HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`These highlights do not include all the information needed to use
`
`
` PERJETA safely and effectively. See full prescribing information for
`PERJETA.
`
`PERJETA® (pertuzumab)
`Injection, for intravenous use
`Initial U.S. Approval: 2012
`
`WARNING: CARDIOMYOPATHY and EMBRYO-FETAL TOXICITY
`
`See full prescribing information for complete boxed warning.
`Cardiomyopathy: PERJETA can result in subclinical and clinical
`cardiac failure manifesting as CHF, and decreased LVEF. Evaluate
`cardiac function prior to and during treatment. Discontinue PERJETA
`treatment for a confirmed clinically significant decrease in left
`
`ventricular function. (2.2, 5.2, 6.1)
`Embryo-fetal Toxicity: Exposure to PERJETA can result in embryo-
`
`fetal death and birth defects. Studies in animals have resulted in
`
`
`oligohydramnios, delayed renal development, and death. Advise patients
`of these risks and the need for effective contraception. (5.1, 8.1, 8.6)
`
`
`---------------------------RECENT MAJOR CHANGES --------------------------­
`Indications and Usage (1.2)
`09/2013
`
`
` 04/2013
`Dosage and Administration (2.1)
`
`09/2013
`Dosage and Administration (2.1, 2.2)
`
`Contraindications (4)
`09/2013
`Warnings and Precautions (5.2, 5.3, 5.4, 5.5)
`09/2013
`--------------------------- INDICATIONS AND USAGE---------------------------­
`PERJETA is a HER2/neu receptor antagonist indicated for:
`
`
` Use in combination with trastuzumab and docetaxel for treatment of
`patients with HER2-positive metastatic breast cancer (MBC) who have
`not received prior anti-HER2 therapy or chemotherapy for metastatic
`disease. (1.1)
`
` Use in combination with trastuzumab and docetaxel as neoadjuvant
`treatment of patients with HER2-positive, locally advanced,
`inflammatory, or early stage breast cancer (either greater than 2 cm in
`diameter or node positive) as part of a complete treatment regimen for
`early breast cancer. This indication is based on demonstration of an
`improvement in pathological complete response rate. No data are
`available demonstrating improvement in event-free survival or overall
`
`
`survival. (1.2, 2.1, 14.2)
`Limitations of Use:
`
`
` The safety of PERJETA as part of a doxorubicin-containing regimen
`
`has not been established.
`
` The safety of PERJETA administered for greater than 6 cycles for
`early breast cancer has not been established.
`
`
`
`-----------------------DOSAGE AND ADMINISTRATION ----------------------­
`
`
` For intravenous infusion only. Do not administer as an intravenous
`
`push or bolus. (2.3)
`
` The initial PERJETA dose is 840 mg administered as a 60-minute
`
`intravenous infusion, followed every 3 weeks thereafter by 420 mg
`
`
`administered as a 30 to 60 minute intravenous infusion. (2.1)
`
`
`
`
`
`
`
`
`
`Reference ID: 3384285
`
`
`
` MBC: Administer PERJETA, trastuzumab, and docetaxel by intravenous
`infusion every 3 weeks. (2.1)
`
`
` Neoadjuvant: Administer PERJETA, trastuzumab, and docetaxel by
`
`
`intravenous infusion preoperatively every 3 weeks for 3 to 6 cycles. (2.1)
`--------------------- DOSAGE FORMS AND STRENGTHS --------------------­
`
`
`420 mg/14 mL single-use vial. (3)
`
`
`------------------------------ CONTRAINDICATIONS -----------------------------­
`PERJETA is contraindicated in patients with known hypersensitivity to
`
`pertuzumab or to any of its excipients. (4)
`
`----------------------- WARNINGS AND PRECAUTIONS ----------------------­
`
`
` Embryo-fetal toxicity: Fetal harm can occur when administered to a
`
`pregnant woman. (5.1, 8.1)
`
` Left Ventricular Dysfunction: Monitor LVEF and withhold dosing as
`
`appropriate. (5.2, 6.1)
`
`
`Infusion-Related Reactions: Monitor for signs and symptoms. If a
