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`
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`

`
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`
`EXHIBIT 22
`
`REDACTED IN ITS ENTIRETY
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`EXHIBIT 22
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`

`
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`
`EXHIBIT 23
`
`REDACTED IN ITS ENTIRETY
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`
`EXHIBIT 23
`
`

`

`EXHIBIT 24
`
`

`

`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to Ilse
`OGIVRI safely and effectively. See full prescribing information for
`OGIVRI.
`
`OGIVRI trastuzumab—dkst. f0" ' .ctio , f ‘lJ t .
`i
`o
`.
`(
`)
`I my)
`11 0'
`I r“ en us use
`I
`'t': I U.S. A
`:1: 2017
`HI I l
`pprov I
`OGIVRI (trastuzumab—dkst) is biosilnilnl" t0 HERCEI’TIN
`
`(tl‘flsmzumflll)
`
`W'ARNING: CARDIOMYOPATHY, INFUSION REACTIONS,
`EMBRYO—FETAL TOXICITY, and PULMONARY TOXICITY
`_
`.
`Seefullprescribing mformattan for complete boxed warning
`Ca rdiomyopathy: trastuzumab products can result in subclinical and
`clinical cardiac failure manifesting as CHF, and decreased LVEF, with
`greatest risk when administered concurrently with anthracyclines.
`Evaluate cardiac function prior to and during treatment. Discontinue
`Ogivri for cardiomyopathy. (2.3, 5.1)
`
`
`
`
`
`
`
`
`
`
`Embryo—Fetal Toxicity: Exposure to trastuzumab products during
`
`pregnancy can result in oligohydranmios, in some cases complicated by
`
`pulmonary hypoplasia and neonatal death. Advise patients of these risks
`
`
`and the need for effective contraception. (5.3, 8.1, 8.3)
`
`Infusion Reactions, Pulmonary Toxicity: Discontinue Ogivri for
`anapllylaxis, angioedenm, interstitial pneumonitis, or acute respiratory
`distress syndrome. [5.2. 5.4)
`
`_. INDICATIONS AND USAGE «—
`Ogivri is a HER2/neu receptor antagonist indicated for:
`o
`The treatment of HER2-overexpressing breast cancer (1.1, 1.2)
`o
`The treatment of HER2-overexpressing metastatic gastric or
`gastroesophageal junction adenocarcinoma. (1.3)
`
`Select pnl icnts for therapy based on an FDA-approved companion diagnostic
`for a trastuzuaiab product (1, 2.1).
`_ DOSAGE AND ADMINISTRATION
`For intravenous (IV) infusion only. Do not administer as an IV push or
`bolus. (2.2)
`Do 101. substitute Ogivi‘imgiuaumab-dksti for or with wirxltiztunah
`enilansine (£1
`Perfonn I FR! lcslinr: usinn Fil-t-a l Tin-‘cd tests lw laboratories with
`
`deig‘ionstriueil ]31'n1'1ci'eiicv._{ l. 2.] 1
`
`
`
`
`
`Adjuvaut 'l'rralment ot' HERZ—Overexpressing Breast Cancer (2.2)
`Administer at either:
`
`0
`
`Initial dose of 4 mg-1;g over 90 minute II" infusion. then 2 rag-“kg m-‘cr 30
`minute IV infusion u cuklv for 12 trucks {with paclitaxel o: doccldxcll or
`18 weeks (with docetaxel/carboplatin). One week after the last weekly dose
`
`-
`
`of Ogivri. administer 6 mg/kg as an IV infusion ovei 30 to 90 minutes
`every three weeks to complete a total of 52 weeks of therapy, or
`Initial dose of 8 nIg/kg over 90 minutes IV infusion, then 6 mg/kg over 30
`to 90 minutes IV infusion every three weeks for 52 weeks.
`Metastatic HERZ-Overexpressing Breast Cancer (2.2)
`,
`,
`.
`_
`_
`0
`Initial dose of4 tug/kg as a 90 minute IV infilSion followed by subsequent
`.
`weekly doses of 2 mg/kg as 30 minute IV inquIons.
`hletasmtjc HERZ—Overexpressing Gastric Cancer (2.2)
`-
`Initial dose of 8 mg/kg over 90 minutes IV infusion, followed by 6
`mg/kg over 30 to 90 minutes IV infusion every 3 weeks.
`.................. DOSAGE FORMS AND STRENGTHS
`o
