HERZUMA POWDER FOR SOLUTION

Canada - English - Health Canada

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Active ingredient:
TRASTUZUMAB
Available from:
CELLTRION HEALTHCARE CO LTD
ATC code:
L01XC03
INN (International Name):
TRASTUZUMAB
Dosage:
150MG
Pharmaceutical form:
POWDER FOR SOLUTION
Composition:
TRASTUZUMAB 150MG
Administration route:
INTRAVENOUS
Units in package:
100
Prescription type:
Prescription
Therapeutic area:
ANTINEOPLASTIC AGENTS
Product summary:
Active ingredient group (AIG) number: 0154252002; AHFS: 10:00.00
Authorization status:
APPROVED
Authorization number:
02506211
Authorization date:
2020-10-20

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page 1 / 117

PRODUCT MONOGRAPH

INCLUDING PATIENT MEDICATION INFORMATION

Herzuma

Trastuzumab for Injection

Powder for concentrate for solution, 440 mg/vial, Intravenous Infusion

Powder for concentrate for solution, 150 mg/vial, Intravenous Infusion

Professed Standard

Antineoplastic

Manufactured by

Celltrion Healthcare Co., Ltd.

19, Academy-ro 51 beon-gil,

Yeonsu-gu, Incheon

Republic of Korea

22014

Distributed by:

Teva Canada Limited.

Toronto, Ontario M1B 2K9

Date of Initial Approval:

September 3, 2019

Date of Revision:

<MON DD,YYYY>

Submission Control Number: 237674 Date of Approval: April 16, 2021

Submission Control No: 237674

Herzuma

is a trademark of Celltrion Healthcare Co., Ltd.

page 2 / 117

RECENT MAJOR LABEL CHANGES

TABLE OF CONTENTS

PART I: HEALTH PROFESSIONAL INFORMATION ................................................................. 4

1

INDICATIONS................................................................................................................ 4

Pediatrics .............................................................................................................. 5

Geriatrics............................................................................................................... 5

2

CONTRAINDICATIONS ................................................................................................. 5

3

SERIOUS WARNINGS AND PRECAUTIONS BOX........................................................ 5

4

DOSAGE AND ADMINISTRATION ................................................................................ 6

Dosing Considerations ........................................................................................... 6

Recommended Dose and Dosage Adjustment ....................................................... 6

Administration........................................................................................................ 8

Reconstitution........................................................................................................ 9

Missed Dose........................................................................................................ 10

5

OVERDOSAGE ........................................................................................................... 11

6

DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ........................ 11

7

DESCRIPTION ............................................................................................................ 12

8

WARNINGS AND PRECAUTIONS .............................................................................. 12

Special Populations ............................................................................................. 25

8.1.1

Pregnant Women .............................................................................................. 25

8.1.2

Breast-feeding................................................................................................... 26

8.1.3

Pediatrics .......................................................................................................... 26

8.1.4

Geriatrics (> 65 years of age) ............................................................................ 26

9

ADVERSE REACTIONS .............................................................................................. 27

Clinical Trial Adverse Drug Reactions .................................................................. 27

Less Common Clinical Trial Adverse Reactions.................................................... 61

Post-Market Adverse Drug Reactions................................................................... 65

10

DRUG INTERACTIONS ............................................................................................... 66

10.1 Overview ............................................................................................................. 66

10.2 Drug-Drug Interactions ........................................................................................ 67

11

ACTION AND CLINICAL PHARMACOLOGY .............................................................. 67

11.1 Mechanism of Action ........................................................................................... 67

11.2 Pharmacokinetics ................................................................................................ 68

12

STORAGE, STABILITY AND DISPOSAL .................................................................... 69

13

SPECIAL HANDLING INSTRUCTIONS ....................................................................... 70

PART II: SCIENTIFIC INFORMATION .................................................................................... 71

14

PHARMACEUTICAL INFORMATION .......................................................................... 71

15

COMPARATIVE CLINICAL TRIALS ............................................................................ 72

15.1 Comparative Trial Design and Study Demographics ............................................. 72

15.2 Comparative Study Results ................................................................................. 73

15.2.1 Comparative Bioavailability Studies ................................................................... 74

15.2.1.1

Pharmacokinetics ......................................................................................... 74

page 3 / 117

15.2.2 Comparative Safety and Efficacy ....................................................................... 74

15.2.2.1

Efficacy......................................................................................................... 74

15.2.2.2

Safety ........................................................................................................... 75

15.2.2.3

Immunogenicity............................................................................................. 75

16

COMPARATIVE NON-CLINICAL PHARMACOLOGY AND TOXICOLOGY ................. 75

16.1 Comparative Non-Clinical Pharmacodynamics ..................................................... 75

16.2 Comparative Toxicology ...................................................................................... 76

17

CLINICAL TRIALS – REFERENCE BIOLOGIC DRUG ................................................ 76

18

NON-CLINICAL TOXICOLOGY– REFERENCE BIOLOGIC DRUG .............................. 94

19

SUPPORTING PRODUCT MONOGRAPHS ............................................................... 103

PATIENT MEDICATION INFORMATION .............................................................................. 104

PATIENT MEDICATION INFORMATION .............................................................................. 111

page 4 / 117

HERZUMA

(trastuzumab) is a biosimilar biologic drug (biosimilar) to HERCEPTIN

PART I: HEALTH PROFESSIONAL INFORMATION

1

INDICATIONS

Indications have been granted on the basis of similarity between HERZUMA

and the reference

biologic drug HERCEPTIN

Early Breast Cancer (EBC)

HERZUMA

(trastuzumab) is indicated for the treatment of patients with early stage breast

cancer with ECOG 0-1 status, whose tumours overexpress HER2,

following surgery and after chemotherapy

following adjuvant chemotherapy consisting of doxorubicin and cyclophosphamide, in

combination with paclitaxel or docetaxel

in combination with adjuvant chemotherapy consisting of docetaxel and carboplatin.

For detailed information on the inclusion criteria for the clinical trials of trastuzumab in EBC

according to the TNM (Tumour, Node, Metastasis) classification system, see Part II: Clinical

Trial – Reference Biologic Drug section.

Based on the analysis of the HERA trial, the benefit of the adjuvant treatment with

trastuzumab for low risk patients not given adjuvant chemotherapy are unknown.

The comparative efficacy and safety between different chemotherapy regimens (i.e.

concurrent versus sequential, anthracycline containing versus non-anthracycline containing)

was not studied.

Metastatic Breast Cancer (MBC)

HERZUMA

is indicated for the treatment of patients with MBC whose tumours overexpress

HER2.

The benefits of treatment with trastuzumab in patients who do not overexpress HER2 (HER2

expression 0 as defined by a validated immunohistochemical [IHC] assay) or who exhibit

lower-level expression (HER2 expression 1+ as defined by a validated IHC assay, and the

subgroup of patients with HER2 overexpression 2+ as defined by a validated IHC assay that

corresponds to 1+ scoring by the investigative clinical trial assay), are unclear (see

WARNINGS AND PRECAUTIONS: Selection of Patients / Diagnostic Tests).

HERZUMA

can be used in combination with pertuzumab 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. For information on the use of HERZUMA

in combination with pertuzumab and docetaxel, consult the Product Monograph for

pertuzumab.

page 5 / 117

Metastatic Gastric Cancer (MGC)

HERZUMA

in combination with capecitabine or intravenous 5-fluorouracil and cisplatin is

indicated for the treatment of patients with HER2 positive metastatic adenocarcinoma of the

stomach or gastro-esophageal junction who have not received prior anti-cancer treatment for

their metastatic disease.

HERZUMA

should only be administered to patients with MGC whose tumours have HER2

overexpression as defined by IHC 2+ confirmed by FISH+, or IHC 3+ as determined by an

accurate and validated assay.

1.1

Pediatrics

The safety and effectiveness of HERZUMA

in pediatric patients (< 18 years of age) have not

been established.

1.2

Geriatrics

The reported clinical experience is not adequate to determine whether older patients respond

differently to trastuzumab treatment than younger patients (see WARNINGS AND

PRECAUTIONS, Geriatrics).

2

CONTRAINDICATIONS

HERZUMA

(trastuzumab) is contraindicated in patients with known hypersensitivity to

trastuzumab, Chinese Hamster Ovary (CHO) cell proteins, or any ingredient in the

formulation, including any non-medicinal ingredient, or component of the container. For a

complete listing, see Dosage Forms, Strengths, Composition and Packaging.

When using in combination with pertuzumab and docetaxel, consult Product Monographs for

pertuzumab and docetaxel for further information on these drugs.

