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.
`
`PERJETATM (pertuzumab)
`Injection, for intravenous use
`Initial U.S. Approval: 2012
`
`
`WARNING: EMBRYO-FETAL TOXICITY
`See full prescribing information for complete boxed warning.
`
`
`
`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)
`
`INDICATIONS AND USAGE
`
`PERJETA is a HER2/neu receptor antagonist indicated 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)
`
`
`DOSAGE AND ADMINISTRATION
`
`
`For intravenous infusion only. Do not administer as an intravenous
`
`
`push or bolus. (2.3)
`
`The initial 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)
`
`
`
`
`
`
`
`DOSAGE FORMS AND STRENGTHS
`
`420 mg/14 mL single-use vial. (3)
`
`
`
`
`CONTRAINDICATIONS
`
`None. (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-Associated Reactions, Hypersensitivity Reactions/Anaphylaxis:
`Monitor for signs and symptoms. If a significant infusion-associated
`
`reaction occurs, slow or interrupt the infusion and administer appropriate
`medical therapies. (5.3)
`HER2 testing: Perform using FDA-approved tests by laboratories with
`demonstrated proficiency. (5.4)
`
`
`
`
`
`
`
`
`
`
`
`
`ADVERSE REACTIONS
`
`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)
`
`
`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: 06/2012
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`
`1
`INDICATIONS AND USAGE
`
`
`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-Associated Reactions,
`
`
`Hypersensitivity Reactions/Anaphylaxis
`
`
`
`5.4 HER2 Testing
`
`
`6 ADVERSE REACTIONS
`
`
`6.1 Clinical Trials Experience
`
`
`6.2
`Immunogenicity
`
`
`7 DRUG INTERACTIONS
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`8.1 Pregnancy
`
`
`8.3 Nursing Mothers
`
`
`8.4 Pediatric Use
`
`U.S. BLA: PertuzumabGenentech, Inc.
`1 of 14/Regional (Metastatic Breast Cancer)
`
`Reference ID: 3143182
`
` Geriatric Use
`8.5
`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
`
`
`
`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.
`
`AVENTIS EXHIBIT 2082
`Mylan v. Aventis, IPR2016-00712
`
`

`
`FULL PRESCRIBING INFORMATION
`
`1
`2
`
`
`
`WARNING: 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)
`
`
`3
`INDICATIONS AND USAGE
`1
`4
`PERJETA is indicated for use in combination with trastuzumab and docetaxel for the treatment
`5
`of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2
`6
`therapy or chemotherapy for metastatic disease.
`7
`2
`DOSAGE AND ADMINISTRATION
`8
`2.1 Recommended Doses and Schedules
`9
`The initial dose of PERJETA is 840 mg administered as a 60-minute intravenous infusion,
`10
`followed every 3 weeks thereafter by a dose of 420 mg administered as an intravenous infusion
`11
`over 30 to 60 minutes.
`12
`13 When administered with PERJETA, the recommended initial dose of trastuzumab is 8 mg/kg
`14
`administered as a 90-minute intravenous infusion, followed every 3 weeks thereafter by a dose of
`15
`6 mg/kg administered as an intravenous infusion over 30 to 90 minutes.
`16 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
`17
`
`18
` every 3 weeks if the initial dose is well tolerated.
`2.2 Dose Modification
`19
`20
`For delayed or missed doses, if the time between two sequential infusions is less than 6 weeks,
`21
`the 420 mg dose of PERJETA should be administered. Do not wait until the next planned dose.
`22
`If the time between two sequential infusions is 6 weeks or more, the initial dose of 840 mg
`23
`PERJETA should be re-administered as a 60-minute intravenous infusion followed every
`24
`3 weeks thereafter by a dose of 420 mg administered as an intravenous infusion over
`25
`30 to 60 minutes.
`26
`The infusion rate of PERJETA may be slowed or interrupted if the patient develops an
`27
`infusion-associated reaction. The infusion should be discontinued immediately if the patient
`experiences a serious hypersensitivity reaction [see Warnings and Precautions (5.2)].
`
`28
`Left Ventricular Ejection Fraction (LVEF):
`29
`30 Withhold PERJETA and trastuzumab dosing for at least 3 weeks for either:
`31
` a drop in LVEF to less than 40% or
`32
` LVEF of 40% to 45% with a 10% or greater absolute decrease below pretreatment values
`[see Warnings and Precautions (5.2)]
`
`33
`PERJETA may be resumed if the LVEF has recovered to greater than 45% or to 40% to 45%
`34
`35
`associated with less than a 10% absolute decrease below pretreatment values.