`significant infusion-associated reaction occurs, slow or interrupt the
`
`
`infusion and administer appropriate medical therapies. (5.3)
`
` Hypersensitivity Reactions/Anaphylaxis: Monitor for signs and
`symptoms. If a severe hypersensitivity reaction/anaphylaxis occurs,
`
`discontinue the infusion immediately and administer appropriate medical
`therapies. (5.4)
`
` HER2 testing: Perform using FDA-approved tests by laboratories with
`
`demonstrated proficiency. (5.5)
`
`
`
`
`
`------------------------------ ADVERSE REACTIONS -----------------------------­
`
`Metastatic Breast Cancer
`
` The most common adverse reactions (> 30%) with PERJETA in
`
`combination with trastuzumab and docetaxel were diarrhea, alopecia,
`
`
`neutropenia, nausea, fatigue, rash, and peripheral neuropathy. (6.1)
`
`Neoadjuvant Treatment of Breast Cancer
`
` The most common adverse reactions (> 30%) with PERJETA in
`combination with trastuzumab and docetaxel were alopecia, diarrhea,
`
`nausea, and neutropenia. (6.1)
`
` The most common adverse reactions (>30%) with PERJETA in
`combination with trastuzumab and docetaxel when given for 3 cycles
`following 3 cycles of FEC were fatigue, alopecia, diarrhea, nausea,
`
`vomiting, and neutropenia. (6.1)
`
` The most common adverse reactions (>30%) with PERJETA in
`
`combination with docetaxel, carboplatin, and trastuzumab (TCH) were
`
`fatigue, alopecia, diarrhea, nausea, vomiting, neutropenia,
`thrombocytopenia, 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.
`
`----------------------- USE IN SPECIFIC POPULATIONS ----------------------­
`
` Nursing mothers: Discontinue nursing or discontinue PERJETA, taking
`into consideration the importance of the drug to the mother. (8.3)
`
`
` Females of Reproductive Potential: Counsel females on pregnancy
`
`
`prevention and planning. Encourage patient participation in the MotHER
`Pregnancy Registry by contacting 1-800-690-6720. (5.1, 8.1, 8.6, 17)
`
`
`See 17 for PATIENT COUNSELING INFORMATION.
`Revised: 09/2013
`
`
`
`
`
`
`
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`
`
`IMMUNOGEN 2212, pg. 1
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`WARNING: CARDIOMYOPATHY AND EMBRYO-FETAL
`
`TOXICITY
`INDICATIONS AND USAGE
`1
`1.1 Metastatic Breast Cancer
`
`
`
`1.2 Neoadjuvant Treatment of Breast Cancer
`
`
`2 DOSAGE AND ADMINISTRATION
`2.1 Recommended Doses and Schedules
`
`
`2.2 Dose Modification
`
`2.3 Preparation for Administration
`
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Embryo-Fetal Toxicity
`
`5.2 Left Ventricular Dysfunction
`
`5.3
`Infusion-Related Reactions
`
`5.4 Hypersensitivity Reactions/Anaphylaxis
`
`5.5 HER2 Testing
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`
`
`Immunogenicity
`
`6.2
`
`7 DRUG INTERACTIONS
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`
`8.3 Nursing Mothers
`8.4 Pediatric Use
`8.5 Geriatric Use
`8.6 Females of Reproductive Potential
`
`8.7 Renal Impairment
`8.8 Hepatic Impairment
`
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`
`12.3 Pharmacokinetics
`
`
`12.6 Cardiac Electrophysiology
`
`13 NONCLINICAL TOXICOLOGY
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`14 CLINICAL STUDIES
`
`
`14.1 Metastatic Breast Cancer
`
`
`
`14.2 Neoadjuvant Treatment of Breast Cancer
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`16.1 How Supplied
`
`
`17 PATIENT COUNSELING INFORMATION
`
`* Sections or subsections omitted from the Full Prescribing Information are
`not listed.
`
`
`
`
`
`
`Reference ID: 3384285
`
`IMMUNOGEN 2212, pg. 2
`Phigenix v. Immunogen
`IPR2014-00676
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`

`

`1
`2
`
`FULL PRESCRIBING INFORMATION
`
`
`WARNING: CARDIOMYOPATHY AND EMBRYO-FETAL TOXICITY
`Cardiomyopathy
`
`PERJETA administration can result in subclinical and clinical cardiac failure.
