• Or, initial dose of 8 mg/kg over 90 minutes IV infusion, then 6 mg/kg over
`90 minutes IV infusion every three weeks for 52 weeks.
`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 (as tolerated).
`---------------------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)
`• Pulmonary Toxicity (5.4, 6.1)
`• Exacerbation of Chemotherapy-Induced Neutropenia (5.3, 6.1)
`• HER2 testing should be performed by laboratories with demonstrated
`proficiency. (5.5)
`• May cause oligohydramnios and fetal harm when administered to a
`pregnant woman. Pregnancy registry available. (5.6, 8.1)
` ------------------------------ADVERSE REACTIONS------------------------------
`Adjuvant Breast Cancer
`• Adverse reactions ( ≥ 2% higher incidence with Herceptin-containing
`treatment compared with control treatment) are fatigue, infection,
`neutropenia, anemia, myalgia, dyspnea, rash/desquamation, headache,
`diarrhea, and nausea. (6.1)
`Metastatic Breast Cancer
`• Adverse reactions (≥ 15% incidence with Herceptin monotherapy or ≥ 5%
`with Herceptin/ paclitaxel) are nausea, fever, infection, rash, increased
`cough, vomiting, diarrhea, headache, and anemia. (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.
`
`See 17 for PATIENT COUNSELING INFORMATION.
`
`
`Revised: 01/2008
`
`
`
`8 USE IN SPECIFIC POPULATIONS
`8.1
`Pregnancy
`8.3 Nursing Mothers
`8.4
`Pediatric Use
`8.5 Geriatric Use
`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
`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.
`
`
`
`FDA APPROVED: 1-18-08
`1.14.1.2 Annotated Draft 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-------------------------
`01/2008
`Indications and Usage, Adjuvant Treatment of Breast Cancer (1.1)
`01/2008
`Dosage and Administration, Recommended Doses and Schedules (2.1)
`01/2008
`Dosage and Administration, Dose Modifications (2.2)
`01/2008
`Warnings and Precautions, Cardiomyopathy (5.1)
`01/2008
`Warnings and Precautions, Interstitial Pneumonitis (5.4)
`01/2008
`Warnings and Precautions, Embryo-Fetal Toxicity (5.6)
`
`---------------------------INDICATIONS AND USAGE----------------------------
` Herceptin is a HER2/neu receptor antagonist indicated for the treatment of
`HER2 overexpressing breast cancer (1.1, 1.2).
`------------------------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.
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`WARNING − CARDIOMYOPATHY, INFUSION REACTIONS,
`PULMONARY TOXICITY
`1
`INDICATIONS AND USAGE
`1.1 Adjuvant Breast Cancer
`1.2 Metastatic Breast 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
`5.6
`Embryo-Fetal Toxicity
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`6.2
`Immunogenicity
`6.3
`Post-Marketing Experience
`7 DRUG INTERACTIONS
`
`
`
`U.S. BL 103792/5175 Amendment: Trastuzumab⎯Genentech, Inc.
`1 of 11/Regional (Adjuvant Breast Cancer [HERA]): 1-18-08 Final Draft FDA Approved (103792-5175).doc
`
`AVENTIS EXHIBIT 2063
`Mylan v. Aventis, IPR2016-00712
`
`

`
`
`
`FULL PRESCRIBING INFORMATION
`
`
`WARNING
`
`CARDIOMYOPATHY, INFUSION REACTIONS,
`and PULMONARY TOXICITY
`Cardiomyopathy
` Herceptin can result in sub-clinical and clinical cardiac failure manifesting
`as CHF and decreased LVEF. The incidence and severity of left ventricular
`cardiac dysfunction was highest in patients who received Herceptin
`concurrently 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 strongly consider discontinuation of Herceptin
`treatment in patients with metastatic breast cancer 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 infusion reactions and
`pulmonary toxicity. Fatal infusion reactions have been reported. In most
`cases, symptoms occurred during or within 24 hours of administration of
`Herceptin. Herceptin infusion should be interrupted for patients experiencing
`dyspnea or clinically significant hypotension. Patients should be monitored
`until signs and symptoms completely resolve. Discontinue Herceptin for
`infusion reactions manifesting as anaphylaxis, angioedema, interstitial
`pneumonitis, or acute respiratory distress syndrome. [see Warnings and
`Precautions (5.2, 5.4)]
`
`INDICATIONS AND USAGE
`
`
`
` 1
`
`1.1 Adjuvant Breast Cancer
` Herceptin is indicated:
`• As part of a treatment regimen containing doxorubicin, cyclophosphamide,
`and paclitaxel for the adjuvant treatment of HER2-overexpressing, breast
`cancer.