3

SERIOUS WARNINGS AND PRECAUTIONS BOX

Serious Warnings and Precautions

There is a risk of medication errors between HERZUMA

(trastuzumab) and KADCYLA

(trastuzumab emtansine). In order to minimize this risk, check the vial labels to ensure that

the drug being prepared and administered is HERZUMA

(trastuzumab) and not

KADCYLA

(trastuzumab emtansine). HERZUMA

should be prescribed using both the

trade name and non-proprietary name (see DOSAGE AND ADMINISTRATION, Dosing

Considerations).

Cardiotoxicity

HERZUMA

(trastuzumab) can result in the development of ventricular dysfunction and

congestive heart failure. In the adjuvant treatment setting, the incidence of cardiac

dysfunction was higher in patients who received trastuzumab plus chemotherapy versus

chemotherapy alone. An increase in the incidence of symptomatic and asymptomatic

cardiac events was observed when trastuzumab was administered after anthracycline-

containing chemotherapy compared to administration with a non-anthracycline regimen of

docetaxel and carboplatin. The incidence was more marked when trastuzumab was

page 6 / 117

administered concurrently with a taxane than when administered sequentially to a taxane.

In the metastatic setting, the incidence and severity of cardiac dysfunction was particularly

high in patients who received trastuzumab concurrently with anthracyclines and

cyclophosphamide (see WARNINGS AND PRECAUTIONS, Cardiovascular).

Evaluate left ventricular function in all patients prior to and during treatment with

HERZUMA

(see WARNINGS AND PRECAUTIONS, Cardiovascular).

Infusion Reactions; Pulmonary Toxicity

HERZUMA

administration can result in serious infusion reactions and pulmonary toxicity.

Fatal infusion reactions have been reported. In most cases, symptoms occurred during or

within 24 hours of administration of trastuzumab. HERZUMA

infusion should be

interrupted for patients experiencing dyspnea or clinically significant hypotension. Patients

should be monitored until signs and symptoms completely resolve. Discontinue

HERZUMA

for infusion reactions manifesting as anaphylaxis, angioedema, interstitial

pneumonitis, or acute respiratory distress syndrome (see WARNINGS AND

PRECAUTIONS).

Embryo-Fetal Toxicity

Exposure to HERZUMA

during pregnancy can result in impairment of fetal renal growth

and/or renal function impairment resulting in oligohydramnios and oligohydramnios

sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, intrauterine

growth retardation and neonatal death (see WARNINGS AND PRECAUTIONS, Special

Populations, Pregnant Women).

4

DOSAGE AND ADMINISTRATION

4.1

Dosing Considerations

There is a risk of medication errors between HERZUMA

(trastuzumab) and KADCYLA

(trastuzumab emtansine). In order to prevent medication errors, it is important to check the vial

labels to ensure that the drug being prepared and administered is HERZUMA

(trastuzumab)

and not KADCYLA

(trastuzumab emtansine). Ensure that the recommended HERZUMA

(trastuzumab) dose is administered (see Recommended Dose and Dosage Adjustment section).

HERZUMA

should be prescribed using both the trade name and non-proprietary name. Do not

substitute HERZUMA

for or with KADCYLA

(trastuzumab emtansine).

When using in combination with pertuzumab and docetaxel for treatment of patients with HER-

2-positive metastatic breast cancer, consult Product Monographs for pertuzumab and docetaxel

for further information, such as dose adjustment, sequence of administration of each medication

and duration of treatment.

4.2

Recommended Dose and Dosage Adjustment

Early Breast Cancer (EBC)

3-Weekly Schedule: The recommended initial loading dose is 8 mg/kg HERZUMA

(trastuzumab) administered as a 90-minute infusion. The recommended maintenance dose is 6

page 7 / 117

mg/kg HERZUMA

3 weeks later and then 6 mg/kg repeated at 3-weekly intervals administered

as infusions over approximately 90 minutes. If the prior dose was well tolerated, the dose can

be administered as a 30-minute infusion. Do not administer as an IV push or bolus (see

Preparation for Administration).

Weekly schedule: As a weekly regimen, the recommended initial loading dose of HERZUMA

is 4 mg/kg followed by 2 mg/kg every week.

See clinical trial – reference biological drug section for chemotherapy combination dosing.

Metastatic Breast Cancer (MBC)

Weekly schedule: The recommended initial loading dose is 4 mg/kg HERZUMA

administered

as a 90-minute infusion. The recommended weekly maintenance dose is 2 mg/kg HERZUMA

®

and can be administered as a 30-minute infusion if the initial loading dose was well tolerated.

HERZUMA

may be administered in an outpatient setting. Do not administer as an IV push or

bolus (see Preparation for Administration).

Metastatic Gastric Cancer (MGC)

3-Weekly Schedule: The recommended initial loading dose is 8 mg/kg HERZUMA

administered as a 90-minute infusion. The recommended maintenance dose is 6 mg/kg

HERZUMA

3 weeks later and then 6 mg/kg repeated at 3-weekly intervals administered as

infusions over approximately 90 minutes. If the prior dose was well tolerated, the dose can be

administered as a 30-minute infusion. Do not administer as an IV push or bolus (see

Preparation for Administration)

Duration of Treatment

In clinical studies, patients with MBC or MGC were treated with trastuzumab until progression of

disease. Patients with EBC should be treated for 1 year or until disease recurrence or

unacceptable cardiac toxicity, whichever occurs first (see WARNINGS AND PRECAUTIONS,

Cardiovascular). Extending treatment in EBC beyond one year is not recommended (see

Clinical Trials – Reference Biological Drug, Early Breast Cancer (EBC), HERA).

Dose Reduction

No reductions in the dose of trastuzumab were made during clinical trials. Patients may

continue therapy with HERZUMA

during periods of reversible, chemotherapy-induced

myelosuppression, but they should be monitored carefully for complications of neutropenia

during this time. The specific instructions to reduce or hold the dose of chemotherapy should be

followed.

Table 1 depicts the criteria for permanent discontinuation of trastuzumab for cardiac dysfunction

in pivotal studies in adjuvant breast cancer.

Table 1 Criteria for Permanent Discontinuation for Cardiac Dysfunction in Pivotal Studies

in Adjuvant Breast Cancer

STUDY

If Symptomatic CHF

If Held for Asymptomatic LVEF Decrease (per algorithm

used in each study protocol)

HERA

required

required if trastuzumab held for 2 consecutive cycles

NSABP B-31,

NCCTG

N9831 and

BCIRG-006

required

required if trastuzumab held for 2 consecutive cycles, or for 3

intermittent cycles; investigator may choose to discontinue

permanently sooner

page 8 / 117

Dose Holding

Monitoring of Cardiac Function (also see WARNINGS AND PRECAUTIONS,

Cardiovascular, Cardiotoxicity)

Table 2 Recommendations for Continuation or Withdrawal of HERZUMA

®

Therapy in

Asymptomatic Patients Based on Serial Measurements of Left Ventricular Ejection

Fraction (LVEF)

a

(Adapted from the Canadian Consensus Guidelines*)

Relationship of LVEF to

LLN

Asymptomatic decrease in LVEF from baseline

≤ 10 percentage points

10–15 percentage points

≥ 15 percentage points

Within

radiology

facility’s

normal limits

Continue HERZUMA

Continue HERZUMA

Hold

HERZUMA

repeat

MUGA

ECHO

after 4 w eeks

1–5

percentage

points

below LLN

Continue HERZUMA

Hold

HERZUMA

repeat

MUGA

ECHO

after 4 w eeks

Hold

HERZUMA

repeat

MUGA

ECHO

after 4 w eeks

≥6

percentage

points

below LLN

Continue

HERZUMA

repeat

MUGA

ECHO

after 4 w eeks

Hold

HERZUMA

repeat

MUGA

ECHO

after 4 w eeks

Hold

HERZUMA

repeat

MUGA

ECHO

after 4 w eeks

Based on NSABP B-31 trial protocol. Modified to include recommendations for cardiology consultation or

treatment of cardiac dysfunction (or both) w hen appropriate, as indicated in the subsequent footnotes.

Consider cardiac assessment and initiation of angiotensin converting-enzyme inhibitor therapy.

After tw o holds, consider permanent discontinuation of HERZUMA

Initiate angiotensin converting-enzyme inhibitor therapy and refer to cardiologist. LLN = low er limit of normal;

MUGA = multiple-gated acquisition scan; ECHO = echocardiography.

