years (range 22 to 74 years). In Study 4, the
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`toxicity profile was similar to that reported in Studies 1, 2, and 3 with the exception of a low
`incidence of CHF in the TCH arm.
`Metastatic Breast Cancer Studies
` The data below reflect exposure to Herceptin in one randomized, open-label study, Study 5, of
`chemotherapy with (n=235) or without (n=234) trastuzumab in patients with metastatic breast
`cancer, and one single-arm study (Study 6; n=222) in