`36
`If after a repeat assessment within approximately 3 weeks, the LVEF has not improved, or has
`37
`declined further, discontinuation of PERJETA and trastuzumab should be strongly considered,
`U.S. BLA: PertuzumabGenentech, Inc.
`2 of 14/Regional (Metastatic Breast Cancer)
`
`
`
`Reference ID: 3143182
`
`

`
`unless the benefits for the individual patient are deemed to outweigh the risks [see Warnings and
`38
`
` Precautions (5.2)].
`39
`PERJETA should be withheld or discontinued if trastuzumab treatment is withheld or
`40
`discontinued.
`41
`If docetaxel is discontinued, treatment with PERJETA and trastuzumab may continue.
`42
`43 Dose reductions are not recommended for PERJETA.
`44
`For docetaxel dose modifications, see docetaxel prescribing information.
`2.3 Preparation for Administration
`45
`46 Administer as an intravenous infusion only. Do not administer as an intravenous push or bolus.
`47 Do not mix PERJETA with other drugs.
`Preparation
`48
`
`Prepare the solution for infusion, using aseptic technique, as follows:
`49
`50
` Parenteral drug products should be inspected visually for particulates and discoloration
`51
`prior to administration.
`52
` Withdraw the appropriate volume of PERJETA solution from the vial(s).
`53
` Dilute into a 250 mL 0.9% sodium chloride PVC or non-PVC polyolefin infusion bag.
`54
` Mix diluted solution by gentle inversion. Do not shake.
`55
` Administer immediately once prepared.
`If the diluted infusion solution is not used immediately, it can be stored at 2oC to 8oC for
`56
`
`57
`up to 24 hours.
`58
` Dilute with 0.9% Sodium Chloride injection only. Do not use dextrose (5%) solution.
`
`DOSAGE FORMS AND STRENGTHS
`3
`59
`60
`PERJETA (pertuzumab) 420 mg/14 mL (30 mg/mL) in a single-use vial
`4
`CONTRAINDICATIONS
`61
`62 None.
`5 WARNINGS AND PRECAUTIONS
`63
`5.1 Embryo-Fetal Toxicity
`64
`65
`PERJETA can cause fetal harm when administered to a pregnant woman. Treatment of pregnant
`66
`cynomolgus monkeys with pertuzumab resulted in oligohydramnios, delayed fetal kidney
`67
`development, and embryo-fetal death. If PERJETA is administered during pregnancy, or if the
`68
`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)].
`69
`70 Verify pregnancy status prior to the initiation of PERJETA. Advise patients of the risks of
`71
`embryo-fetal death and birth defects and the need for contraception during and after treatment.
`72 Advise patients to contact their healthcare provider immediately if they suspect they may be
`73
`pregnant. If PERJETA is administered during pregnancy or if a patient becomes pregnant while
`74
`receiving PERJETA, immediately report exposure to the Genentech Adverse Event Line at
`75
`1-888-835-2555. Encourage women who may be exposed during pregnancy to enroll in the
`76 MotHER Pregnancy Registry by contacting 1-800-690-6720 [see Patient Counseling
`Information (17)].
`
`77
`U.S. BLA: PertuzumabGenentech, Inc.
`3 of 14/Regional (Metastatic Breast Cancer)
`
`
`
`Reference ID: 3143182
`
`

`
`78 Monitor patients who become pregnant during PERJETA therapy for oligohydramnios. If
`
`79
` 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
`80
`81 management of oligohydramnios due to PERJETA exposure is not known.
`5.2 Left Ventricular Dysfunction
`82
`83 Decreases in LVEF have been reported with drugs that block HER2 activity, including
`84
`PERJETA. In the randomized trial, PERJETA in combination with trastuzumab and docetaxel
`85 was not associated with increases in the incidence of symptomatic left ventricular systolic
`86
`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
`87
`88
`4.4% of patients in the PERJETA-treated group and 8.3% of patients in the placebo-treated
`89
`group. Symptomatic left ventricular systolic dysfunction (congestive heart failure) occurred in
`90
`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
`91
`92
`radiotherapy to the chest area may be at higher risk of decreased LVEF.