*Source: Mackey JR, Clemons M, Côté MA, et al. Cardiac management during adjuvant trastuzumab therapy:

recommendations of the Canadian Trastuzumab Working Group. Curr Oncol. 2008 Jan;15(1):24-35.

For the frequency of cardiac monitoring see WARNINGS AND PRECAUTIONS, Cardiovascular,

Cardiotoxicity.

Health Canada has not authorized an indication for pediatric use (see Indications section).

4.3

Administration

Weekly Schedule: Treatment may be administered in an outpatient setting by administration of

a 4 mg/kg loading dose of HERZUMA

by intravenous (IV) infusion over 90 minutes. Do not

administer as an IV push or bolus. Patients should be observed for fever and chills or other

infusion associated symptoms. Serious adverse reactions to infusions of trastuzumab including

dyspnea, hypotension, hypertension, wheezing, bronchospasm, tachycardia, reduced oxygen

saturation and respiratory distress have been reported infrequently (also see ADVERSE

REACTIONS). Interruption of the infusion may help control such symptoms. The infusion may

be resumed when symptoms abate.

If prior infusion was well tolerated, subsequent weekly doses of 2 mg/kg HERZUMA

may be

administered over 30 minutes (see Recommended Dose and Dosage Adjustment). Patients

should still be observed for fever and chills or other infusion-associated symptoms (see

ADVERSE REACTIONS).

3-Weekly Schedule: Treatment may be administered in an outpatient setting by administration

of an 8 mg/kg loading dose of HERZUMA

by intravenous (IV) infusion over 90 minutes. Do not

administer as an IV push or bolus. Patients should be observed for fever and chills or other

page 9 / 117

infusion associated symptoms (see ADVERSE REACTIONS). Interruption of the infusion may

help control such symptoms. The infusion may be resumed when symptoms abate.

If prior infusion was well tolerated, subsequent 3-weekly doses of 6 mg/kg HERZUMA

may be

administered over 30 minutes (see Recommended Dose and Dosage Adjustment). Patients

should still be observed for fever and chills or other infusion-associated symptoms (see

ADVERSE REACTIONS).

HERZUMA

should not be mixed or diluted with other drugs. Infusions of HERZUMA

should not be administered or mixed with dextrose solutions.

Flush the intravenous line with 0.9% Sodium Chloride Injection, USP after each dose.

4.4

Reconstitution

Table 3 Reconstitution

Vial Size

Volume of Diluent to be

Added to Vial

Approximate

Available Volume

Nominal Concentration per mL

440 mg/vial

20 mL of Bacteriostatic

Water for Injection (BWFI)

21 mL

21 mg/mL trastuzumab

150 mg/vial

7.2 mL of Sterile Water for

Injection (SWFI)

7.4 mL

21 mg/mL trastuzumab

Preparation for Administration

Use appropriate aseptic technique.

440 mg/vial

Each vial of HERZUMA

should be reconstituted with 20 mL of BWFI, containing 1.1%

benzyl alcohol, as supplied, to yield a multi-dose solution containing 21 mg/mL

trastuzumab. Immediately upon reconstitution with BWFI, the vial of HERZUMA

must be

labelled with “Do not use after:” followed by the future date that is 28 days from the date of

reconstitution.

If the patient has a known hypersensitivity to benzyl alcohol, HERZUMA

must be

reconstituted with Sterile Water for Injection (see WARNINGS AND PRECAUTIONS).

HERZUMA

which has been reconstituted with SWFI must be used immediately and

any unused portion discarded. Use of other reconstitution diluents should be

avoided.

150 mg/vial

Each vial of HERZUMA

should be reconstituted with 7.2 mL of Sterile Water for Injection

(SWFI) (not supplied), to yield a single-dose solution containing 21 mg/mL trastuzumab.

The reconstituted solution should be used immediately and any remaining reconstituted

solution should be discarded.

HERZUMA

should be carefully handled during reconstitution. Causing excessive foaming

during reconstitution or shaking the reconstituted HERZUMA

may result in problems with the

amount of HERZUMA

that can be withdrawn from the vial.

page 10 / 117

Reconstitution:

440 mg/vial

Using a sterile syringe, slowly inject 20 mL of Bacteriostatic Water for Injection in the

vial containing the lyophilized HERZUMA

directing the stream into the lyophilized cake.

Swirl vial gently to aid reconstitution. Do not shake.

150 mg/vial

Using a sterile syringe, slowly inject 7.2 mL of Sterile Water for Injection (not supplied)

in the vial containing the lyophilized HERZUMA

directing the stream into the

lyophilized cake.

Swirl vial gently to aid reconstitution. Do not shake.

Slight foaming of the product upon reconstitution is not unusual. Allow the vial to stand

undisturbed for approximately 5 minutes. The reconstituted HERZUMA

results in a colorless to

pale yellow transparent solution and should be essentially free of visible particles.

Determine the volume in mL of HERZUMA

solution needed:

Weekly Schedule: based on a loading dose of 4 mg trastuzumab/kg body weight or a

maintenance dose of 2 mg trastuzumab/kg body weight.

Volume

[Body Weight (kg) x Dose (4 mg/kg for loading OR 2 mg/kg for maintenance)]

21 mg/mL (concentration of reconstituted solution)

3-Weekly Schedule: based on a loading dose of 8 mg trastuzumab/kg body weight, or a

subsequent 3 weekly dose of 6 mg trastuzumab/kg body weight:

Volume

[Body Weight (kg) x Dose (8 mg/kg for loading OR 6 mg/kg for maintenance)]

21 mg/mL (concentration of reconstituted solution)

Withdraw the appropriate volume of solution calculated from the vial and add it to an infusion

bag containing 250 mL of 0.9% sodium chloride, USP. Dextrose (5%) solution should not be

used since it causes aggregation of the protein. To mix the solution and avoid foaming, invert

the bag gently. The reconstituted preparation results in a colourless to pale yellow transparent

solution. Parenteral drug products should be inspected visually for particulates and

discolouration prior to administration. No incompatibilities between HERZUMA

®

polyvinylchloride, polyethylene or polypropylene bags have been observed.

4.5

Missed Dose

Weekly schedule: If the patient has missed a dose of HERZUMA

by one week or less, then

the usual maintenance dose (2 mg/kg) should be given as soon as possible (do not wait until

the next planned cycle). Subsequent maintenance HERZUMA

doses of 2 mg/kg should be

administered 7 days later according to the weekly schedule.

If the patient has missed a dose of HERZUMA

by more than one week, a re-loading dose of

HERZUMA

should be administered (4 mg/kg over approximately 90 minutes) as soon as

page 11 / 117

possible. Subsequent maintenance HERZUMA

doses of 2 mg/kg should be administered 7

days later according to the weekly schedule.

3-Weekly Schedule: If the patient has missed a dose of HERZUMA

by one week or less, then

the usual maintenance dose (6 mg/kg) should be administered as soon as possible (do not wait

until the next planned cycle). Subsequent maintenance HERZUMA

doses of 6 mg/kg should be

administered 21 days later according to the 3-weekly schedule.

If the patient has missed a dose of HERZUMA

by more than one week, a re-loading dose of

HERZUMA

should be administered (8 mg/kg over approximately 90 minutes) as soon as

possible. Subsequent maintenance HERZUMA

doses of 6 mg/kg should be administered 21

days later according to the 3-weekly schedule.

5

OVERDOSAGE

There is no experience with overdosage in human clinical trials. Single doses higher than 500

mg (10 mg/kg) have not been tested.

Ensure that the recommended HERZUMA

(trastuzumab) dose and NOT KADCYLA

(trastuzumab emtansine) dose is administered. For information on the risk of KADCYLA

overdose due to medication errors, see KADCYLA

Product Monograph.

For management of a suspected drug overdose, contact your regional Poison Control

Centre.

6

DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

To help ensure the traceability of biologic products, including biosimilars, health professionals

should recognise the importance of recording both the brand name and the non-proprietary

(active ingredient) name as well as other product-specific identifiers such as the Drug

Identification Number (DIN) and the batch/lot number of the product supplied.

Table 4 Dosage Forms, Strengths, Composition and Packaging

Composition:

HERZUMA

(trastuzumab) is a sterile, white to pale yellow, preservative-free lyophilized powder

for intravenous (IV) administration.

Route of

Administration

Dosage Form / Strength /

Composition

Non-medicinal Ingredients

IV Infusion

Lyophilized pow der for

reconstitution

440 mg tratruzumab/vial

150 mg trastuzumab/vial

L-histidine, L-histidine HCl, polysorbate 20, α,α-trehalose

dihydrate.