`For Injection: 420 mg lyophilized powder in a multiple-dose vial for
`reconstitution
`
`"' CONTRAINDICATIONS —" "“‘——
`
`' None (4)
`.................... WARNINGS AND PRECAUTIONS ———-
`0
`Exacerbation of Chemotherapy-Induced Neutropenia. (5.5, 6.1)
`—------——————------————-— ADVERSE REACTIONS - - -
`Adjuvant Breast Cancer
`0 Most common adverse reactions 8 5%) are headache, diarrhea, nausea,
`and chills. (6.1)
`Metastatic Breast Cancer
`- Most common adverse reactions (2 10%) are fever, chills, headache,
`infection, congestive heart failure, insomnia, cough, and rash. (6 1)
`Metastatic Gastric Cancer
`
`. Most common adverse reactions (2 10%) are neutropcnia, diarrhea,
`fatigue, anemia, stomatitis, weight loss, upper respiratory tract infections,
`fever, throinbocytopenia, mucosal inflammation, nasopharyngitis, and
`dysgeusia. (6.1)
`
`To report SUSPECTED ADVERSE REACTIONS, contact Mylan
`Pharmaceuticals Inc. at 1—877-446—3679 (1—877-4-INFO-RX) or FDA at 1-
`800-FDA—1088 or www.fda.gov/mcdwatch.
`
`—---———————— USE IN SPECIFIC POPULATIONS
`Females and Males of Reproductive Potential: Verify the pregnancy status of
`females prior In initiation of Ogivi'i i'8.3).
`
`See 17 for PATIENT COUNSELING INFORMATION.
`
`*Biosimilar means that the biological product is approved based on data
`demonrlraling that it is lilghly similar to an FDA-approved biological product,
`known as a rel'urcnce pin-lust, and that there an: no clinically meaningful
`differences between the liiuniiru'lai' producl and the reference prodilcl.
`[Iiosimilarity ol‘Ogivri 11m: been dcmormraicd forth-z condiIionts) oi'ttsc (e.g.
`indicationis}. rinsmg rcgi:ncn(s)_}. strcngllits), dosage l'ormtsl. and mutt-(5) of
`administration described in its Full Prescribing Information.
`
`7
`
`DRUG TNT E R.-\ (.TIONS
`
`Revised: 12/2017
`
`3% IN bplyrgvliiitigVPOPUI-IAI IONS
`FULL PRESCRIBING INFORMATION: CONTENTS*
`8 2
`lactt’at‘im;
`WARNING: CARDIOMYOPATHY, INFUSION REACTIONS,
`8 3
`Females 1nd Miles of Re rodnctiV‘ Pohntial
`EMBRYO—FETAL TOXICITY, and PULMONARY TOXICITY
`‘
`.
`.
`‘
`‘
`‘
`‘
`P
`‘
`“
`1
`INDICATIONS AND USAGE
`8 4
`Pediatric Use
`.
`-
`.
`.
`,
`1.]
`Adjuvant Breast Cancer
`8'3
`Geriatric Lse
`Metast't'c B m tC'l c
`1 2
`OVERDOSAGE
`‘
`‘
`“ “ f
`‘ r ‘5.
`“1 6’
`DESCRIPTION
`1.3
`Metastatic Gastric Cancer
`CLINICAL PHARMACOLOGY
`DOSAGE MID ADMMHRMION
`.
`.
`.
`2.1
`Patient Selection
`12 1
`i\/lechanisni OI Action
`.
`,
`,
`.
`2.2
`Recommended Doses and Schedules
`12.2
`Pharniacodynamics
`.
`.
`.
`.
`._
`2.3
`Important Dosmg Conmderations
`12'3
`Phannacokinetics
`Preparation for L\dministr‘ttion
`2 4
`.
`_.
`_
`_
`.
`NONCLIMC'jAP IOMPOPOGY .
`DOSAGE FORMS AND STRENGTHS
`13.1
`Caicmogenesm, Mutagenests, Impairment of Fertility
`.
`»,
`. ..
`CLINICAL STUDIES
`CONTRAINDICATIONS
`.
`,
`‘
`.
`‘.
`WARNINGS AND PRECAUTIONS
`14.1
`Adjuvant Bicast Cancm
`5 1
`C‘ d'
`y m :
`Metastatic Breast Cancer
`14.2
`_’
`Jr 1.0111509
`‘3
`~
`.
`,
`.
`‘
`5.2
`Infuswn Reactions
`14.3
`Metastatic Gastric Lancet
`5 3
`Embryo—Fetal Toxicity
`HOW SUPPLIED/STORAGE AND HANDLING
`_‘
`_.
`‘.
`.
`3.4
`Pulmonarv Toxicity
`l 6.1
`How Supplied
`.
`,
`.
`,
`..
`i
`16 2
`Storage
`3 5
`hxaccrbatt on of (.hemotherapy-Induccd Neutropcnia
`PATIENT COUNSELING INFORMATION
`17
`6‘1“ ERSE BEACTIQM. ,
`.
`0.1
`Clinical lrials hxpcucncc
`*Sections or subsections omitted from the full prescribing infonnation are not
`6.2
`Iinmunogenicity
`listed.
`6.3
`Post-Marketing Experience
`
`
`8
`
`10
`11
`12
`
`13
`14
`
`16
`
`2
`
`3
`4
`5
`
`6
`
`Reference ID: 4188826
`
`CONFIDENTIAL
`
`GNE-HER_000960425
`
`