`93
`PERJETA has not been studied in patients with a pretreatment LVEF value of  50%, a prior
`94
`history of CHF, decreases in LVEF to  50% during prior trastuzumab therapy, or conditions
`95
`that could impair left ventricular function such as uncontrolled hypertension, recent myocardial
`96
`infarction, serious cardiac arrhythmia requiring treatment or a cumulative prior anthracycline
`exposure to  360 mg/m2 of doxorubicin or its equivalent.
`97
`98 Assess LVEF prior to initiation of PERJETA and at regular intervals (e.g., every three months)
`99
`during treatment to ensure that LVEF is within the institution’s normal limits. If LVEF is
`100
` 40%, or is 40% to 45% with a 10% or greater absolute decrease below the pretreatment value,
`101 withhold PERJETA and trastuzumab and repeat LVEF assessment within approximately
`102
`3 weeks. Discontinue 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
`103
`Administration (2.2)].
`104
`5.3
`Infusion-Associated Reactions, Hypersensitivity Reactions/Anaphylaxis
`105
`
` PERJETA has been associated with infusion and hypersensitivity reactions [see Adverse
`106
`Reactions (6.1)]. An infusion reaction was defined in the randomized trial as any event
`107
`108
`described as hypersensitivity, anaphylactic reaction, acute infusion reaction or cytokine release
`109
`syndrome occurring during an infusion or on the same day as the infusion. The initial dose of
`110
`PERJETA was given the day before trastuzumab and docetaxel to allow for the examination of
`111
`PERJETA-associated reactions. On the first day, when only PERJETA was administered, the
`112
`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
`113
`reactions ( 1.0%) were pyrexia, chills, fatigue, headache, asthenia, hypersensitivity, and
`114
`115
`vomiting.
`116 During the second cycle when all drugs were administered on the same day, the most common
`117
`infusion reactions in the PERJETA-treated group ( 1.0%) were fatigue, dysgeusia,
`118
`hypersensitivity, myalgia, and vomiting.
`119
`In the randomized trial, the overall frequency of hypersensitivity/anaphylaxis reactions was
`120
`10.8% in the PERJETA-treated group and 9.1% in the placebo-treated group. The incidence of
`121 Grade 3 – 4 hypersensitivity/anaphylaxis reactions was 2% in the PERJETA-treated group and
`122
`2.5% in the placebo-treated group according to National Cancer Institute – Common
`
`U.S. BLA: PertuzumabGenentech, Inc.
`4 of 14/Regional (Metastatic Breast Cancer)
`
`Reference ID: 3143182
`
`

`
`Terminology Criteria for Adverse Events (NCI - CTCAE) (version 3). Overall, 4 patients in
`
`123
`PERJETA-treated group and 2 patients in the placebo-treated group experienced anaphylaxis.
`
`124
`125 Observe patients closely for 60 minutes after the first infusion and for 30 minutes after
`
`126
`subsequent infusions of PERJETA. If a significant infusion-associated reaction occurs, slow or
`
`127
`interrupt the infusion and administer appropriate medical therapies. Monitor patients carefully
`
`128
`until complete resolution of signs and symptoms. Consider permanent discontinuation in
`
`patients with severe infusion reactions [see Dosage and Administration (2.2)].
`
`129
`
`5.4 HER2 Testing
`130
`131 Detection of HER2 protein overexpression is necessary for selection of patients appropriate for
`
`132
`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)]. In the randomized trial,
`
`133
`134
`patients with breast cancer were required to have evidence of HER2 overexpression defined as
`
`3+ IHC by Dako Herceptest™ or FISH amplification ratio  2.0 by Dako HER2 FISH
`
`135
`136
`PharmDx™ test kit. Only limited data were available for patients whose breast cancer was
`
`137
`positive by FISH, but did not demonstrate protein overexpression by IHC.
`
`138 Assessment of HER2 status should be performed by laboratories with demonstrated proficiency
`
`139
`in the specific technology being utilized. Improper assay performance, including use of sub­
`140
`optimally fixed tissue, failure to utilize specified reagents, deviation from specific assay
`
`141
`instructions, and failure to include appropriate controls for assay validation, can lead to
`
`142
`unreliable results.