Note: The Bacteriostatic Water for Injection (BWFI)

supplied w ith HERZUMA

®

(trastuzumab) 440 mg/vial

contains 1.1% benzyl alcohol (see WARNINGS

PRECA UTIONS).

The Sterile Water for Injection (SWFI) for

dilution of the 150 mg/vial is not supplied.

page 12 / 117

440 mg/vial

Each vial of HERZUMA

contains 440 mg trastuzumab, 6.4 mg L-histidine, 9.9 mg L-histidine

HCl, 1.8 mg polysorbate 20, and 879 mg α,α-trehalose dihydrate. Reconstitution with 20 mL of

the supplied BWFI, containing 1.1% benzyl alcohol as a preservative, yields a multi-dose

solution containing 21 mg/mL trastuzumab, at a pH of approximately 6.

150 mg/vial

Each vial of HERZUMA

contains 150 mg trastuzumab, 2.2 mg L-histidine, 3.4 mg L-histidine

HCl, 0.6 mg polysorbate 20, and 299.6 α,α-trehalose dihydrate. Reconstitution with 7.2 mL of

the SWFI (not supplied), yields a single-dose solution containing 21 mg/mL trastuzumab, at a

pH of approximately 6.

Availability:

440 mg/vial

HERZUMA

is supplied as a lyophilized, sterile powder containing 440 mg trastuzumab per vial

under vacuum.

BWFI is supplied as a 20 mL vial of sterile solution containing 1.1% benzyl alcohol as an

antimicrobial preservative.

Each carton contains one vial of 440 mg HERZUMA

®

and one 20 mL vial of BWFI containing

1.1% benzyl alcohol.

150 mg/vial

HERZUMA

is supplied as a lyophilized, sterile powder containing 150 mg trastuzumab per vial

under vacuum.

Each carton contains one vial of 150 mg HERZUMA

®

.

7

DESCRIPTION

HERZUMA

(trastuzumab) is a biosimilar to HERCEPTIN

. It consists of humanized

immunoglobulin G1 (IgG

) monoclonal antibody that selectively binds with high affinity to

extra cellular domain (ECD) of the human epidermal growth factor receptor 2 (HER2).

8

WARNINGS AND PRECAUTIONS

Please see the Serious Warnings and Precautions Box at the beginning of Part I: Health

Professional Information.

General

Therapy with HERZUMA

should only be initiated under supervision of a physician experienced

in the treatment of cancer patients.

page 13 / 117

When using in combination with pertuzumab and docetaxel, consult Product Monographs for

pertuzumab and docetaxel for further information on these drugs.

In order to improve traceability of biological medicinal products, the trade name and the batch

number of the administered product should be clearly recorded (or stated) in the patient file.

Early Breast Cancer (EBC)

The safety of the various combination chemotherapy regimens prior to trastuzumab therapy was

not separately analyzed in the HERA trial. The data provided in the Product Monograph reflects

the safety and efficacy of trastuzumab for the recommended 1 year treatment duration.

Benzyl Alcohol: Benzyl alcohol, used as a preservative in BWFI, has been associated with

toxicity in neonates and children up to 3 years old. For patients with a known hypersensitivity to

benzyl alcohol (the preservative in BWFI), reconstitute HERZUMA

with Sterile Water for

Injection (SWFI). Use SWFI-reconstituted HERZUMA

®

immediately and discard the vial

(see DOSAGE AND ADMINISTRATION).

Cardiovascular

Cardiotoxicity: Administration of HERZUMA

can result in the development of ventricular

dysfunction and congestive heart failure. In the adjuvant treatment setting, the incidence of

cardiac dysfunction was higher in patients who received trastuzumab plus chemotherapy versus

chemotherapy alone. In patients with EBC, an increase in the incidence of symptomatic and

asymptomatic cardiac events was observed when trastuzumab was administered after

anthracycline-containing chemotherapy compared to administration with a non-anthracycline

regimen of docetaxel and carboplatin. The incidence was more marked when trastuzumab was

administered concurrently with a taxane than when administered sequentially to a taxane. In the

metastatic setting, the incidence and severity of cardiac dysfunction were particularly high in

patients who received trastuzumab concurrently with anthracyclines and cyclophosphamide.

The incidence of cardiac adverse events was also higher in patients with previous exposure to

anthracyclines based on post-market data.

Because the half-life of trastuzumab, using a population pharmacokinetic method, is

approximately 28.5 days (95% CI, 25.5 - 32.8 days), trastuzumab may persist in the circulation

for approximately 24 weeks (range: 22-28 weeks) after stopping treatment with HERZUMA

Since the use of an anthracycline during this period could possibly be associated with an

increased risk of cardiac dysfunction, a thorough assessment of the risks versus the potential

benefits is recommended in addition to careful cardiac monitoring. If possible, physicians should

avoid anthracycline based therapy while trastuzumab persists in the circulation.

Patients who receive HERZUMA

either as a component of adjuvant treatment or as a

treatment for metastatic HER2 positive breast cancer may experience signs and symptoms of

cardiac dysfunction such as dyspnea, increased cough, paroxysmal nocturnal dyspnea,

peripheral edema, S

gallop, or reduced ejection fraction. Cardiac dysfunction associated with

therapy with HERZUMA

®

may be severe and has been associated with disabling cardiac failure,

death, and mural thrombosis leading to stroke.

Left ventricular function should be evaluated in all patients prior to and during treatment with

HERZUMA

. If LVEF drops 10 ejection points from baseline and/or to below 50%, HERZUMA

page 14 / 117

should be withheld and a repeat LVEF assessment performed within approximately 3 weeks. If

LVEF has not improved, or declined further, discontinuation of HERZUMA

should be strongly

considered, unless the benefits for the individual patient are deemed to outweigh the risks. The

scientific basis of cardiac dysfunction has been incompletely investigated in pre-clinical studies.

Extreme caution should be exercised in treating patients with pre-existing cardiac dysfunction,

and in EBC, in those patients with an LVEF of 55% or less. Candidates for treatment with

HERZUMA

as part of adjuvant treatment for operable breast cancer or for MBC, especially

those with prior anthracycline and cyclophosphamide (AC) exposure, should undergo thorough

baseline cardiac assessment including history and physical exam, electrocardiogram (ECG) and

either 2D echocardiogram or multiple gated acquisition (MUGA) scan. A careful risk-benefit

assessment should be made before deciding to treat with HERZUMA

. Cardiac assessments,

as performed at baseline, should be repeated every 3 months during treatment and every 6

months following discontinuation of treatment until 24 months from the last administration of

HERZUMA

. In patients with EBC who receive anthracycline containing chemotherapy further

monitoring is recommended, and should occur yearly up to 5 years from the last administration

of HERZUMA

, or longer if a continued decrease of LVEF is observed. Monitoring may help to

identify patients who develop cardiac dysfunction. Patients who develop asymptomatic cardiac

dysfunction may benefit from more frequent monitoring (e.g. every 6-8 weeks). If patients have

a continued decrease in left ventricular function, but remain asymptomatic, the physician should

consider discontinuing therapy unless the benefits for the individual patient are deemed to

outweigh the risks.

If symptomatic cardiac failure develops during therapy with HERZUMA

, it should be treated

with the standard medications for this purpose. Discontinuation of HERZUMA

should be

strongly considered in patients who develop clinically significant congestive heart failure. In the

MBC clinical trials, approximately two-thirds of patients with cardiac dysfunction were treated for

cardiac symptoms, most patients responded to appropriate medical therapy (which may include

one or more of the following: diuretics, angiotensin-converting enzyme inhibitors, β-blockers,

angiotensin II receptor blockers, or cardiac glycosides) often including discontinuation of

trastuzumab. The safety of continuation or resumption of trastuzumab in patients who have

previously experienced cardiac toxicity has not been prospectively studied.

Early Breast Cancer (EBC)

HERZUMA

and anthracyclines should not be given concurrently in the adjuvant treatment

setting.

Risk factors for a cardiac event identified in four large adjuvant studies included advanced age

(> 50 years), low level of baseline and declining LVEF (< 55%), low LVEF prior to or following

the initiation of paclitaxel treatment, trastuzumab treatment, and prior or concurrent use of anti-

hypertensive medications. In patients receiving trastuzumab after completion of adjuvant

chemotherapy the risk of cardiac dysfunction was associated with a higher cumulative dose of

anthracycline given prior to initiation of trastuzumab and a high body mass index (BMI > 25

kg/m

In EBC, the following patients were excluded from the HERA, JA (NSABP B-31 and NCCTG

N9831) and BCIRG-006 trials there are no data about the benefit risk balance, and therefore

treatment cannot be recommended in such patients:

page 15 / 117

history of myocardial infarction (MI),

angina pectoris requiring medication,

history of or present CHF (NYHA II–IV),

other cardiomyopathy,

cardiac arrhythmia requiring medication,

clinically significant cardiac valvular disease,

poorly controlled hypertension (hypertension controlled by standard medication eligible) and

clinically significant pericardial effusion.