`• As a single agent, for the adjuvant treatment of HER2-overexpressing
`node-negative (ER/PR negative or with one high-risk feature) or node-
`positive breast cancer, following multi-modality anthracycline based
`therapy. [see Clinical Studies (14.1)]
`1.2 Metastatic Breast Cancer
` Herceptin is indicated:
`• In combination with paclitaxel is indicated for 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.
`DOSAGE AND ADMINISTRATION
`
`2
`
`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:
`• Initiate Herceptin following completion of anthracycline and concurrently
`with paclitaxel for the first 12 weeks. Administer Herceptin 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, as tolerated, for a total of 52 doses. [see Dose Modifications
`(2.2)]
`• Initiate Herceptin following completion of all chemotherapy. Administer
`Herceptin at an initial dose of 8 mg/kg followed by subsequent doses of
`6 mg/kg every three weeks for a total of 17 doses (52 weeks of therapy).
`Administer all doses >4 mg/kg as 90 minute intravenous infusions. [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.
`
`U.S. BL 103792/5175 Amendment: Trastuzumab⎯Genentech, Inc.
`2 of 11/Regional (Adjuvant Breast Cancer [HERA]): 1-18-08 Final Draft FDA Approved (103792-5175).doc
`
`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:
`• 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 a
`symptomatic 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,
`prior to the first dose of Herceptin. The following schedule was used to
`monitor cardiac function in clinical studies:
`• Baseline LVEF measurement immediately prior to initiation of Herceptin
`• LVEF measurements every 3 months during and upon completion of
`Herceptin
`• LVEF measurements every 6 months for at least 2 years following
`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)]
`
`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).
` 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. 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
`
`Study
`
`1 & 2
`
`3
`
`Event
`
`Herceptin
`
`Control
`
`Congestive heart failure* 2% (32/1677)
`
`0.4% (7/1600)
`
`Congestive heart failure
`
`2% (30/1678)
`
`0.3% (5/1708)
`
`*Includes 1 patient with fatal cardiomyopathy.
`
`Table 2
`Incidence of Cardiac Dysfunction* in Metastatic Breast Cancer Studies
`
`
`
`
`
`Incidence
`
`NYHA I-IV
`
`NYHA III-IV
`
`Event
`
`Herceptin Control Herceptin Control
`
`Study
`
`4
`(AC)
`
`Cardiac
`Dysfunction
`
`4
`(paclitaxel)
`
`Cardiac
`Dysfunction
`
`5
`
`Cardiac
`Dysfunction**
`
`28%
`
`11%
`
`7%
`
`1%
`
`7%
`
`N/A
`
`19%
`
`3%
`
`4%
`
`5%
`
`1%
`
`N/A
`
`* Congestive heart failure or significant asymptomatic decrease in LVEF
`** Includes 1 patient with fatal cardiomyopathy.
`
`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 in women with metastatic breast
`cancer, 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 not significantly
`increased. [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. Assessment for HER2
`overexpression and of HER2 gene amplification 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 patients for Herceptin therapy. These include HercepTest™ and
`Pathway® HER-2/neu (IHC assays) and PathVysion® and HER2 FISH
`pharmDx™ (FISH assays). Users should refer to the package inserts of
`specific assay kits for information on the validation and performance of each
`assay.