`

`
`FULL PRESCRIBING INFORMATION
`
`
`
`WARNING: CARDIOMYOPATHY, INFUSION REACTIONS, ElVIBRYO-FETAL
`TOXICITY, and PULMONARY TOXICITY
`
`Cardiomyopathy
`Administration of trastuzumab products can result in sub-clinical and clinical cardiac
`failure. The incidence and severity was highest in patients receiving trastuzumab with
`anthracyclinc-containing chemotherapy regimens.
`
`Evaluate left ventricular function in all patients prior to and during treatment with Ogivri.
`Discontinue Ogivri treatment in patients receiving adjuvant therapy and withhold Ogivri in
`patients with metastatic disease for clinically significant decrease in left ventricular function
`[see Dosage and Administration (2.3) and Warnings and Precautions (5.1)].
`
`Infusion Reactions; Pulmonary Toxicity
`Administration of trastuzumab products can result in serious and fatal infusion reactions
`and pulmonary toxicity. Symptoms usually occur during or within 24 hours of
`administration. Interrupt Ogivri infusion for dyspnea or clinically significant hypotension.
`Monitor patients until symptoms completely resolve. Discontinue Ogivri for anaphylaxis,
`angioedema, interstitial pneumonitis, or acute respiratory distress syndrome [see Warnings
`and Precautions (5.2, 5.4)].
`
`Embryo-Fetal Toxicity
`Exposure to trastuzumab products during pregnancy can result in oligohydramnios and
`oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities,
`and neonatal death. Advise patients of these risks and the need for effective contraception
`[see Warnings and Precautions (53) and Use in Specific Populations (8.1, 8.3)].
`
`
`1
`
`INDICATIONS AND USAGE
`
`Adj uvant Breast Cancer
`1.1
`Ogivri is indicated for adjuvant treatment of I-IERZ overexpressing node positive or node negative
`(ER/PR negative or with one high risk feature [see Clinical Studies (14.1)]) breast cancer
`0
`as part of a treatment regimen consisting of doxorubicin, cyclophosphamide, and either
`paclitaxel or docetaxel
`as part of a treatment regimen with docetaxel and carboplatin
`o
`as a single agent following multi—modality anthracycline based therapy.
`o
`Select patients for therapy based on an FDA-approved companion diagnostic for a trastuzumab
`product [see Dosage and Administration (2.1)].
`
`1.2 Metastatic Breast Cancer
`
`Ogivri is indicated:
`0
`In combination with paclitaxel for first-line treatment of HERZ-overexpressing metastatic
`breast cancer
`
`0 As a single agent for treatment of HERZ—overexpressing breast cancer in patients who have
`received one or more chemotherapy regimens for metastatic disease.
`
`Reference ID: 4188826
`
`CONFIDENTIAL
`
`GNE-HER_000960426
`
`

`

`Select patients for therapy based on an FDA—approved companion diagnostic for a trastuzumab
`product[see Dosage and Administration (2.1)].
`
`1.3 Metastatic Gastric Cancer
`
`Ogivri is indicated, in combination with cisplatin and capecitabine or 5-fluorouracil, for the
`treatment of patients with I-IERZ-overexpressing metastatic gastric or gastroesophageal junction
`adenocarcinoma who have not received prior treatment for metastatic disease.
`
`Select patients for therapy based on an FDA-approved companion diagnostic for a trastuzumab
`product [see Dosage and Administration (2.1)].
`
`2
`2.1
`
`DOSAGE AND ADMINISTRATION
`Patient Selection
`
`Select patients based on HER2 protein overexpression or HER2 gene amplification in tumor
`specimens [see Indications and Usage (1) and Clinical Studies (14)]. Assessment of HER2
`protein overexpression and HER2 gene amplification should be performed using FDA-approved
`tests specific for breast or gastric cancers by laboratories with demonstrated proficiency.
`Information on the FDA—approved tests for the detection of HER2 protein overexpression and
`HER2 gene amplification is available at: http://www.fda.gov/CompanionDiagnostics.
`
`Assessment of HER2 protein overexpression and HER2 gene amplification in metastatic gastric
`cancer should be performed using FDA—approved tests specifically for gastric cancers due to
`differences in gastric vs. breast histopathology, including incomplete membrane staining and
`more frequent heterogeneous expression of HER2 seen in gastric cancers.
`
`Improper assay performance, including use of suboptimally fixed tissue, failure to utilize
`specified reagents, deviation from specific assay instructions, and failure to include appropriate
`controls for assay validation, can lead to unreliable results.
`
`2.2
`
`Recommended Doses and Schedules
`
`0 Do not administer as an intravenous push or bolus. Do not mix Ogivri with other
`drugs.
`0 Do not substitute Ogivri (trastuzumab-dkst) for or with ado-trastuzumab emtansine.
`
`Adjuvant Treatment, Breast Cancer:
`Administer according to one of the following doses and schedules for a total of 52 weeks of
`Ogivri therapy:
`During and following paclitaxel, docetaxel, or docetaxel/carboplatin:
`0
`Initial dose of4 mg/kg as an intravenous infusion over 90 minutes then at 2 mg/kg as an
`intravenous infusion over 30 minutes weekly during chemotherapy for the first 12 weeks
`(paclitaxel or docetaxel) or 18 weeks (docetaxel/carboplatin).
`0 One week following the last weekly dose of Ogivri, administer Ogivri at 6 mg/kg as an
`intravenous infusion over 30 to 90 minutes every three weeks.
`As a single agent within three weeks following completion of multi—modality, anthracycline-
`based chemotherapy regimens:
`0
`Initial dose at 8 mg/kg as an intravenous infusion over 90 minutes
`
`Reference ID: 4188826
`
`CONFIDENTIAL
`
`0.)
`
`GNE-HER_000960427
`
`