The safety of continuation or resumption of trastuzumab in patients who have previously

experienced cardiac toxicity has not been prospectively studied. According to the narrative

reports of cardiac events, about half of the events had resolved completely by the time of the

interim analysis. Please see

Table 7 and

Table 8 below.

For patients with EBC, cardiac assessments, as performed at baseline, should be repeated

every 3 months during treatment and every 6 months following discontinuation of treatment until

24 months from the last administration of HERZUMA

. In patients who receive anthracycline

containing chemotherapy further monitoring is recommended, and should occur yearly up to 5

years from the last administration of HERZUMA

, or longer if a continued decrease of LVEF is

observed.

A high index of clinical suspicion is warranted for discontinuing treatment in the setting of

cardiopulmonary symptoms. Close monitoring of cardiac function should be carried out for all

patients and adequate treatment for CHF should be administered regardless of the

discontinuation of HERZUMA

therapy. Please see Table 2 in DOSAGE AND

ADMINISTRATION: Dose Holding, Monitoring of Cardiac Function, for information on

continuation and discontinuation of HERZUMA

based on interval LVEF assessments.

HERA

In the HERA trial, cardiac monitoring (electrocardiogram [ECG], left ventricular ejection fraction

[LVEF], signs/symptoms and cardiac questionnaire) was performed at baseline and regularly

throughout the study. The assessment schedule for cardiac monitoring was at months 3 and 6

and then every 6 months until month 36 (3 years from the date of therapy) and in month 60 (5

years from the date of therapy). In addition, LVEF was measured at 48 months (4 years from

the date of therapy) and followed up every 12 months from year 6 to year 10.

When trastuzumab was administered after completion of adjuvant chemotherapy, NYHA class

III-IV heart failure was observed in 0.6% of patients in the one-year arm after a median follow-up

of 12 months.

Table 5 Absolute Numbers and Rates of Cardiac Endpoints in HERA (Median follow-up of

12 months)

HERA study

Observation

Trastuzumab

n (%)

n (%)

N=1708

N=1678

Primary cardiac endpoint

1 (0.1%)

10 (0.6%)

Secondary cardiac endpoint

9 (0.5%)

51 (3.0%)

Total “cardiac endpoints”

10 (0.6%)

61 (3.6%)

page 16 / 117

Table 6 Absolute Numbers and Rates of Cardiac Endpoints in HERA (Median follow-up of

8 years)

HERA study

Observation

Trastuzumab

n (%)

1 year arm

N=1744

n (%)

N=1682

Primary cardiac endpoint

2 (0.1%)

14 (0.8%)

Events after 1 year

0 (0.0%)

1 (0.1%)

Secondary cardiac endpoint

15 (0.9%)

78 (4.6%)

(69 – excluding patients w ith

primary endpoint)

Events after 1 year

7 (0.4%)

14 (0.8%)

(13 – excluding patients w ith

primary endpoint)

Total “cardiac endpoints”

17 (1.0%)

83 (4.9%)

Table 7 Median Time to Return to Baseline LVEF/ Stabilizations of LVEF in the HERA Trial

(Median follow-up of 8 years) - Primary Cardiac Endpoint

HERA study

Primary Cardiac Endpoint

Observation

(n = 2)

trastuzumab 1-year

(n=14)

Return to baseline LVEF

11 (79%)

Median time to return to baseline

LVEF

218 d

Stabilization of LVEF

5 (36%)

Table 8 Median Time to Return to Baseline LVEF/ Stabilizations of LVEF in the HERA Trial

(Median follow-up of 8 years) - Secondary Cardiac Endpoint

HERA study

Secondary Cardiac Endpoint

(excluding patients w ith primary cardiac endpoint)

Observation

(n = 15)

trastuzumab 1-year

(n=69)

Return to baseline LVEF

10 (67%)

60 (87%)

Median time to return to baseline

LVEF

189 d

240 d

Stabilization of LVEF

4 (27%)

18 (26%)

A significant drop in left ventricular ejection fraction (LVEF) is defined as an absolute decrease

of 10 EF points or more from baseline and to below 50%, measured by MUGA scan or

echocardiogram.

A primary cardiac endpoint was defined as the occurrence at any time after randomization but

prior to any new therapy for recurrent disease of symptomatic congestive heart failure of NYHA

class III or IV, confirmed by a cardiologist and a significant drop in LVEF, or cardiac death.

A secondary cardiac endpoint was defined as asymptomatic (NYHA class I) or mildly

symptomatic (NYHA class II) cardiac dysfunction with a significant LVEF drop. In addition

events which did not meet the above criteria for a secondary cardiac endpoint but which in the

opinion of the Cardiac Advisory Board should be classed as secondary cardiac endpoints were

included.

After a median follow-up of 3.6 years the incidences of severe CHF, symptomatic CHF and at

least one significant LVEF decrease (an absolute decline of at least 10% from baseline LVEF

and to less than 50%) after 1 year of trastuzumab therapy was 0.8%, 1.9% and 9.8%,

respectively.

page 17 / 117

After a median follow-up of 8 years the incidence of severe CHF (NYHA III & IV) in the

trastuzumab 1 year treatment arm was 0.8%, and the rate of mild symptomatic and

asymptomatic left ventricular dysfunction was 4.6%. At least one LVEF assessment was

missing for 20.8% of patients in the observation only arm and 32.0% of patients in the

trastuzumab 1-year arm. During the follow-up until month 60, at least one LVEF assessment

was missed for 18.0% of patients in the observation only arm and 17.9% of patients in the

trastuzumab 1-year arm.

Reversibility of severe CHF (defined as a sequence of at least two consecutive LVEF values

≥50% after the event) was evident for 71.4% of trastuzumab-treated patients. Reversibility of

mild symptomatic and asymptomatic left ventricular dysfunction was demonstrated for 79.5% of

patients. Approximately 17% (14/83) of cardiac endpoints occurred after completion of

trastuzumab in the trastuzumab one-year arm.

Joint Analysis: NSABP B-31 and NCCTG N9831

Cardiac dysfunction adverse events were defined in both B-31 and N9831 as symptomatic

cardiac events and asymptomatic LVEF events. Symptomatic cardiac events were reviewed

and confirmed by the cardiac committee of each study and included the occurrence of

symptomatic congestive heart failure with objective findings and confirmation by imaging,

deaths due to cardiac causes (CHF, MI, or documented primary arrhythmia) and probable

cardiac deaths (sudden death without documented etiology). Asymptomatic LVEF events were

defined as absolute drop in LVEF ≥10% to < 55% or an absolute drop in LVEF of ≥5% to below

the institution’s lower limit of normal (LLN). In study B-31, 15.5% of patients discontinued

trastuzumab due to asymptomatic LVEF decrease (12.2%), CHF (2.2%) or Cardiac diagnosis

other than CHF (1.1%) in the trastuzumab + chemotherapy arm; no patients in the

chemotherapy alone arm discontinued treatment for these reasons. In all analyses the rate of

cardiac dysfunction was higher in patients in the trastuzumab + chemotherapy arm compared

with those in the chemotherapy alone arm. From the paclitaxel baseline to the six month, nine

month and eighteen month assessment, the average change in LVEF was more pronounced in

the trastuzumab + chemotherapy arm (-4.2%, -5.1% and -3.1% in the trastuzumab +

chemotherapy alone arm, respectively versus -0.5%, -0.4% and -0.9% in the chemotherapy

alone arm, respectively).