`
`Limitations in assay precision (particularly for the IHC method) and in the
`direct linkage between assay result and overexpression of the Herceptin target
`(for the FISH method) make it inadvisable to rely on a single method to rule
`out potential Herceptin benefit. A negative FISH result does not rule out
`HER2 overexpression and potential benefit from Herceptin. Treatment
`outcomes for metastatic breast cancer (Study 4) as a function of IHC and
`FISH testing are provided in Table 9. Treatment outcomes for adjuvant breast
`cancer (Studies 2 and 3) as a function of IHC and FISH testing are provided in
`Table 7.
`HER2 Protein Overexpression Detection Methods
` HER2 protein overexpression can be established by measuring HER2
`protein using an IHC method. HercepTest®, one test approved for this use,
`was assessed for concordance with the Clinical Trial Assay (CTA), using
`tumor specimens collected and stored independently from those obtained in
`Herceptin clinical studies in women with metastatic breast cancer. Data are
`provided in the package insert for HercepTest®.
`HER2 Gene Amplification Detection Method
`
`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)].
`U.S. BL 103792/5175 Amendment: Trastuzumab⎯Genentech, Inc.
`3 of 11/Regional (Adjuvant Breast Cancer [HERA]): 1-18-08 Final Draft FDA Approved (103792-5175).doc
`
`

`
`Table 3 (cont’d)
`Adverse Reactions for Study 3, All Grades*:
`
`MedDRA (v. 7.1)
`Adverse Event Preferred Term
`Cough
`Influenza
`Dyspnea
`URI
`Rhinitis
`Pharyngolaryngeal Pain
`Sinusitis
`Epistaxis
`Pulmonary Hypertension
`Interstitial Pneumonitis
`
`Gastrointestinal Disorders
`Diarrhea
`Nausea
`Vomiting
`Constipation
`Dyspepsia
`Upper Abdominal Pain
`
`1 Year Herceptin
`(n= 1678)
`81 (5%)
`70 (4%)
`57 (3%)
`46 (3%)
`36 (2%)
`32 (2%)
`26 (2%)
`25 (2%)
`4 (0.2%)
`4 (0.2%)
`
`Observation
`(n=1708)
`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%)
`
`123 (7%)
`108 (6%)
`58 (3.5%)
`33 (2%)
`30 (2%)
`29 (2%)
`
`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%)
`
`49 (3%)
`11 (0.6%)
`
`10 (.6%)
`0 (0%)
`10 (0.6%)
`
`6 (0.4%)
`37 (2%)
`0 (0%)
`30 (2%)
`3 (0.2%)
`0 (0%)
`
`43 (3%)
`13 (0.8%)
`
`1 (0.06%)
`0 (0%)
`
`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
`
`General Disorders
`Pyrexia
`Edema Peripheral
`Chills
`Aesthenia
`Influenza-like Illness
`Sudden Death
`
`Infections
`Nasopharyngitis
`UTI
`
`Immune System Disorders
`Hypersensitivity
`Autoimmune Thyroiditis
`
`162 (10%)
`29 (2%)
`
`70 (4%)
`43 (2%)
`40 (2%)
`
`100 (6%)
`79 (5%)
`85 (5%)
`75 (4.5%)
`40 (2%)
`1 (.06%)
`
`135 (8%)
`39 (3%)
`
`10 (0.6%)
`4 (0.3%)
`
` * The incidence of Grade 3/4 adverse reactions was <1% in both arms for
`each listed term.
`** Higher level grouping term.
`
`
`
`The data from Studies 1 and 2 were obtained from 3206 patients enrolled,
`of which 1635 patients received Herceptin; the median treatment duration was
`
`
`
`The presence of HER2 protein overexpression and gene amplification are
`
`highly correlated, therefore the use of FISH to detect gene amplification may
`be employed for selection of patients appropriate for Herceptin therapy.
`PathVysion®, one test approved for this use, was evaluated in an exploratory,
`retrospective assessment of available CTA 2+ or 3+ tumor specimens
`collected as part of patient screening for clinical studies in metastatic breast
`cancer (Studies 4 and 5). Data are provided in the package insert for
`PathVysion®.
`5.6 Embryo-Fetal Toxicity (Pregnancy Category D)
` 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 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)].