`Evaluate left ventricular function in all patients prior to and during treatment with
`PERJETA. Discontinue PERJETA treatment for a confirmed clinically significant
`decrease in left ventricular function. (2.2, 5.2, 6.1)
`Embryo-Fetal Toxicity
`Exposure to PERJETA can result in embryo-fetal death and birth defects. Studies in
`
`animals have resulted in oligohydramnios, delayed renal development, and death. Advise
`patients of these risks and the need for effective contraception. (5.1, 8.1, 8.6)
`
`
`1
`INDICATIONS AND USAGE
`
`1.1 Metastatic Breast Cancer (MBC)
`PERJETA is indicated for use in combination with trastuzumab and docetaxel for the treatment
`of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2
`therapy or chemotherapy for metastatic disease.
`1.2
`Neoadjuvant Treatment of Breast Cancer
`PERJETA is indicated for use in combination with trastuzumab and docetaxel for the
`neoadjuvant treatment of patients with HER2-positive, locally advanced, inflammatory, or early
`stage breast cancer (either greater than 2 cm in diameter or node positive) as part of a complete
`treatment regimen for early breast cancer. This indication is based on demonstration of an
`improvement in pathological complete response rate. No data are available demonstrating
`improvement in event-free survival or overall survival [see Clinical Studies (14.2) and Dosage
`and Administration (2.1)].
`Limitations of Use:
`
` The safety of PERJETA as part of a doxorubicin-containing regimen has not been
`established.
`
` The safety of PERJETA administered for greater than 6 cycles for early breast cancer has
`not been established.
`
`DOSAGE AND ADMINISTRATION
`2
`2.1 Recommended Doses and Schedules
`The initial dose of PERJETA is 840 mg administered as a 60-minute intravenous infusion,
`followed every 3 weeks by a dose of 420 mg administered as an intravenous infusion over
`30 to 60 minutes.
`When administered with PERJETA, the recommended initial dose of trastuzumab is 8 mg/kg
`administered as a 90-minute intravenous infusion, followed every 3 weeks by a dose of 6 mg/kg
`administered as an intravenous infusion over 30 to 90 minutes.
`PERJETA, trastuzumab, and docetaxel should be administered sequentially. PERJETA and
`trastuzumab can be given in any order. Docetaxel should be administered after PERJETA and
`trastuzumab. An observation period of 30 to 60 minutes is recommended after each PERJETA
`infusion and before commencement of any subsequent infusion of trastuzumab or docetaxel [see
`Warnings and Precautions (5.3)].
`
`U.S. BLA: Perjeta® (pertuzumab) – Genentech, Inc.
`3 of 24/Regional (Neoadjuvant Treatment of Breast Cancer)
`
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`Reference ID: 3384285
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`IMMUNOGEN 2212, pg. 3
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`Metastatic Breast Cancer (MBC)
`When administered with PERJETA, the recommended initial dose of docetaxel is 75 mg/m2
`administered as an intravenous infusion. The dose may be escalated to 100 mg/m2 administered
`every 3 weeks if the initial dose is well tolerated.
`
`Neoadjuvant Treatment of Breast Cancer
`PERJETA should be administered every 3 weeks for 3 to 6 cycles as part of one of the following
`treatment regimens for early breast cancer [see Clinical Studies (14.2)]:
`
` Four preoperative cycles of PERJETA in combination with trastuzumab and docetaxel
`followed by 3 postoperative cycles of fluorouracil, epirubicin, and cyclophosphamide
`(FEC) as given in Study 2
`
` Three preoperative cycles of FEC alone followed by 3 preoperative cycles of PERJETA
`in combination with docetaxel and trastuzumab as given in Study 3
`
` Six preoperative cycles of PERJETA in combination with docetaxel, carboplatin, and
`trastuzumab (TCH) (escalation of docetaxel above 75 mg/m2 is not recommended) as
`given in Study 3
`Following surgery, patients should continue to receive trastuzumab to complete 1 year of
`treatment. There is insufficient evidence to recommend continued use of PERJETA for greater
`than 6 cycles for early breast cancer. There is insufficient evidence to recommend concomitant
`administration of an anthracycline with PERJETA, and there are no safety data to support
`sequential use of doxorubicin with PERJETA.
`2.2 Dose Modification
`For delayed or missed doses, if the time between two sequential infusions is less than 6 weeks,
`
`the 420 mg dose of PERJETA should be administered. Do not wait until the next planned dose.