Table 9 Joint Analysis: (NSABP B-31 and NCCTG N9831)

The Incidence and Type of Cardiac Events (Median Duration of More Than 8 Years**

Safety Follow up)

B31

N9831

B-31+N9831

AC→T

AC→T + H

AC→T

AC→T + H

AC→T

AC→T + H

(n = 889)

(n = 1031)

(n = 766)

(n = 969)

(n = 1655)

(n = 2000)

Symptomatic

CHF (non-death)

11 (1.2%)

38 (3.7%)

5 (0.7%)

24 (2.5%)

16 (1.0%)

62 (3.1%)

Cardiac death

2 (0.2%)

1 (0.1%)

3 (0.4%)

1 (0.1%)

5 (0.3%)

2 (0.1%)

Death due to

CHF, MI, or

primary

arrhythmia

0 (0.0%)

0 (0.0%)

2 (0.3%)

1 (0.1%)

2 (0.1%)

1 (0.1%)

Sudden death

w ithout

documented

etiology

2 (0.2%)

1 (0.1%)

1 (0.1%)

0 (0.0%)

3 (0.2%)

1 (0.1%)

page 18 / 117

B31

N9831

B-31+N9831

AC→T

AC→T + H

AC→T

AC→T + H

AC→T

AC→T + H

(n = 889)

(n = 1031)

(n = 766)

(n = 969)

(n = 1655)

(n = 2000)

Any cardiac or

asymptomatic

LVEF events

(30.4%)

(38.9%)

(27.3%)

(37.9%)

(28.9%)

(38.4%)

Drop in LVEF of

10 points

compared

w ith

baseline to

below

(26.5%)

(36.5%)

(24.0%)

(35.1%)

(25.4%)

(35.8%)

Drop in LVEF of 5

points compared

w ith baseline to

below the low er

limit of normal*

(18.1%)

(25.9%)

(16.6%)

(24.6%)

(17.4%)

(25.3%)

A = doxorubicin; C = cyclophosphamide; CHF = congestive heart failure; H = trastuzumab; LVEF = left

ventricular

ejection fraction; MI = myocardial infarction; T = paclitaxel.

*Asymptomatic LVEF per protocol events at any time after AC initiation: 1. Drop in LVEF of 10 points compared

w ith AC baseline LVEF to below 55. or 2. Drop in LVEF of 5 points compared w ith AC baseline LVEF to below

low er limit of normal.

** In the joint analysis safety population, the median duration of follow -up w as 8.1 years for the AC→T + H group

and 8.5 years for the AC→T group

16 AC→T patients had adjudicated and confirmed symptomatic CHF out of the 62 possible CHF patients review ed

by the study committees.

62 AC→T + H patients had adjudicated and confirmed symptomatic CHF out of the 135 possible CHF patients

review ed by the study committees.

A patient received AC→T in study B-31; not included here and had “emphysema” listed on autopsy.

At 3 years, the cardiac event rate in patients receiving ACTH (doxorubicin plus

cyclophosphamide followed by paclitaxel + trastuzumab) was estimated at 3.2%, compared with

0.9% in ACT treated patients. Between 5 and 7 years of follow-up, an additional patient in

each treatment group experienced a cardiac event; the cardiac event rate at 9 years follow-up in

patients receiving ACTH was estimated at 3.2%, compared with 1.0% in ACT treated

patients.

Table 10 summarizes the follow-up information for 84 patients (52 from study B-31 and 32 from

study N9831) for whom symptomatic CHF was adjudicated and confirmed by the study

committee.

Table 10 Joint Analysis (NSABP B-31 and NCCTG N9831)

Follow-Up of Symptomatic CHF Events (Median Duration of More Than 8 Years* Safety

Follow up)

(Patients from the Joint Safety Population with Symptomatic CHF Confirmed by Study

Committee)

B-31

N9831

Joint Analysis

AC→T

(n = 11)

AC→T + H

(n = 38)

AC→T

(n = 5)

AC→T + H

(n = 24)

AC→T

(n = 16)

AC→T + H

(n = 62)

Months from onset to first overall recovery

Mean (SD)

10.1 (2.2)

21.5 (11.1)

10.5 (8.6)

10.1 (2.2)

18.3 (11.5)

Median

10.2

16.9

10.2

14.5

Range

8–12

9–50

3–31

8–12

3–50

page 19 / 117

B-31

N9831

Joint Analysis

AC→T

(n = 11)

AC→T + H

(n = 38)

AC→T

(n = 5)

AC→T + H

(n = 24)

AC→T

(n = 16)

AC→T + H

(n = 62)

Current overall recovery status

Recovery

(LVEF ≥ 50%

and no symptoms)

3 (27.3%)

8 (21.1%)

(0.0%)

7 (29.2%)

3 (18.8%)

15 (24.2%)

No recovery

(LVEF < 50%

or symptoms)

2 (18.2%)

7 (18.4%)

3 (60.0%)

6 (25.0%)

5 (31.3%)

13 (21.0%)

Unknow n

6 (54.5%)

23 (60.5%)

2 (40.0%)

11 (45.8%)

8 (50.0%)

34 (54.8%)

A = doxorubicin; C = cyclophosphamide; H = trastuzumab; LVEF = left ventricular ejection fraction;

SD = standard

deviation; T = paclitaxel;

* = In the joint analysis safety population, the median duration of follow -up w as 8.1 years for the AC→T + H group

8.5 years for the AC→T group.

Following initiation of paclitaxel therapy, 344 patients treated with AC→TH (18.5%) experienced

an LVEF percentage decrease of ≥ 10 points from paclitaxel baseline to < 50 points, compared

with 82 patients treated with AC→T (7.0%) at a median follow-up of 8.1 years for the

AC→TH

group. The per patient incidence of new onset cardiac dysfunction, after initiation of paclitaxel

therapy, as determined by LVEF, remained unchanged compared to the analysis performed at a

median follow up of 2.0 years in the AC→TH group.

An independent clinical review was performed on 62 patients with symptomatic congestive heart

failure in the trastuzumab + chemotherapy arm to assess treatment and resolution status. Most

patients were treated with oral medications commonly used to manage congestive heart failure.

Complete or partial LVEF recovery was documented in 56 patients (90.3%), with complete

recovery in 17 of these patients (27.4%) and partial recovery in 39 of these patients (62.9%),

compared to 6 patients (9.7%) experiencing no recovery. This analysis also showed evidence of

reversibility of left ventricular dysfunction in 64.5% of patients who experienced a symptomatic

CHF in the AC→TH group being asymptomatic at the latest follow up.

Risk factors for a cardiac event included trastuzumab treatment, increased age, prior or current

use of anti-hypertensive medications and low LVEF prior to or following the initiation of paclitaxel

treatment. In the trastuzumab + chemotherapy arm, the risk of a cardiac event

increased with the

number of these risk factors present. In study B-31, there was no association between the

incidence of cardiac events and either radiation to the left side of the chest or smoking.

BCIRG-006

In study BCIRG-006, cardiac events were defined as congestive heart failure (CHF; grade 3 or 4

cardiac left ventricular function [CLVF], per the NCI-CTC, v 2.0), grade 3 or 4 cardiac

arrhythmia,

grade 3 or 4 cardiac ischemia/infarction, cardiac death and serious adverse events

with cardiac

etiology not pre-defined as a cardiac event in the protocol but assessed as being a

significant

cardiac event by the Independent Cardiac Review Panel (ICRP). Asymptomatic

LVEF events

were defined as an absolute decline in LVEF value of >15 % from baseline to a

value that was

below the institution’s lower limit of normal (LLN). [Note: asymptomatic LVEF events defined in

HERA as: a drop in LVEF of at least 10 EF points from baseline and to below

50%, and in the

JA as: absolute drop in LVEF ≥10% to < 55% or an absolute drop in LVEF of ≥5% to below the

institution’s LLN.]

Table 11 summarizes symptomatic cardiac events reported at any time during the study.

page 20 / 117

Table 11 Symptomatic Cardiac Events per the Independent Cardiac Review Panel (ICRP)

Occurring at Any Time during the Study (Safety Population) 5 Year Follow Up

Event Type

AC→T

(n = 1041)

AC→TH

(n = 1077)

TCH

(n = 1056)

CHF (Grade 3/4 CLVF)

6 (0.6%)

20 (1.9%)

4 (0.4%)

Grade 3/4 cardiac ischemia/infarction

3 (0.3%)

2 (0.2%)

Grade 3/4 arrhythmia

6 (0.6%)

3 (0.3%)

6 (0.6%)

Cardiac death

Any symptomatic cardiac event

10 (1.0%)

25 (2.3%)

12 (1.1%)

ACT = doxorubicin plus cyclophosphamide, follow ed by docetaxel; ACTH = doxorubicin plus

cyclophosphamide,

follow ed by docetaxel plus trastuzumab; CHF = congestive heart failure; CLVF = cardiac left ventricular function; TCH =

docetaxel, carboplatin, and trastuzumab.