`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.
`
`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.
`
`
`Table 3
`Adverse Reactions for Study 3, All Grades*:
`
`MedDRA (v. 7.1)
`Adverse Event Preferred Term
`
`1 Year Herceptin
`(n= 1678)
`
`Observation
`(n=1708)
`
`Cardiac
`Hypertension
`Dizziness
`Ejection Fraction Decreased
`Palpitations
`Cardiac Arrhythmias**
`Cardiac Failure Congestive
`Cardiac Failure
`Cardiac Disorder
`Ventricular Dysfunction
`
`64 (4%)
`60 (4%)
`58 (3.5%)
`48 (3%)
`40 (3%)
`30 (2%)
`9 (0.5%)
`5 (0.3%)
`4 (0.2%)
`
`35 (2%)
`29 (2%)
`11 (0.6%)
`12 (0.7%)
`17 (1%)
`5 (0.3%)
`4 (0.2%)
`0 (0%)
`0 (0%)
`
`Respiratory Thoracic Mediastinal Disorders
`Nasopharyngitis
`
`
`135 (8%)
`
`43 (3%)
`
`U.S. BL 103792/5175 Amendment: Trastuzumab⎯Genentech, Inc.
`4 of 11/Regional (Adjuvant Breast Cancer [HERA]): 1-18-08 Final Draft FDA Approved (103792-5175).doc
`
`

`
`
`
`50 weeks. The median age was 49.0 years (range: 24-80); 84% of patients
`were White, and 7% were Black, 4% were Hispanic, and 4% were 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.
`Metastatic Breast Cancer Studies
`
`The data below reflect exposure to Herceptin in one randomized, open-
`label study, Study 4, of chemotherapy with (n=235) or without (n=234)
`trastuzumab in patients with metastatic breast cancer, and one single-arm
`study (Study 5; n=222) in patients with metastatic breast cancer. Data in
`Table 4 are based on Studies 4 and 5.
` Among the 464 patients treated in Study 4, 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 Herceptin followed by 2 mg/kg weekly. The percentages of patients who
`received Herceptin treatment for ≥ 6 months and ≥ 12 months were 58% and
`9%, respectively.
` Among the 352 patients treated in single agent studies (213 patients from
`Study 5), the median age was 50 years (range 28−86 years), 100% had breast
`cancer, 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
`Herceptin followed by 2 mg/kg weekly. The percentages of patients who
`received Herceptin treatment for ≥ 6 months and ≥ 12 months were 31% and
`16%, respectively.
`
`
`Table 4
`Per-Patient Incidence of Adverse Reactions Occurring in ≥ 5% of
`Patients in Uncontrolled Studies or at Increased Incidence in the
`Herceptin Arm (Studies 4 and 5) (Percent of Patients)
`
`Single
`Agent*
`n = 352
`
`47
`42
`36
`32
`26
`22
`22
`20
`10
`6
`3
`
`Herceptin
`+
`Paclitaxel
`n = 91
`
`61
`62
`49
`41
`36
`34
`34
`47
`12
`13
`8
`
`Paclitaxel
`Alone
`n = 95
`
`62
`57
`23
`4
`28
`22
`30
`27
`5
`3
`2
`
`Herceptin
`+ AC
`n = 143
`
`57
`54
`56
`35
`44
`23
`27
`47
`12
`9
`4
`
`AC
`Alone
`n = 135
`
`42
`55
`34
`11
`31
`18
`15
`31
`6
`4
`2
`
`
`
`Body as a Whole
`Pain
`Asthenia
`Fever
`Chills
`Headache
`Abdominal pain
`Back pain
`Infection
`Flu syndrome
`Accidental injury
`Allergic reaction
`
`Table 4 (cont’d)
`Per-Patient Incidence of Adverse Events Occurring in ≥ 5% of
`Patients in Uncontrolled Studies or at Increased Incidence in the
`Herceptin Arm (Studies 4 and 5) (Percent of Patients)