`
`ADVERSE REACTIONS
`6
`
`143
`The following adverse reactions are discussed in greater detail in other sections of the label:
`
`144
`
` Embryo-Fetal Toxicity [see Warnings and Precautions (5.1)]
`
`145
`
` Left Ventricular Dysfunction [see Warnings and Precautions (5.2)]
`146
`
`
`Infusion-Associated Reactions, Hypersensitivity Reactions/Anaphylaxis [see Warnings
`147
`
`and Precautions (5.3)]
`
`148
`6.1 Clinical Trials Experience
`149
`150 Because clinical trials are conducted under widely varying conditions, adverse reaction rates
`151
`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.
`152
`
`In clinical trials, PERJETA has been evaluated in more than 1400 patients with various
`153
`154 malignancies and treatment with PERJETA was predominantly in combination with other
`155
`anti-neoplastic agents.
`156
`The adverse reactions described in Table 1 were identified in 804 patients with HER2-positive
`157 metastatic breast cancer treated in the randomized trial. Patients were randomized to receive
`158
`either PERJETA in combination with trastuzumab and docetaxel or placebo in combination with
`159
`trastuzumab and docetaxel. The median duration of study treatment was 18.1 months for
`160
`patients in the PERJETA-treated group and 11.8 months for patients in the placebo-treated
`161
`group. No dose adjustment was permitted for PERJETA or trastuzumab. The rates of adverse
`162
`events resulting in permanent discontinuation of all study therapy were 6.1% for patients in the
`163
`PERJETA-treated group and 5.3% for patients in the placebo-treated group. Adverse events led
`164
`to discontinuation of docetaxel alone in 23.6% of patients in the PERJETA-treated group and
`165
`23.2% of patients in the placebo-treated group. Table 1 reports the adverse reactions that
`166
`occurred in at least 10% of patients in the PERJETA-treated group.
`U.S. BLA: PertuzumabGenentech, Inc.
`5 of 14/Regional (Metastatic Breast Cancer)
`
`Reference ID: 3143182
`
`
`
`
`
`

`
`167
`168
`169
`170
`171
`172
`173
`174
`175
`176
`
`The most common adverse reactions ( 30%) seen with PERJETA in combination with
`trastuzumab and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and
`peripheral neuropathy. The most common NCI - CTCAE (version 3) Grade 3 – 4 adverse
`reactions ( 2%) were neutropenia, febrile neutropenia, leukopenia, diarrhea, peripheral
`neuropathy, anemia, asthenia, and fatigue. An increased incidence of febrile neutropenia was
`observed for Asian patients in both treatment arms compared with patients of other races and
`from other geographic regions. Among Asian patients, the incidence of febrile neutropenia was
`higher in the pertuzumab-treated group (26%) compared with the placebo-treated group (12%).
`Table 1
`Summary of Adverse Reactions Occurring in  10% of Patients on the
`PERJETA Treatment Arm in the Randomized Trial
`Placebo
`Body System/Adverse
`PERJETA
`+ trastuzumab
`Reactions
`+ trastuzumab
`+ docetaxel
`+ docetaxel
`
`
`
`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
`
`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
`
`
`52.8
`Neutropenia
`23.1
`Anemia
`18.2
`Leukopenia
`13.8
`Febrile neutropenia*
`U.S. BLA: PertuzumabGenentech, Inc.
`6 of 14/Regional (Metastatic Breast Cancer)
`
`Reference ID: 3143182
`
`
`
`
`
`
`
`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
`
`
`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
`
`
`
`
`
`
`
`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
`
`
`
`n=397
`
`Frequency rate %
`
`All
`Grades
`
`3 – 4
`Grades
`%
`%
`
`
`
`
`
`n=407
`
`Frequency rate %
`
`All
`Grades
`
`3 – 4
`Grades
`%
`%
`
`
`
`

`
`Nervous system
`disorders
`
`Neuropathy peripheral
`Headache
`Dysgeusia
`Dizziness
`Musculoskeletal and
`connective tissue
`disorders
`
`Myalgia
`Arthralgia
`Infections and
`infestations
`
`Upper respiratory tract
`infection
`Nasopharyngitis
`Respiratory, thoracic
`and mediastinal
`disorders
`
`Dyspnea
`Metabolism and
`nutrition disorders
`
`Decreased appetite
`Eye disorders
`
`Lacrimation increased
`Psychiatric disorders
`0.0
`13.4
`0.0
`13.3
`Insomnia
`177
`* In this table this denotes an adverse reaction that has been reported in association with a fatal
`178
`outcome
`179
`
`180 The following clinically relevant adverse reactions were reported in  10% of patients in
`the PERJETA-treated group:
`181
`Skin and subcutaneous tissue disorders: Paronychia (7.1% in the PERJETA-treated group vs.