`
`If the time between two sequential infusions is 6 weeks or more, the initial dose of 840 mg
`
`PERJETA should be re-administered as a 60-minute intravenous infusion followed every
`
`3 weeks thereafter by a dose of 420 mg administered as an intravenous infusion over
`
`30 to 60 minutes.
`
`PERJETA should be discontinued if trastuzumab treatment is discontinued.
`
`Dose reductions are not recommended for PERJETA.
`
`For docetaxel dose modifications, see relevant prescribing information.
`
`Left Ventricular Ejection Fraction (LVEF):
`Withhold PERJETA and trastuzumab dosing for at least 3 weeks for either:
`
` a drop in LVEF to less than 45% or
`
` LVEF of 45% to 49% with a 10% or greater absolute decrease below pretreatment values
`[see Warnings and Precautions (5.2)]
`
`PERJETA may be resumed if the LVEF has recovered to greater than 49% or to 45% to 49%
`associated with less than a 10% absolute decrease below pretreatment values.
`If after a repeat assessment within approximately 3 weeks, the LVEF has not improved, or has
`declined further, PERJETA and trastuzumab should be discontinued, unless the benefits for the
`individual patient are deemed to outweigh the risks [see Warnings and Precautions (5.2)].
`
`U.S. BLA: Perjeta® (pertuzumab) – Genentech, Inc.
`4 of 24/Regional (Neoadjuvant Treatment of Breast Cancer)
`
`Reference ID: 3384285
`
`IMMUNOGEN 2212, pg. 4
`Phigenix v. Immunogen
`IPR2014-00676
`
`

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`Infusion-Related Reactions
`The infusion rate of PERJETA may be slowed or interrupted if the patient develops an
`infusion-related reaction [see Warnings and Precautions (5.3)].
`Hypersensitivity Reactions/Anaphylaxis
`The infusion should be discontinued immediately if the patient experiences a serious
`hypersensitivity reaction [see Warnings and Precautions (5.4)].
`
`
`2.3 Preparation for Administration
`Administer as an intravenous infusion only. Do not administer as an intravenous push or bolus.
`Do not mix PERJETA with other drugs.
`Preparation
`
`Prepare the solution for infusion, using aseptic technique, as follows:
`
` Parenteral drug products should be inspected visually for particulates and discoloration
`prior to administration.
`
` Withdraw the appropriate volume of PERJETA solution from the vial(s).
`
` Dilute into a 250 mL 0.9% sodium chloride PVC or non-PVC polyolefin infusion bag.
`
` Mix diluted solution by gentle inversion. Do not shake.
`
` Administer immediately once prepared.
`If the diluted infusion solution is not used immediately, it can be stored at 2oC to 8oC for
`
`
`up to 24 hours.
` Dilute with 0.9% Sodium Chloride injection only. Do not use dextrose (5%) solution.
`
`
`DOSAGE FORMS AND STRENGTHS
`3
`PERJETA (pertuzumab) 420 mg/14 mL (30 mg/mL) in a single-use vial
`4
`CONTRAINDICATIONS
`PERJETA is contraindicated in patients with known hypersensitivity to pertuzumab or to any of
`its excipients.
`5 WARNINGS AND PRECAUTIONS
`5.1 Embryo-Fetal Toxicity
`PERJETA can cause fetal harm when administered to a pregnant woman. Treatment of pregnant
`cynomolgus monkeys with pertuzumab resulted in oligohydramnios, delayed fetal kidney
`development, and embryo-fetal death. If PERJETA is administered during pregnancy, or if the
`patient becomes pregnant while receiving this drug, the patient should be apprised of the
`potential hazard to a fetus [see Use in Specific Populations (8.1)].
`Verify pregnancy status prior to the initiation of PERJETA. Advise patients of the risks of
`embryo-fetal death and birth defects and the need for contraception during and after treatment.
`Advise patients to contact their healthcare provider immediately if they suspect they may be
`pregnant. If PERJETA is administered during pregnancy or if a patient becomes pregnant while
`receiving PERJETA, immediately report exposure to the Genentech Adverse Event Line at
`1-888-835-2555. Encourage women who may be exposed during pregnancy to enroll in the
`
`U.S. BLA: Perjeta® (pertuzumab) – Genentech, Inc.