`

`0
`
`Subsequent doses at 6 mg/kg as an intravenous infusion over 30 to 90 minutes every three
`weeks [see Dosage and Administration (2.3)].
`o Extending adjuvant treatment beyond one year is not recommended [see Adverse Reactions
`(6.1)].
`Metastatic Treatment, Breast Cancer:
`0 Administer Ogivri, alone or in combination with paclitaxel, at an initial dose of 4 mg/kg as a
`90-minute intravenous infusion followed by subsequent once weekly doses of 2 mg/kg as
`30-minute intravenous infusions until disease progression.
`Metastatic Gastric Cancer:
`
`- Administer Ogivri at an initial dose of 8 mg/kg as a 90 minute intravenous infusion
`followed by subsequent doses of 6 mg/kg as an intravenous infusion over 30 to 90 minutes
`every three weeks until disease progression [see Dosage and Administration (2.3)].
`
`Important Dosing Considerations
`2.3
`If the patient has missed a dose of Ogivri by one week or less, then the usual maintenance dose
`(weekly schedule: 2 mg/kg; three-weekly schedule: 6 mg/kg) should be administered as soon as
`possible. Do not wait until the next planned cycle. Subsequent Ogivri maintenance doses should
`be administered 7 days or 21 days later according to the weekly or three-weekly schedules,
`respectively.
`
`If the patient has missed a dose of Ogivri by more than one week, a re-loading dose of Ogivri
`should be administered over approximately 90 minutes (weekly schedule: 4 mg/kg; three-weekly
`schedule: 8 mg/kg) as soon as possible. Subsequent Ogivri maintenance doses (weekly schedule:
`2 mg/kg; three-weekly schedule 6 mg/kg) should be administered 7 days or 21 days later
`according to the weekly or three-weekly schedules, respectively.
`
`Infusion Reactions
`[see Boxed Warning, Warnings and Precautions (5.2)]
`- Decrease the rate of infusion for mild or moderate infusion reactions
`
`0
`
`Interrupt the infusion in patients with dyspnea or clinically significant hypotension
`o Discontinue Ogivri 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 Ogivri and at regular
`intervals during treatment. Withhold Ogivri closing for at least 4 weeks for either of the following:
`o
`216% absolute decrease in LVEF from pre-treatment values
`0 LVEF below institutional limits of normal and Z 10% absolute decrease in LVEF from
`
`pretreatment values.
`
`Ogivri may be resumed if, within 4 to 8 weeks, the LVEF retums to normal limits and the
`absolute decrease from baseline is 315%.
`
`Permanently discontinue Ogivri for a persistent (>8 weeks) LVEF decline or for suspension of
`Ogivri dosing on more than 3 occasions for cardiomyopathy.
`
`Reference ID: 4188826
`
`CONFIDENTIAL
`
`GNE-HER_000960428
`
`