`182
`183
`3.5% in the placebo-treated group)
`184 Respiratory, thoracic and mediastinal disorders: Pleural effusion (5.2% in the PERJETA­
`185
`treated group vs. 5.8% in the placebo-treated group)
`186 Cardiac disorders: Left ventricular dysfunction (4.4% in the PERJETA-treated group vs. 8.3%
`187
`in the placebo-treated group) including symptomatic left ventricular systolic dysfunction (CHF)
`188
`(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
`189
`190
`placebo-treated group)
`191 Adverse Reactions Reported in Patients Receiving PERJETA and Trastuzumab after
`192 Discontinuation of Docetaxel
`193
`In the randomized trial, adverse reactions were reported less frequently after discontinuation of
`194
`docetaxel treatment. All adverse reactions in the PERJETA and trastuzumab treatment group
`
`
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`U.S. BLA: PertuzumabGenentech, Inc.
`7 of 14/Regional (Metastatic Breast Cancer)
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`Reference ID: 3143182
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`
`
`
`
`
`
`
`
`
`
`
`
`32.4
`20.9
`18.4
`12.5
`
`22.9
`15.5
`
`16.7
`
`11.8
`
`14.0
`
`29.2
`
`14.0
`
`3.2
`1.2
`0.0
`0.5
`
`1.0
`0.2
`
`0.7
`
`0.0
`
`1.0
`
`1.7
`
`0.0
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`33.8
`16.9
`15.6
`12.1
`
`23.9
`16.1
`
`13.4
`
`12.8
`
`15.6
`
`26.4
`
`13.9
`
`2.0
`0.5
`0.0
`0.0
`
`0.8
`0.8
`
`0.0
`
`0.3
`
`2.0
`
`1.5
`
`0.0
`
`

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`occurred in  10% of patients with the exception of diarrhea (19.1%), upper respiratory tract
`195
`infection (12.8%), rash (11.7%), headache (11.4%), and fatigue (11.1%).
`196
`6.2
`Immunogenicity
`197
`198 As with all therapeutic proteins, there is the potential for an immune response to PERJETA.
`199
`Patients in the randomized trial were tested at multiple time-points for antibodies to PERJETA.
`200 Approximately 2.8% (11/386) of patients in the PERJETA-treated group and 6.2% (23/372) of
`
`patients in the placebo-treated group tested positive for anti-PERJETA antibodies. Of these
`201
`34 patients, none experienced anaphylactic/hypersensitivity reactions that were clearly related to
`202
`203
`the anti-therapeutic antibodies (ATA). The presence of pertuzumab in patient serum at the levels
`204
`expected at the time of ATA sampling can interfere with the ability of this assay to detect anti­
`205
`pertuzumab antibodies. In addition, the assay may be detecting antibodies to trastuzumab. As a
`206
`result, data may not accurately reflect the true incidence of anti-pertuzumab antibody
`207
`development.
`208
`Immunogenicity data are highly dependent on the sensitivity and specificity of the test methods
`209
`used. Additionally, the observed incidence of a positive result in a test method may be
`210
`influenced by several factors, including sample handling, timing of sample collection, drug
`211
`interference, concomitant medication, and the underlying disease. For these reasons, comparison
`212
`of the incidence of antibodies to PERJETA with the incidence of antibodies to other products
`213 may be misleading.
`7
`DRUG INTERACTIONS
`214
`215 No drug-drug interactions were observed between pertuzumab and trastuzumab, or between
`216
`pertuzumab and docetaxel.
`8
`USE IN SPECIFIC POPULATIONS
`217
`8.1 Pregnancy
`218
`Pregnancy Category D
`219
`220 Risk Summary
`
`There are no adequate and well-controlled studies of PERJETA in pregnant women. Based on
`221
`222
`findings in animal studies, PERJETA can cause fetal harm when administered to a pregnant
`223 woman. The effects of PERJETA are likely to be present during all trimesters of pregnancy.