At 5.5 years, the rates of symptomatic cardiac or LVEF events were 1.0%, 2.3%, and 1.1% in the

AC→T (doxorubicin plus cyclophosphamide, followed by docetaxel), AC→TH (doxorubicin

plus

cyclophosphamide, followed by docetaxel plus trastuzumab), and TCH (docetaxel,

carboplatin

and trastuzumab) treatment arms, respectively. For symptomatic CHF (Grade 3 - 4), the 5-year

rates were 0.6%, 1.9%, and 0.4% in the AC→T, AC→TH, and TCH treatment arms,

respectively. The overall risk of developing symptomatic cardiac events was similar for patients

in AC→T and TCH arms. There was an increased risk of developing a symptomatic cardiac

event for patients in the AC→TH arm, where the cumulative rate of symptomatic cardiac or

LVEF events was 2.3% compared to approximately 1% in the two comparator arms (AC→T and

TCH, respectively).

In BCIRG-006 study, 155 patients treated with AC→TH (14.4%) experienced an LVEF decrease

of ≥ 10% from baseline to < 50%, compared with 79 (7.6%) patients treated with AC→T and 63

(6.0%) patients treated with TCH.

Table 12 presents the incidence of symptomatic and asymptomatic LVEF events.

Table 12 Asymptomatic and Symptomatic LVEF Declines by Baseline Events, Using the

Same Assessment Method as Baseline (Safety Population) 5 Year Follow Up

Event Type

AC→T

(n = 1041)

AC→TH

(n = 1077)

TCH

(n = 1056)

Absolute decline of >15% from baseline and to a

value

below the LLN

50 (4.8%)

111 (10.3%)

42 (4.0%)

Absolute decline of >10% from baseline and to a

value

<

71 (6.8%)

137 (12.7%)

50 (4.7%)

Symptomatic and/or asymptomatic decline of

>15%, below the LLN

56 (5.4%)

128 (11.9%)

57 (5.4%)

AC-T = doxorubicin plus cyclophosphamide, follow ed by docetaxel; AC-TH = doxorubicin plus

cyclophosphamide,

follow ed by docetaxel plus trastuzumab; ANC = absolute neutrophil count; LLN = low er

limit of normal; TCH =

docetaxel, carboplatin, and trastuzumab.

Metastatic Breast Cancer (MBC)

HERZUMA

and anthracyclines should not be given concurrently in the MBC setting.

In particular, moderate to severe cardiac dysfunction has been observed in MBC patients treated

with trastuzumab in combination with an anthracycline (doxorubicin or epirubicin) and

cyclophosphamide (see ADVERSE REACTIONS). The clinical status of patients in the trials who

page 21 / 117

developed congestive heart failure were classified for severity using the New York Heart

Association classification system (I-IV

where IV is the most severe level of cardiac failure).

(See Table 13).

Table 13 Incidence and Severity of Cardiac Dysfunction in Metastatic Breast Cancer

Patients

trastuzumab +

Anthracycline +

cyclop ho s ph a m id e

b

Anthracycline

+

cyclophosphamide

b

trastuzumab

+

Paclitaxel

b

Paclitaxel

b

trastuzumab

a

Alone

(n=143)

(n= 135)

(n= 91)

(n= 95)

(n= 338)

Any Cardiac

Dysfunction

Class III-IV

Single agent studies H0551g, H0649g and H0650g.

Randomized Phase III

study comparing chemotherapy plus trastuzumab to chemotherapy alone, w here

chemotherapy is either

anthracycline/cyclophosphamide or paclitaxel.

In a subsequent trial with prospective monitoring of cardiac function, the incidence of

symptomatic heart failure was 2.2% in patients receiving trastuzumab and docetaxel, compared

with 0% in patients receiving docetaxel alone. In the MBC trials, the probability of cardiac

dysfunction was highest in patients who received trastuzumab concurrently with

anthracyclines.

The MBC data suggest that advanced age may increase the probability of cardiac

dysfunction.

Pre-existing cardiac disease or prior cardiotoxic therapy (e.g., anthracycline or radiation therapy)

to the chest may decrease the ability to tolerate therapy with trastuzumab; however, the data is

not adequate to evaluate correlation between cardiac dysfunction observed with trastuzumab

and these factors in patients with HER2 positive MBC.

Hematologic

Exacerbation of Chemotherapy-Induced Neutropenia: In randomized, controlled clinical

trials in both adjuvant and MBC designed to assess the impact of the addition of trastuzumab on

chemotherapy, the per-patient incidences of moderate to severe neutropenia and of febrile

neutropenia were higher in patients receiving trastuzumab in combination with

myelosuppressive chemotherapy compared with those receiving chemotherapy alone.

Using NCI-CTC criteria, in the adjuvant HERA trial, 0.4% of patients treated with trastuzumab

experienced a shift of 3 or 4 grades from baseline, compared with 0.6% in the observation arm.

In the adjuvant studies, NSABP B-31 and NCCTG N9831, there were 6 deaths due to

septicemia or severe neutropenia. Five deaths occurred on the chemotherapy alone arm: 2

New York Heart Association Functional Classification

Class I:

Patients w ith cardiac disease but w ithout resulting limitations of physical activity. Ordinary physical activity

does not

cause undue fatigue, palpitation, dyspnea or anginal pain.

Class II:

Patients w ith cardiac disease resulting in slight limitation of physical activity. They are comfortable at rest.

Ordinary

physical activity results in fatigue, palpitation, dyspnea or anginal pain.

Class III:

Patients w ith cardiac disease resulting in marked limitation of physical activity. They are comfortable at rest.

Less

than ordinary physical activity causes fatigue, palpitation, dyspnea or anginal pain.

Class IV:

Patients w ith cardiac disease resulting in inability to carry on any physical activity w ithout discomfort.

Symptoms of

cardiac insufficiency or of the anginal syndrome may be present even at rest. If any physical

activity is undertaken,

discomfort is increased.

page 22 / 117

patients died of pneumonia with febrile neutropenia and 3 patients died of septicemia. One

death occurred on the trastuzumab + chemotherapy arm and the patient died of

infection/neutropenic fever with lung infiltrates. All except 2 septicemia deaths occurred during

protocol treatment period.

In the post-market setting in MBC, deaths due to sepsis in patients with severe neutropenia

have been reported in patients receiving trastuzumab and myelosuppressive chemotherapy,

although in controlled MBC clinical trials (pre- and post-market), the incidence of septic death

was not significantly increased.

The pathophysiologic basis for exacerbation of neutropenia has not been determined; the effect

of trastuzumab on the pharmacokinetics of chemotherapeutic agents has not been fully

evaluated. If neutropenia occurs, the appropriate management should be instituted as per local

practice/guidelines and the labelled instructions for chemotherapy agents should be followed

with regard to dose interruption or dose reduction (see DOSAGE AND ADMINISTRATION:

Recommended Dose and Dosage Adjustment, Dose Reduction).

Hypersensitivity Reactions Including Anaphylaxis, Infusion-Associated Reactions and

Pulmonary Events

Administration of HERZUMA

can result in severe hypersensitivity reactions (including

anaphylaxis), infusion reactions and pulmonary events. In rare cases, these reactions have

been fatal. See discussion below.

There are no data regarding the most appropriate method of identification of patients who may

safely be retreated with trastuzumab after experiencing a severe reaction. Trastuzumab has

been readministered to some patients who fully recovered from a previous severe reaction.

Prior to readministration of trastuzumab the majority of these patients were prophylactically

treated with pre-medications including antihistamines and/or corticosteroids. While some of

these patients tolerated retreatment, others had severe reactions again despite the use of

prophylactic pre-medications.

Hypersensitivity Reactions Including Anaphylaxis: Severe hypersensitivity reactions have

been infrequently reported in patients treated with trastuzumab. Signs and symptoms include

anaphylaxis, urticaria, bronchospasm, angioedema, and/or hypotension. In some cases, the

reactions have been fatal. The onset of symptoms generally occurred during an infusion, but

there have also been reports of symptom onset after the completion of an infusion. Reactions

were most commonly reported in association with the initial infusion. In HERA 1 observation and

10 trastuzumab treated patients experienced hypersensitivity. Eight out of the 10 events were

considered related to trastuzumab treatment. The incidence of allergic reactions in the Joint

Analysis (chemotherapy alone versus trastuzumab + chemotherapy: 3.6% versus 3.1% in study

B-31 and 1.1% versus 0.3% in study N9831) was comparable between the two treatment arms

in both studies. In study BCIRG-006, the incidence of allergic reactions according to the NCI-

CTC v 2.0 classification was 9.4%, 12.3% and 14.9% in AC→T, AC→TH and TCH arms,

respectively.