`

`Preparation for Administration
`2.4
`To prevent medication errors, it is important to check the vial labels to ensure that the drug being
`prepared and administered is Ogivri (trastuzumab—dkst) and not ado-trastuzumab emtansine.
`
`420 mg Multiple-dose vial
`
`Reconstitution: Reconstitute each 420 mg vial of Ogivri with 20 mL of Bacteriostatic Water for
`Injection (BWFI), USP, containing 1.1% benzyl alcohol as a preservative to yield a multiple—dose
`solution containing 21 mg/mL trastuzumab-dkst that delivers 20 mL (420 mg trastuzumab-dkst).
`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:
`0 Using a sterile syringe, slowly inject the 20 mL of diluent into the vial containing the
`lyophilized cake of Ogivri. The stream of diluent should be directed into the lyophilized
`cake. The reconstituted Vial yields a solution for multiple—dose use, containing 21 mg/mL
`trastuzumab-dkst.
`
`o
`o
`
`Swirl the vial gently to aid reconstitution. DO NOT SHAIGE.
`Slight foaming of the product may be present upon reconstitution. Allow the vial to stand
`undisturbed for approximately 5 minutes.
`0 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 Ogivri in the refr‘igflitor at 2° to 8°C L36° to 46W). discard unused
`Ogivri after 28 days. lfOeivri is reconstituted with SWFI without preservative, use
`immediately and discard any unused portion. Do not freeze.
`
`0
`
`Dilution:
`
`0 Determine the dose (mg) of Ogivri [see Dosage and Administration (2.1)]. Calculate the
`volume of the 21 mg/mL reconstituted Ogivri 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.
`o Gently invert the bag to mix the solution.
`0 The solution of Ogivri for infusion diluted in polyvinylchloride or polyethylene bags
`containing 0.9% Sodium Chloride Injection, USP, should be stored at 2° to 8°C (36° to
`46°F) for no more than 24 hours prior to use. Do not freeze.
`
`7
`
`3
`
`4
`
`DOSAGE FORMS AND STRENGTHS
`For injection: 420 mg of Ogivri as an off-white to pale yellow, preservative-free
`lyophilized powder in a multiple-dose vial.
`
`CONTRAINDICATIONS
`None.
`
`Reference ID: 4188826
`
`CONFIDENTIAL
`
`GNE-HERT000960429
`
`

`

`5
`
`WARNINGS AND PRECAUTIONS
`
`Cardiomyopathy
`5.1
`Trastuzumab products can cause left ventricular cardiac dysfunction, arrhythmias, hypertension,
`disabling cardiac failure, cardiomyopathy, and cardiac death [see Boxed Warning:
`Cardiomyopathy]. Trastuzumab products can also cause asymptomatic decline in left ventricular
`ejection fraction (LVEF).
`'
`
`There is a 4 to 6 fold increase in the incidence of symptomatic myocardial dysfunction among
`patients receiving trastuzumab products as a single agent or in combination therapy compared
`with those not receiving trastuzumab products. The highest absolute incidence occurs when a
`trastuzumab product is administered with an anthracycline.
`
`Withhold Ogivri for Z 16% absolute decrease in LVEF from pre—treatment values or an LVEF
`value below institutional limits of normal and Z 10% absolute decrease in LVEF from
`
`pretreatment values [see Dosage and Administration (2.3)]. The safety of continuation or
`resumption of Ogivri in patients with trastuzumab product—induced left ventricular cardiac
`dysfunction has not been studied.
`
`Patients who receive anthracycline after stopping Ogivri may also be at increased risk of cardiac
`dysfunction [see Drug Interactions (7) and Clinical Pharmacology (12.3)].
`
`Cardiac Monitoring: Conduct thorough cardiac assessment, including history, physical
`examination, and determination of LVEF by echocardiogram or MUGA scan. The following
`schedule is recommended:
`
`0 Baseline LVEF measurement immediately prior to initiation of Ogivri
`o LVEF measurements every 3 months during and upon completion of Ogivri
`0 Repeat LVEF measurement at 4 week intervals if Ogivri is withheld for significant left
`ventricular cardiac dysfunction [see Dosage and Administration (2. 3)]
`o LVEF measurements every 6 months for at least 2 years following completion of Ogivri
`as a component of adjuvant therapy.
`
`In Study 1, 15% (158/1031) of patients discontinued trastuzumab due to clinical evidence of
`myocardial dysfunction or significant decline in LVEF after a median follow-up duration of 8.7
`years in the AC-TH arm. In Study 3 (one-year trastuzumab treatment), the number of patients
`who discontinued trastuzumab due to cardiac toxicity at 12.6 months median duration of follow-
`up was 2.6% (44/1678). In Study 4, a total of 2.9% (31/1056) of patients in the TCH arm (1.5%
`during the chemotherapy phase and 1.4% during the monotherapy phase) and 5.7% (61/1068) of
`patients in the AC-TH arm (1.5% during the chemotherapy phase and 4.2% during the
`monotherapy phase) discontinued trastuzumab due to cardiac toxicity.
`
`Among 64 patients receiving adjuvant chemotherapy (Studies 1 and 2) who developed congestive
`heart failure, one patient died of cardiomyopathy, one patient died suddenly without documented
`etiology and 33 patients were receiving cardiac medication at last follow-up. Approximately 24%
`of the surviving patients had recovery to a normal LVEF (defined as 2 50%) and no symptoms on
`continuing medical management at the time of last follow-up. Incidence of congestive heart
`
`Reference ID: 4188826
`
`CONFIDENTIAL
`
`GNE-HER_000960430
`
`