`5 of 24/Regional (Neoadjuvant Treatment of Breast Cancer)
`
`Reference ID: 3384285
`
`IMMUNOGEN 2212, pg. 5
`Phigenix v. Immunogen
`IPR2014-00676
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`

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`
`MotHER Pregnancy Registry by contacting 1-800-690-6720 [see Patient Counseling
`Information (17)].
`
`Monitor patients who become pregnant during PERJETA therapy for oligohydramnios. If
`oligohydramnios occurs, perform fetal testing that is appropriate for gestational age and
`
`consistent with community standards of care. The efficacy of intravenous hydration in the
`management of oligohydramnios due to PERJETA exposure is not known.
`5.2 Left Ventricular Dysfunction
`Decreases in LVEF have been reported with drugs that block HER2 activity, including
`PERJETA. In Study 1, for patients with MBC, PERJETA in combination with trastuzumab and
`docetaxel was not associated with increases in the incidence of symptomatic left ventricular
`systolic dysfunction (LVSD) or decreases in LVEF compared with placebo in combination with
`trastuzumab and docetaxel [see Clinical Studies (14.1)]. Left ventricular dysfunction occurred in
`4.4% of patients in the PERJETA-treated group and 8.3% of patients in the placebo-treated
`group. Symptomatic left ventricular systolic dysfunction (congestive heart failure) occurred in
`1.0% of patients in the PERJETA-treated group and 1.8% of patients in the placebo-treated
`group [see Adverse Reactions (6.1)]. Patients who have received prior anthracyclines or prior
`radiotherapy to the chest area may be at higher risk of decreased LVEF.
`In patients receiving neoadjuvant treatment in Study 2, the incidence of LVSD was higher in the
`PERJETA-treated groups compared to the trastuzumab- and docetaxel-treated group. An
`increased incidence of LVEF declines was observed in patients treated with PERJETA in
`combination with trastuzumab and docetaxel. In the overall treatment period, LVEF decline
` 10% and a drop to less than 50% occurred in 1.9% of patients treated with neoadjuvant
`trastuzumab and docetaxel as compared to 8.4% of patients treated with neoadjuvant PERJETA
`in combination with trastuzumab and docetaxel. Symptomatic LVSD occurred in 0.9% of
`patients treated with neoadjuvant PERJETA in combination with trastuzumab and no patients in
`
`the other 3 arms. LVEF recovered to  50% in all patients.
`In patients receiving neoadjuvant PERJETA in Study 3, in the overall treatment period, LVEF
`decline  10% and a drop to less than 50% occurred in 6.9% of patients treated with PERJETA
`plus trastuzumab and FEC followed by PERJETA plus trastuzumab and docetaxel, 16.0% of
`patients treated with PERJETA plus trastuzumab and docetaxel following FEC, and 10.5% of
`patients treated with PERJETA in combination with TCH. Symptomatic LVSD occurred in
`4.0% of patients treated with PERJETA plus trastuzumab and docetaxel following FEC, 1.3% of
`patients treated with PERJETA in combination with TCH, and none of the patients treated with
`PERJETA plus trastuzumab and FEC followed by PERJETA plus trastuzumab and docetaxel.
`LVEF recovered to  50% in all but one patient.
`PERJETA has not been studied in patients with a pretreatment LVEF value of  50%, a prior
`history of CHF, decreases in LVEF to  50% during prior trastuzumab therapy, or conditions
`that could impair left ventricular function such as uncontrolled hypertension, recent myocardial
`infarction, serious cardiac arrhythmia requiring treatment or a cumulative prior anthracycline
`exposure to  360 mg/m2 of doxorubicin or its equivalent.
`Assess LVEF prior to initiation of PERJETA and at regular intervals (e.g., every three months in
`the metastatic setting and every six weeks in the neoadjuvant setting) during treatment to ensure
`that LVEF is within the institution’s normal limits. If LVEF is  45%, or is 45% to 49% with a
`10% or greater absolute decrease below the pretreatment value, withhold PERJETA and
`trastuzumab and repeat LVEF assessment within approximately 3 weeks. Discontinue
`U.S. BLA: Perjeta® (pertuzumab) – Genentech, Inc.
`6 of 24/Regional (Neoadjuvant Treatment of Breast Cancer)
`
`Reference ID: 3384285
`
`IMMUNOGEN 2212, pg. 6
`Phigenix v. Immunogen
`IPR2014-00676
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`

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`PERJETA and trastuzumab if the LVEF has not improved or has declined further, unless the
`benefits for the individual patient outweigh the risks [see Dosage and Administration (2.2)].