`
`Single
`Agent*
`n = 352
`
`5
`7
`
`Herceptin
`+
`Paclitaxel
`n = 91
`
`12
`11
`
`Paclitaxel
`Alone
`n = 95
`
`4
`1
`
`Herceptin
`+ AC
`n = 143
`
`10
`28
`
`AC
`Alone
`n = 135
`
`5
`7
`
`
`33
`25
`23
`8
`
`14
`
`4
`3
`
`10
`8
`
`7
`6
`
`14
`13
`9
`6
`2
`1
`
`
`26
`22
`14
`12
`9
`
`18
`2
`2
`
`
`5
`
`
`51
`45
`37
`14
`
`24
`
`14
`24
`
`22
`10
`
`24
`37
`
`25
`22
`48
`12
`23
`13
`
`
`41
`27
`22
`22
`21
`
`38
`12
`11
`
`
`18
`
`
`9
`29
`28
`11
`
`16
`
`9
`17
`
`20
`8
`
`18
`21
`
`13
`24
`39
`13
`16
`5
`
`
`22
`26
`5
`14
`7
`
`18
`3
`3
`
`
`14
`
`
`76
`45
`53
`18
`
`31
`
`36
`52
`
`20
`11
`
`7
`8
`
`29
`24
`17
`20
`2
`4
`
`
`43
`42
`22
`30
`13
`
`27
`7
`3
`
`
`13
`
`
`77
`26
`49
`9
`
`26
`
`26
`34
`
`17
`5
`
`7
`9
`
`15
`18
`11
`12
`2
`4
`
`
`29
`25
`16
`18
`6
`
`17
`9
` < 1
`
`
`7
`
`
`
`Cardiovascular
`Tachycardia
`Congestive heart
`failure
`
`Digestive
`Nausea
`Diarrhea
`Vomiting
`Nausea and
`vomiting
`Anorexia
`
`Heme & Lymphatic
`Anemia
`Leukopenia
`
`Metabolic
`Peripheral edema
`Edema
`
`Musculoskeletal
`Bone pain
`Arthralgia
`
`Nervous
`Insomnia
`Dizziness
`Paresthesia
`Depression
`Peripheral neuritis
`Neuropathy
`
`Respiratory
`Cough increased
`Dyspnea
`Rhinitis
`Pharyngitis
`Sinusitis
`Skin
`Rash
`Herpes simplex
`Acne
`
`Urogenital
`Urinary tract
`infection
`
` * Data for Herceptin single agent were from 4 studies, including 213
`patients from Study 5.
`
`
`
`U.S. BL 103792/5175 Amendment: Trastuzumab⎯Genentech, Inc.
`5 of 11/Regional (Adjuvant Breast Cancer [HERA]): 1-18-08 Final Draft FDA Approved (103792-5175).doc
`
`

`
`Figure 2
`Study 3: Cumulative Incidence of Time to First LVEF
`Decline of ≥ 10 Percentage Points from Baseline and to
`Below 50% with Death as a Competing Risk Event
`
`
`
`
`
`Time 0 is the date of randomization.
`The incidence of treatment emergent congestive heart failure among
`
`patients in the metastatic breast cancer trials was classified for severity using
`the New York Heart Association classification system (I−IV, where IV is the
`most severe level of cardiac failure) (see Table 2). In the metastatic breast
`cancer trials the probability of cardiac dysfunction was highest in patients who
`received Herceptin concurrently with anthracyclines.
`Infusion Reactions
` During the first infusion with Herceptin, the symptoms most commonly
`reported were chills and fever, occurring in approximately 40% of patients in
`clinical trials. Symptoms were treated with acetaminophen, diphenhydramine,
`and meperidine (with or without reduction in the rate of Herceptin infusion);
`permanent discontinuation of Herceptin for infusional toxicity was required in
` < 1% of patients. Other signs and/or symptoms may include nausea,
`vomiting, pain (in some cases at tumor sites), rigors, headache, dizziness,
`dyspnea, hypotension, elevated blood pressure, rash, and asthenia. Infusional
`toxicity occurred in 21% and 35% of patients, and was severe in 1.4% and 9%
`of patients, on second or subsequent Herceptin infusions admini