`

`failure is presented in Table 1. The safety of continuation or resumption of Ogivri in patients with
`trastuzumab product-induced left ventricular cardiac dysfunction has not been studied.
`
`Table 1
`
`Incidence of Congestive Heart Failure in Adjuvant Breast Cancer Studies
`
`
`
`Incidence of CHF
`Regimen
`Trastuzumab
`Control
`’
`Study
`
`
`
`
`
`
`ACb —> Paclitaxel + Trastuzumab
`3.2% (64/2000)0
`1.3% (21/1655)
`1 & 2‘1
`
`
`Chemo —>Trastuzumab
`2% (30/1678)
`0.3% (5/1708)
`
`
`
`ACb —> Docetaxel + Trastuzumab
`
`
`2% (20/1068)
`0.3% (3/1050)
`
`
`0.3% (3/1050)
`Docetaxel + Carbo + Trastuzumab
`
`0.4% (4/1056)
`a Median follow-up duration for studies 1 and 2 combined was 8.3 years in the AC —> TH arm.
`b Anthracycline (doxorubicin) and cyclophosphamide.
`° Includes | patient with fatal cardiomyopathy and l paliem w 1111 sudden death without documented etiology.
`p
`dIHClHdCS N I HA I] -.lV 311d cardiac death E]!
`.12 6 I‘IIUIlll'lS median dllfllllflll Of fOHOVV-U 111 the one—year trastuzumab
`8.1111.
`
`
`
`
`
`In Study 3 (one-year trastuzumab treatment), at a median follow—up duration of 8 years, the
`incidence of severe CHF (NYHA III & IV) was 0.8%, and the rate of mild symptomatic and
`asymptomatic left ventricular dysfunction was 4.6%.
`
`Incidence of Cardiac Dysfunction“ in Metastatic Breast Cancer Studies
`
`
`Table 2
`
`Incidence
`
`NYHA I—IV
`
`NYHA III—IV
`
`(AC)b
`
`
`Cardlac Dysfunction
`
`Cardiac Dysfunction
`Cardiac Dysfunctionc
`‘
`
`
`5 (
`
`paclitaxel)
`
`
`
`“ Congestive heart failure or significant asymptomatic decrease in LVEF
`hAnthracycline (doxorubicin or epirubicin) and cyclophosphamide.
`° Includes 1 patient with fatal cardiomyopathy.
`
`In Study 4, the incidence of NCI—CTC Grade 3/4 cardiac ischemia/infarction was higher in the
`trastuzumab containing regimens (AC—TH: 0.3% (3/ 1068) and TCH: 0.2% (2/ 1056)) as compared
`to none in AC—T.
`
`5.2
`
`Infusion Reactions
`
`Infusion reactions consist of a symptom complex characterized by fever and chills, and on
`occasion included nausea, vomiting, pain (in some cases at tumor sites), headache, dizziness,
`dyspnea, hypotension, rash, and asthenia [see Adverse Reactions (6.1)].
`
`Reference ID: 4188826
`
`CONFIDENTIAL
`
`GNE-HER_000960431
`
`

`

`In post-marketing reports, serious and fatal infusion reactions have been reported. Severe
`reactions, which include bronchospasm, anaphylaxis, angioedema, hypoxia, and severe
`hypotension, were usually reported during or immediately following the initial infusion.
`However, the onset and clinical course were variable, including progressive worsening, initial
`improvement followed by clinical deterioration, or delayed post-infusion events with rapid
`clinical deterioration. For fatal events, death occurred within hours to days following a serious
`infusion reaction.
`
`Interrupt Ogivri 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 trastuzumab products after experiencing a severe infusion reaction. Prior
`to resumption of trastuzumab infusion, the majority of patients who experienced a severe infusion
`reaction were pre—medicated with antihistamines and/or corticosteroids. While some patients
`tolerated trastuzumab infusions, others had recurrent severe infusion reactions despite pre-
`medications.
`
`Embryo-Fetal Toxicity
`5.3
`Trastuzumab products can cause fetal harm when administered to a pregnant woman. In post-
`marketing reports, use of trastuzumab during pregnancy resulted in cases of oligohydramnios and
`oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and
`neonatal death.
`
`Verify the pregnancy status of females of reproductive potential prior to the initiation of Ogivri.
`Advise pregnant women and females of reproductive potential that exposure to Ogivri during
`pregnancy or within 7 months prior to conception can result in fetal harm. Advise females of
`reproductive potential to use effective contraception during treatment and for 7 months following
`the last dose of Ogivri [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology
`(12.3)].
`
`Pulmonary Toxicity
`5.4
`Trastuzumab product use can result in seiious 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
`toxrcrty.
`
`Reference ID: 4188826
`
`CONFIDENTIAL
`
`GNE-HER_000960432
`
`