`5.3
`Infusion-Related Reactions
`PERJETA has been associated with infusion reactions [see Adverse Reactions (6.1)]. An
`infusion reaction was defined in Study 1 as any event described as hypersensitivity, anaphylactic
`reaction, acute infusion reaction, or cytokine release syndrome occurring during an infusion or
`on the same day as the infusion. The initial dose of PERJETA was given the day before
`trastuzumab and docetaxel to allow for the examination of PERJETA-associated reactions. On
`the first day, when only PERJETA was administered, the overall frequency of infusion reactions
`was 13.0% in the PERJETA-treated group and 9.8% in the placebo-treated group. Less than 1%
`were Grade 3 or 4. The most common infusion reactions ( 1.0%) were pyrexia, chills, fatigue,
`headache, asthenia, hypersensitivity, and vomiting.
`During the second cycle when all drugs were administered on the same day, the most common
`infusion reactions in the PERJETA-treated group ( 1.0%) were fatigue, dysgeusia,
`hypersensitivity, myalgia, and vomiting.
`In Study 2 and Study 3, PERJETA was administered on the same day as the other study
`treatment drugs. Infusion reactions were consistent with those observed in Study 1, with a
`majority of reactions being National Cancer Institute - Common Terminology Criteria for
`Adverse Events (NCI - CTCAE v3.0) Grade 1 – 2.
`Observe patients closely for 60 minutes after the first infusion and for 30 minutes after
`subsequent infusions of PERJETA. If a significant infusion-related reaction occurs, slow or
`interrupt the infusion, and administer appropriate medical therapies. Monitor patients carefully
`until complete resolution of signs and symptoms. Consider permanent discontinuation in
`patients with severe infusion reactions [see Dosage and Administration (2.2)].
`5.4 Hypersensitivity Reactions/Anaphylaxis
`In Study 1, the overall frequency of hypersensitivity/anaphylaxis reactions was 10.8% in the
`PERJETA-treated group and 9.1% in the placebo-treated group. The incidence of Grade 3 – 4
`hypersensitivity/anaphylaxis reactions was 2.0% in the PERJETA-treated group and 2.5% in the
`placebo-treated group according to NCI - CTCAE v3.0. Overall, 4 patients in PERJETA-treated
`group and 2 patients in the placebo-treated group experienced anaphylaxis.
`In Study 2 and Study 3, hypersensitivity/anaphylaxis events were consistent with those observed
`in Study 1. In Study 2, two patients in the PERJETA- and docetaxel-treated group experienced
`anaphylaxis. In Study 3, the overall frequency of hypersensitivity/anaphylaxis was highest in the
`PERJETA plus TCH treated group (13.2%), of which 2.6% were NCI-CTCAE (version 3) Grade
`3 – 4.
`Patients should be observed closely for hypersensitivity reactions. Severe hypersensitivity,
`including anaphylaxis, has been observed in clinical trials with treatment of PERJETA [see
`Clinical Trials Experience (6.1)]. Medications to treat such reactions, as well as emergency
`equipment, should be available for immediate use. PERJETA is contraindicated in patients with
`known hypersensitivity to pertuzumab or to any of its excipients [see Contraindications (4)].
`
`5.5 HER2 Testing
`Detection of HER2 protein overexpression is necessary for selection of patients appropriate for
`PERJETA therapy because these are the only patients studied and for whom benefit has been
`shown [see Indications and Usage (1) and Clinical Studies (14)]. Patients with breast cancer
`U.S. BLA: Perjeta® (pertuzumab) – Genentech, Inc.
`7 of 24/Regional (Neoadjuvant Treatment of Breast Cancer)
`
`Reference ID: 3384285
`
`IMMUNOGEN 2212, pg. 7
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`203 were required to have evidence of HER2 overexpression defined as 3+ IHC or FISH
`204
`amplification ratio  2.0 in the clinical studies. Only limited data were available for patients
`205 whose breast cancer was positive by FISH, but did not demonstrate protein overexpression by
`206
`IHC.