`224
`Pertuzumab administered to pregnant cynomolgus monkeys resulted in oligohydramnios,
`225
`delayed fetal kidney development, and embryo-fetal deaths at clinically relevant exposures of
`226
`2.5 to 20-fold greater than the recommended human dose, based on Cmax. If PERJETA is
`227
`administered during pregnancy, or if a patient becomes pregnant while receiving PERJETA, the
`
`patient should be apprised of the potential hazard to the fetus.
`228
`If PERJETA is administered during pregnancy or if a patient becomes pregnant while receiving
`229
`230
`PERJETA, immediately report exposure to the Genentech Adverse Event Line at
`231
`1-888-835-2555. Encourage women who may be exposed during pregnancy to enroll in the
`232 MotHER Pregnancy Registry by contacting 1-800-690-6720 [see Patient Counseling
`Information (17)].
`233
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`234 Animal Data
`235 Reproductive toxicology studies have been conducted in cynomolgus monkeys. Pregnant
`236 monkeys were treated on Gestational Day (GD)19 with loading doses of 30 to 150 mg/kg
`237
`pertuzumab, followed by bi-weekly doses of 10 to 100 mg/kg. These dose levels resulted in
`238
`clinically relevant exposures of 2.5 to 20-fold greater than the recommended human dose, based
`U.S. BLA: PertuzumabGenentech, Inc.
`8 of 14/Regional (Metastatic Breast Cancer)
`
`Reference ID: 3143182
`
`

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`on Cmax. Intravenous administration of pertuzumab from GD19 through GD50 (period of
`
`239
`organogenesis) was embryotoxic, with dose-dependent increases in embryo-fetal death between
`
`240
`241 GD25 to GD70. The incidences of embryo-fetal loss were 33, 50, and 85% for dams treated with
`
`242
`bi-weekly pertuzumab doses of 10, 30, and 100 mg/kg, respectively (2.5 to 20-fold greater than
`
`243
`the recommended human dose, based on Cmax). At Caesarean section on GD100,
`
`244
`oligohydramnios, decreased relative lung and kidney weights and microscopic evidence of renal
`
`245
`hypoplasia consistent with delayed renal development were identified in all pertuzumab dose
`
`246
`groups. Pertuzumab exposure was reported in offspring from all treated groups, at levels of
`
`247
`29% to 40% of maternal serum levels at GD100.
`
`8.3 Nursing Mothers
`248
`249
`It is not known whether PERJETA is excreted in human milk, but human IgG is excreted in
`
`250
`human milk. Because many drugs are secreted in human milk and because of the potential for
`
`251
`serious adverse reactions in nursing infants from PERJETA, a decision should be made whether
`
`252
`to discontinue nursing, or discontinue drug, taking into account the elimination half-life of
`
`PERJETA and the importance of the drug to the mother [See Warnings and Precautions (5.1),
`
`253
`254 Clinical Pharmacology (12.3)].
`
`
`8.4 Pediatric Use
`255
`256
`The safety and effectiveness of PERJETA have not been established in pediatric patients.
`
`8.5 Geriatric Use
`257
`258 Of 402 patients who received PERJETA in the randomized trial, 60 patients (15%) were
`
`259
` 65 years of age and 5 patients (1%) were  75 years of age. No overall differences in efficacy
`
`260
`and safety of PERJETA were observed between these patients and younger patients.
`
`261 Based on a population pharmacokinetic analysis, no significant difference was observed in the
`
`262
`pharmacokinetics of pertuzumab between patients < 65 years (n=306) and patients ≥ 65 years
`
`263
`(n=175).
`
`8.6 Females of Reproductive Potential
`264
`265
`PERJETA can cause embryo-fetal harm when administered during pregnancy. Counsel patients
`
`266
`regarding pregnancy prevention and planning. Advise females of reproductive potential to use
`
`267
`effective contraception while receiving PERJETA and for 6 months following the last dose of
`
`268
`PERJETA.
`
`269
`If PERJETA is administered during pregnancy or if a patient becomes pregnant while receiving
`
`270
`PERJETA, immediately report exposure to the Genentech Adverse Event Line at
`
`271
`1-888-835-2555. Encourage women who may be exposed during pregnancy to enroll in the
`
`272 MotHER Pregnancy Registry by contacting1-800-690-6720 [see Patient Counseling
`
`Information (17)].