`

`Exacerbation of Chemotherapy-Induced Neutropenia
`5.5
`In randomized, controlled clinical trials, the per—patient incidences of NCI-CTC Grade 3 to 4
`neutropenia and of febrile neutropenia were higher in patients receiving trastuzumab in
`combination with myelosuppressive chemotherapy as compared to those who received
`chemotherapy alone. The incidence of septic death was similar among patients who received
`trastuzumab and those who did not [see Adverse Reactions (6.1)].
`
`6
`
`ADVERSE REACTIONS
`
`The following adverse reactions are discussed in greater detail in other sections of the label:
`0 Cardiomyopathy [see Warnings and Precautions (5.1)]
`o
`Infusion Reactions [see Warnings and Precautions (5.2)]
`Embryo-Fetal Toxicity [see Warnings and Precautions (5.3)]
`Pulmonary Toxicity [see Warnings and Precautions (5.4)]
`- Exacerbation of Chemotherapy-induced Neutropenia [see Warnings and Precautions (5.5)]
`
`The most common adverse reactions in patients receiving trastuzumab products in the adjuvant
`and metastatic breast cancer setting are fever, nausea, vomiting, infusion reactions, diarrhea,
`infections, increased cough, headache, fatigue, dyspnea, rash, neutropenia, anemia, and myalgia.
`Adverse reactions requiring interruption or discontinuation of trastuzumab product treatment
`include CHF, significant decline in left ventricular cardiac function, severe infusion reactions, and
`pulmonary toxicity [see Dosage and Administration (2.3)].
`
`In the metastatic gastric cancer setting, the most common adverse reactions (2 10%) that were
`increased (2 5% difference) in patients receiving trastuzumab products as compared to patients
`receiving chemotherapy alone were neutropenia, diarrhea, fatigue, anemia, stomatitis, weight loss,
`upper respiratory tract infections, fever, thrombocytopenia, mucosal inflammation,
`nasopharyngitis, and dysgeusia. The most common adverse reactions which resulted in
`discontinuation of trastuzumab product treatment in the absence of disease progression were
`infection, diarrhea, and febrile neutropenia.
`
`Clinical Trials Experience
`6.1
`Because clinical trials are conducted under widely varying conditions, adverse reaction rates
`observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of
`another drug and may not reflect the rates observed in practice.
`
`Adjuvant Breast Cancer Studies
`The data below reflect exposure to one—year trastuzumab therapy across three randomized, open—
`label studies, Studies I, 2, and 3, with (n = 3678) or without (n = 3363) trastuzumab in the
`adjuvant treatment of breast cancer.
`
`The data summarized in Table 3 below, from Study 3, reflect exposure to trastuzumab in 1678
`patients; the median treatment duration was 51 weeks and median number of infusions was 18.
`Among the 3386 patients enrolled in the observation and one-year trastuzumab arms of Study 3 at
`a median duration of follow-up of 12.6 months in the trastuzumab arm, the median age was 49
`years (range: 21 to 80 years), 83% of patients were Caucasian, and 13% were Asian.
`
`Reference ID: 4188826
`
`CONFIDENTIAL
`
`GNE—HER_000960433
`
`