`207 Assessment of HER2 status should be performed by laboratories using FDA-approved tests with
`208
`demonstrated proficiency in the specific technology being utilized. Improper assay performance,
`including use of sub-optimally fixed tissue, failure to utilize specified reagents, deviation from
`209
`
`specific assay instructions, and failure to include appropriate controls for assay validation, can
`210
`lead to unreliable results.
`211
`
`ADVERSE REACTIONS
`6
`
`212
`The following adverse reactions are discussed in greater detail in other sections of the label:
`213
`
` Embryo-Fetal Toxicity [see Warnings and Precautions (5.1)]
`
`214
`
` Left Ventricular Dysfunction [see Warnings and Precautions (5.2)]
`215
`
`
`Infusion-Related Reactions [see Warnings and Precautions (5.3)]
`
`216
`
`
` Hypersensitivity Reactions/Anaphylaxis [see Warnings and Precautions (5.4)]
`
`217
`6.1 Clinical Trials Experience
`218
`219 Because clinical trials are conducted under widely varying conditions, adverse reaction rates
`220
`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 clinical practice.
`221
`
`222 Metastatic Breast Cancer (MBC)
`223
`The adverse reactions described in Table 1 were identified in 804 patients with HER2-positive
`224 metastatic breast cancer treated in Study 1. Patients were randomized to receive either
`225
`PERJETA in combination with trastuzumab and docetaxel or placebo in combination with
`226
`trastuzumab and docetaxel. The median duration of study treatment was 18.1 months for
`227
`patients in the PERJETA-treated group and 11.8 months for patients in the placebo-treated
`228
`group. No dose adjustment was permitted for PERJETA or trastuzumab. The rates of adverse
`229
`events resulting in permanent discontinuation of all study therapy were 6.1% for patients in the
`230
`PERJETA-treated group and 5.3% for patients in the placebo-treated group. Adverse events led
`231
`to discontinuation of docetaxel alone in 23.6% of patients in the PERJETA-treated group and
`232
`23.2% of patients in the placebo-treated group. Table 1 reports the adverse reactions that
`233
`occurred in at least 10% of patients in the PERJETA-treated group. The safety profile of
`234
`PERJETA remained unchanged with an additional year of follow-up (median total follow-up of
`235
`30 months) in Study 1.
`236
`The most common adverse reactions ( 30%) seen with PERJETA in combination with
`237
`trastuzumab and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and
`238
`peripheral neuropathy. The most common NCI - CTCAE v3.0 Grade 3 – 4 adverse reactions
`239
`( 2%) were neutropenia, febrile neutropenia, leukopenia, diarrhea, peripheral neuropathy,
`240
`anemia, asthenia, and fatigue. An increased incidence of febrile neutropenia was observed for
`241 Asian patients in both treatment arms compared with patients of other races and from other
`242
`geographic regions. Among Asian patients, the incidence of febrile neutropenia was higher in
`243
`the pertuzumab-treated group (26%) compared with the placebo-treated group (12%).
`
`U.S. BLA: Perjeta® (pertuzumab) – Genentech, Inc.
`8 of 24/Regional (Neoadjuvant Treatment of Breast Cancer)
`
`Reference ID: 3384285
`
`IMMUNOGEN 2212, pg. 8
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

` Table 1 Summary of Adverse Reactions Occurring in  10%
`
`of Patients on the PERJETA Treatment Arm in Study 1
`PERJETA
`+ trastuzumab
`+ docetaxel
`n=407
`Frequency rate
`
`%
`Grades
`3 – 4
`%
`
`Placebo
`+ trastuzumab
`+ docetaxel
`n=397
`Frequency rate
`%
`Grades
`3 – 4
`%
`
`All
`Grades
`%
`
`All
`Grades
`%
`
`244
`245
`
`Body System/
`Adverse Reactions
`
`
`General disorders and administration site
`conditions
`Fatigue
`Asthenia
`Edema peripheral
`Mucosal inflammation
`Pyrexia
`Skin and subcutaneous tissue disorders
`Alopecia
`
`Rash
`Nail disorder
`Pruritus
`Dry skin
`Gastrointestinal disorders
`Diarrhea
`Nausea
`Vomiting
`Constipation
`Stomatitis
`Blood and lymphatic system disorders
`Neutropenia
`Anemia
`Leukopenia
`Febrile neutropenia*
`Nervous system disorders
`Neuropathy peripheral
`Headache
`
`
`37.6
`26.0
`23.1
`27.8
`18.7
`
`60.9
`33.7
`22.9
`14.0
`10.6
`
`66.8
`42.3
`24.1
`15.0
`18.9
`
`52.8
`23.1
`18.2
`13.8
`
`32.4
`20.9
`
`
`2.2
`2.5
`0.5
`1.5
`1.2
`
`0.0
`0.7
`1.2
`0.0
`0.0
`
`7.9
`1.2
`1.5
`0.0
`0.5
`
`48.9
`2.5
`12.3
`13.0
`
`3.2
`1.2
`
`
`36.8
`30.2
`30.0
`19.9
`17.9
`
`60.5
`24.2
`22.9
`10.1
`4.3
`
`46.3
`41.6
`23.9
`24.9
`15.4
`
`49.6
`18.9
`20.4
`7.6
`
`33.8
`16.9
`
`
`3.3
`1.5
`0.8
`1.0
`0.5
`
`0.3
`0.8
`0.3
`0.0
`0.0
`
`5.0
`0.5
`1.5
`1.0
`0.3
`
`45.8
`3.5
`14.6
`7.3
`
`2.0
`0.5
`
`U.S. BLA: Perjeta® (pertuzumab) – Genentech, Inc.