`
`273
`8.7 Renal Impairment
`274
`275 Dose adjustments of PERJETA are not needed in patients with mild (creatinine clearance [CLcr]
`
`
`276
`60 to 90 mL/min) or moderate (CLcr 30 to 60 mL/min) renal impairment. No dose adjustment
`
`277
`can be recommended for patients with severe renal impairment (CLcr less than 30 mL/min)
`
`because of the limited pharmacokinetic data available [see Clinical Pharmacology (12.3)].
`
`278
`
`8.8 Hepatic Impairment
`279
`280 No clinical studies have been conducted to evaluate the effect of hepatic impairment on the
`
`281
`pharmacokinetics of pertuzumab.
`
`
`U.S. BLA: PertuzumabGenentech, Inc.
`9 of 14/Regional (Metastatic Breast Cancer)
`
`Reference ID: 3143182
`
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`

`
`10 OVERDOSAGE
`282
`283 No drug overdoses have been reported with PERJETA to date.
`11 DESCRIPTION
`284
`285
`Pertuzumab is a recombinant humanized monoclonal antibody that targets the extracellular
`
`286
` dimerization domain (Subdomain II) of the human epidermal growth factor receptor 2 protein
`(HER2). Pertuzumab is produced by recombinant DNA technology in a mammalian cell
`287
`288
`(Chinese Hamster Ovary) culture containing the antibiotic, gentamicin. Gentamicin is not
`289
`detectable in the final product. Pertuzumab has an approximate molecular weight of 148 kDa.
`290
`PERJETA is a sterile, clear to slightly opalescent, colorless to pale brown liquid for intravenous
`291
`infusion. Each single use vial contains 420 mg of pertuzumab at a concentration of 30 mg/mL in
`292
`20 mM L-histidine acetate (pH 6.0), 120 mM sucrose and 0.02% polysorbate 20.
`12 CLINICAL PHARMACOLOGY
`
`293
`12.1 Mechanism of Action
`294
`295
`Pertuzumab targets the extracellular dimerization domain (Subdomain II) of the human
`
`epidermal growth factor receptor 2 protein (HER2) and, thereby, blocks ligand-dependent
`296
`297
`heterodimerization of HER2 with other HER family members, including EGFR, HER3 and
`298 HER4. As a result, pertuzumab inhibits ligand-initiated intracellular signaling through two
`299 major signal pathways, mitogen-activated protein (MAP) kinase and phosphoinositide 3-kinase
`300
`(PI3K). Inhibition of these signaling pathways can result in cell growth arrest and apoptosis,
`301
`respectively. In addition, pertuzumab mediates antibody-dependent cell-mediated cytotoxicity
`302
`(ADCC).
`303 While pertuzumab alone inhibited the proliferation of human tumor cells, the combination of
`304
`pertuzumab and trastuzumab significantly augmented anti-tumor activity in
`305 HER2-overexpressing xenograft models.
`12.3 Pharmacokinetics
`306
`307
`Pertuzumab demonstrated linear pharmacokinetics at a dose range of 2 – 25 mg/kg. Based on a
`308
`population PK analysis that included 481 patients, the median clearance (CL) of pertuzumab was
`309
`0.24 L/day and the median half-life was 18 days. With an initial dose of 840 mg followed by a
`310 maintenance dose of 420 mg every three weeks thereafter, the steady-state concentration of
`311
`pertuzumab was reached after the first maintenance dose.
`312
`The population PK analysis suggested no PK differences based on age, gender, and ethnicity
`313
`(Japanese vs. non-Japanese). Baseline serum albumin level and lean body weight as covariates
`314
`only exerted a minor influence on PK parameters. Therefore, no dose adjustments based on
`315
`body weight or baseline albumin level are needed.
`316 No drug-drug interactions were observed between pertuzumab and trastuzumab, or between
`317
`pertuzumab and docetaxel in a sub-study of 37 patients in the randomized trial.
`318 No dedicated renal impairment trial for PERJETA has been conducted. Based on the results of
`319
`the population pharmacokinetic analysis, pertuzumab exposure in patients with mild (CLcr
`320
`60 to 90 mL/min, n=200) and moderate renal impairment (CLcr 30 to 60 mL/min, n=71) were
`321
`similar to those in patients with normal renal function (CLcr greater than 90 mL/min, n=200).
`3