`

`Adverse Reactions for Study 3“, All Gradesb
`
`
`
`Adverse Reaction
`
`One year Trastuzumab
`(n = 1678)
`
`Observation
`(n = 1708)
`
`Table 3
`
`
`
`
`
`
`Cardiac
`
`
`Hypertension
`64 (4%)
`35 (2%)
`Dizziness
`60 (4%)
`29 (2%)
`E'ection Fraction Decreased
`58 (3.5%)
`11 (0.6%)
`
`
`Palpitations
`48 (3%)
`12 (0.7%)
`Cardiac Arrhvthmiasc
`40 (3%)
`17 ( 1%)
`
`Cardiac Failure Congestive
`3O (2%)
`5 (0.3%)
`
`Cardiac Failure
`9 ( 0.5%)
`4 (0.2%)
`
`Cardiac Disorder
`5 (0.3%)
`0 (0%)
`
`Ventricular Dysfunction
`4 (0.2%)
`0 (0%)
`
`Respiratory Thoracic Mediastinal Disorders
`
`
`Couh
`
`34 (2%)
`
`81 (5%)
`
`9 (0.5%)
`7O (4%)
`Influenza
`26 (2%)
`Dvsnea
`57 (3%)
`
`URI
`46 (3%)
`20 (1%)
`
`Rhinitis
`36 (2%)
`6 (0.4%)
`
`Pharvn_olarvneal Pain
`32 (2%)
`8 (0.5%)
`
`Sinusitis
`26 (2%)
`5 (0.3%)
`
`25 (2%)
`1 (0.06%)
`Eoistaxis
`
`
`4 (0.2%)
`0 (0%)
`Pulmonary Hypertension
`
`
`4 (0.2%)
`0 (0%)
`Interstitial Pneumonitis
`
`
`
`
`
`
`
`
`
`
`
`Gastrointestinal Disorders
`
`Diarrhea
`123 (7%)
`16 (1%)
`
`108 (6%)
`Nausea
`19 (1%)
`
`Vomiting
`58 (3.5%)
`10 (0.6%)
`
`33 (2%)
`17 (1%)
`Constiation
`
`
`Dyspepsia
`30 (2%)
`9 (0.5%)
`
`
`Upper Abdominal Pain
`29 (2%)
`15 (1%)
`
`
`WWW
`
`
`Arthralgia
`Back Pain
`
`
`
`
`Mvalgia
`Bone Pain
`
`Muscle Spasm
`
`137 (8%)
`91 (5%)
`
`63 (4%)
`49 (3%)
`46 (3%)
`
`
`
`98 (6%)
`
`58 (3%)
`
`
`Nervous System Disorders
`
`Reference ID: 4188826
`
`CONFIDENTIAL
`
`GNE-HER*000960434
`
`17 (1%)
`26 (2%)
`3 (0.2%)
`
`10
`
`

`

`
`
`Headache
`
`
`162 (10%)
`49 (3%)
`
`
`
`29 (2%)
`11 (0.6%)
`
`
`0 (0%)
`
`Paraesthesia
`
`
`
`
`
`Skin & Subcutaneous Tissue Disorders
`
`Rash
`
`
` 7O (4%)
`
`10 (0.6%)
`
`
`Nail Disorders
`43 (2%)
`
`
`Pruritus
`
`40 (2%)
`10 (0.6%)
`
`
` General Disorders
`
`
`
`
`100 (6%)
`6 (0.4%)
`
`
`
`
`79 (5%)
`Edema Per_iph_eral
`37 (2%)
`
`
`
`
`Chills
`85 (5%)
`O (0%)
`
`
`
`
`Asthenia
`75 (4.5%)
`30 (2%)
`
`
`
`
`3 (0.2%)
`40 (2%)
`Influenza-like Illness
`
`
`Sudden Death
`1 (0.06%)
`0 (0%)
`
`
`
`Infections
`
`
`
`
`
`
`
`
`Naso ha ngitis
`
`
`UTI
`
`
`
`
`Immune System Disorders
`10 (0.6%)
`H ersensitivi
`1 (0.06%)
`
`
`
`0 (0%)
`4 (0.3%)
`Autoimmune Thyroiditis
`“ Median follow-up duration of 12.6 months in the one-year trastuzumab treatment arm.
`bThe incidence of Grade 3 or higher adverse reactions was < 1% in both arms for each listed term.
`° Higher level grouping term.
`
`135 (8%)
`39 (3%)
`
`
`
`In Study 3, a comparison of 3-weekly trastuzumab treatment for two years versus one year was
`also performed. The rate of asymptomatic cardiac dysfunction was increased in the 2-year
`trastuzumab treatment arm (8.1% versus 4.6% in the one-year trastuzumab treatment arm), More
`patients experienced at least one adverse reaction of Grade 3 or higher in the 2—year trastuzumab
`treatment arm (20.4%) compared with the one-year trastuzumab treatment arm (16.3%).
`
`The safety data from Studies 1 and 2 were obtained from 3655 patients, of whom 2000 received
`trastuzumab; the median treatment duration was 51 weeks. The median age was 49 years (range:
`24 to 80); 84% of patients were White, 7% Black, 4% Hispanic, and 3% Asian.
`
`In Study 1, only Grade 3 to 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 to 5 occurred at an incidence of at least 2%
`greater among patients receiving trastuzumab plus chemotherapy as compared to chemotherapy
`alone: fatigue (29.5% vs. 22.4%), infection (24.0% vs. 12.8%), hot flashes (17.1% vs. 15.0%),
`anemia (12.3% vs. 6.7%), dyspnea (11.8% vs. 4.6%), rash/desquamation (10.9% vs. 7.6%),
`leukopenia (10 5% vs 8.4%), neutropenia (6.4% vs. 4.3%), headache (6.2% vs. 3.8%), pain
`(5.5% vs. 3.0%), edema (4.7% vs. 2.7%) and insomnia (4.3% vs. 1.5%). The majority ofthese
`events were Grade 2 in severity.
`
`Reference ID: 4188826
`
`CONFIDENTIAL
`
`11
`
`GNE-HER_000960435
`
`

`

`In Study 2, data collection was limited to the foll