`9 of 24/Regional (Neoadjuvant Treatment of Breast Cancer)
`
`Reference ID: 3384285
`
`IMMUNOGEN 2212, pg. 9
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`0.0
`15.6
`0.0
`18.4
`Dysgeusia
`0.0
`12.1
`0.5
`12.5
`Dizziness
`Musculoskeletal and connective tissue disorders
`
`
`
`
`0.8
`23.9
`1.0
`22.9
`Myalgia
`0.8
`16.1
`0.2
`15.5
`Arthralgia
`Infections and infestations
`
`
`
`
`0.0
`13.4
`0.7
`16.7
`Upper respiratory tract infection
`0.3
`12.8
`0.0
`11.8
`Nasopharyngitis
`Respiratory, thoracic, and mediastinal disorders
`
`
`
`
`2.0
`15.6
`1.0
`14.0
`Dyspnea
`Metabolism and nutrition disorders
`
`
`
`
`1.5
`26.4
`1.7
`29.2
`Decreased appetite
`Eye disorders
`
`
`
`
`0.0
`13.9
`0.0
`14.0
`Lacrimation increased
`Psychiatric disorders
`
`
`
`
`0.0
`13.4
`0.0
`13.3
`Insomnia
`* In this table this denotes an adverse reaction that has been reported in association with a fatal
`246
`outcome
`247
`248 The following clinically relevant adverse reactions were reported in  10% of patients in
`the PERJETA-treated group in Study 1:
`249
`Skin and subcutaneous tissue disorders: Paronychia (7.1% in the PERJETA-treated group vs.
`250
`251
`3.5% in the placebo-treated group)
`252 Respiratory, thoracic and mediastinal disorders: Pleural effusion (5.2% in the PERJETA­
`253
`treated group vs. 5.8% in the placebo-treated group)
`254 Cardiac disorders: Left ventricular dysfunction (4.4% in the PERJETA-treated group vs. 8.3%
`255
`in the placebo-treated group) including symptomatic left ventricular systolic dysfunction (CHF)
`256
`(1.0% in the PERJETA-treated group vs. 1.8% in the placebo-treated group)
`Immune system disorders: Hypersensitivity (10.1% in the PERJETA-treated group vs. 8.6% in
`257
`258
`placebo-treated group)
`259 Adverse Reactions Reported in Patients Receiving PERJETA and Trastuzumab after
`260 Discontinuation of Docetaxel
`261
`In Study 1, adverse reactions were reported less frequently after discontinuation of docetaxel
`262
`treatment. All adverse reactions in the PERJETA and trastuzumab treatment group occurred in
`263
` 10% of patients with the exception of diarrhea (19.1%), upper respiratory tract infection
`264
`(12.8%), rash (11.7%), headache (11.4%), and fatigue (11.1%).
`265 Neoadjuvant Treatment of Breast Cancer (Study 2)
`266
`In Study 2, the most common adverse reactions seen with PERJETA in combination with
`267
`trastuzumab and docetaxel administered for 4 cycles were similar to those seen in the PERJETA­
`268
`treated group in Study 1. The most common adverse reactions (> 30%) were alopecia