Infusional administration of HERZUMA

®

should be interrupted in all patients with severe

hypersensitivity reactions. In the event of a hypersensitivity reaction, appropriate medical

therapy should be administered, which may include epinephrine, corticosteroids,

page 23 / 117

diphenhydramine, bronchodilators, and oxygen. Patients should be evaluated and carefully

monitored until complete resolution of signs and symptoms.

Infusion-Related Reactions (IRRs): IRRs are known to occur with trastuzumab. Pre-

medication may be used to reduce risk of occurrence of IRRs.

Serious IRRs to infusions of trastuzumab including dyspnea, hypotension, hypertension,

wheezing, bronchospasm, tachycardia, reduced oxygen saturation and respiratory distress,

supraventricular tachyarrhythmia and urticaria have been reported (see ADVERSE

REACTIONS). Patients should be observed for IRRs. Interruption of an IV infusion may help

control such symptoms and the infusion may be resumed when symptoms abate. These

symptoms can be treated with an analgesic/antipyretic such as meperidine or paracetamol, or

an antihistamine such as diphenhydramine. Serious reactions have been treated successfully

with supportive therapy such as oxygen, beta-agonists and corticosteroids (see ADVERSE

REACTIONS). The appropriate management of patients with uncontrolled hypertension or

history of hypertension should be considered prior to infusion with HERZUMA

These severe reactions were usually associated with the first infusion of trastuzumab and

generally occurred during or immediately following the infusion. For some patients, symptoms

later worsened and led to further pulmonary complications. Initial improvement followed by

clinical deterioration and delayed reactions with rapid clinical deterioration have also been

reported. Fatalities have occurred within hours and up to one week following infusion. On very

rare occasions, patients have experienced the onset of infusion symptoms or pulmonary

symptoms more than six hours after the start of the infusion of trastuzumab. Patients should be

warned of the possibility of such a late onset and should be instructed to contact their physician

if those symptoms occur. In rare cases, these reactions are associated with a clinical course

culminating in a fatal outcome. Patients who are experiencing dyspnea at rest due to

complications of advanced malignancy and comorbidities may be at increased risk of a fatal

infusion reaction. Therefore, these patients should not be treated with trastuzumab.

Pulmonary Events: Severe pulmonary events leading to death have been reported with the

use of trastuzumab in the adjuvant breast cancer clinical studies and the post-market MBC

setting. These events may occur as part of an infusion-related reaction or with a delayed onset

(See Infusion-Related Reactions subsection of WARNINGS AND PRECAUTIONS), and were

reported to occur at varying latencies, from within 24 hours to over 30 days, since the start of

treatment with trastuzumab. Cases of interstitial lung disease (which often present with

dyspnea) including lung infiltrates, pneumonitis, pleural effusion, respiratory distress, acute

pulmonary edema, respiratory insufficiency, acute respiratory distress syndrome, and

pneumonia have been reported. Risk factors associated with interstitial lung disease include

prior or concomitant therapy with other anti-neoplastic therapies known to be associated with it

such as taxanes, gemcitabine, vinorelbine and radiation therapy. Patients with dyspnea at rest

due to complications of advanced malignancy and co-morbidities may be at increased risk of

pulmonary events. Therefore, these patients should not be treated with HERZUMA

Other severe events reported rarely in the post-market MBC setting include pneumonitis and

pulmonary fibrosis. All of the confirmed cases of pulmonary fibrosis received to date are

characterized by one or more significant confounding factors including pre-existing lung disease

and prior/concomitant chemotherapy such as cyclophosphamide. However, a causal

relationship between trastuzumab and pulmonary fibrosis cannot be excluded.

page 24 / 117

Immune

Immunogenicity:

Samples for assessment of human anti-human antibody (HAHA) were not collected in studies of

adjuvant breast cancer. Of 903 patients that have been evaluated in the MBC trials, human anti-

human antibody (HAHA) to trastuzumab was detected in 1 patient, who had no allergic

manifestations.

Respiratory

Refer to Pulmonary Events subsection of WARNINGS AND PRECAUTIONS.

Thrombosis/Embolism

Thrombosis/embolism has been observed in patients who receive trastuzumab + chemotherapy

in both the adjuvant and metastatic treatment setting, and in rare cases, has been fatal (see

ADVERSE REACTIONS section).

Ability to Drive and Use Machines

Trastuzumab has a minor influence on the ability to drive and use machines. Dizziness and

somnolence may occur during treatment with HERZUMA

Patients experiencing infusion-

related symptoms should be advised not to drive or use machines until symptoms resolve

completely.

Selection of Patients / Diagnostic Tests

Early Breast Cancer (EBC)/Metastatic Breast Cancer (MBC)

HERZUMA

®

should only be used in patients whose tumours overexpress HER2 as

determined by immunohistochemistry. CICH or FISH testing for HER2 status also may be

used, provided that the testing is done in experienced laboratories that have validated

the test.

To ensure accurate and reproducible results, the protocol described in the package insert of an

appropriate diagnostic test needs to be strictly followed. However, based on the current

scientific knowledge, no standard test can be recommended at this time. There is no standard

method of staining and no standard for the type of antibodies used. The grading for

overexpression is subjective, and the signal may fade with time on stored slides.

The test method for HER2 overexpression used to determine eligibility of patients for inclusion

in the MBC clinical trials employed immunohistochemical staining for HER2 of fixed material

from tissue biopsy using the murine monoclonal antibodies CB11 and 4D5. Patients classified

as staining 2+ or 3+ were included, while those staining 0 or 1+ were excluded. Greater than

70% of patients enrolled exhibited 3+ overexpression. The data suggest that beneficial effects

were greater among those patients with higher levels of overexpression of HER2.

In the studies, an investigative clinical trial assay was employed which utilized a 0 to 3+ scale.

The degree of HER2 overexpression indicated by different test methods may not correlate with

page 25 / 117

that used as the eligibility criterion for inclusion in the clinical trials. For example, a validated IHC

assay utilizes a scale of 0 to 3+. A reading of 3+ with the validated IHC assay is likely to

correspond to that of a 2+ or 3+ with the investigative clinical trial assay. A 2+ reading with the

validated IHC assay would likely incorporate a significant number of patients who were scored

as 1+ by the investigative clinical trial assay. These patients (1+) would not have met the

inclusion criteria. Test methods having increased sensitivity, relative to the investigative clinical

trial assay, may alter the benefit-to-risk ratio compared to that seen in the clinical trials. In

deciding which patients should receive HERZUMA

, the risk of cardiac dysfunction (see

WARNINGS and PRECAUTIONS) must be weighed against the potential benefits of treatment,

especially for those not in the high range of HER2 overexpression.

For inclusion criteria in terms of HER2 expression in clinical trials in EBC see Clinical Trials -

Reference Biologic Drug section.

Metastatic Gastric Cancer (MGC)

HERZUMA

should only be administered to patients with MGC whose tumours have HER2

overexpression as determined by validated immunohistochemistry (IHC) and fluorescent in situ

hybridization (FISH) testing. The testing should be done in experienced laboratories that have

validated the test.

Patients are eligible for HERZUMA

treatment if they demonstrate strong HER2 protein

overexpression, defined by a 3+ score by IHC, or a 2+ score by IHC and a positive FISH result.

8.1

Special Populations

8.1.1

Women and Men of Reproductive Potential:

Fertility

It is not known whether HERZUMA

can affect reproductive capacity. Animal reproduction

studies revealed no evidence of impaired fertility or harm to the foetus (see NON-CLINICAL

TOXICOLOGY – REFERENCE BIOLOGIC DRUG, Reproductive Toxicity).

Contraception

Women of childbearing potential should be advised to use effective contraception during

treatment with HERZUMA

and for at least 7 months after treatment has concluded (see

ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics)

8.1.2

Pregnant Women

Reproduction studies have been conducted in cynomolgus monkeys at doses up to 25 times the

weekly human maintenance dose of 2 mg/kg trastuzumab and have revealed no evidence of

impaired fertility or harm to the fetus (see NON-CLINICAL TOXICOLOGY – REFERENCE

BIOLOGIC DRUG, Reproductive Toxicity). However, when assessing the risk of reproductive

toxicity in humans, it is important to consider the significance of the rodent form of the HER2

receptor in normal embryonic development and the embryonic death in mutant mice lacking this

receptor. Placental transfer of trastuzumab during the early (days 20-50 of gestation) and late

(days 120-150 of gestation) fetal development period was observed.

HERZUMA

can cause fetal harm when administered to a pregnant woman. In the post-market

page 26 / 117

setting, cases of impairment of fetal renal growth and/or renal function impairment, intrauterine

growth retardation and skeletal abnormalities in association with oligohydramnios during the

second and third trimesters, some associated with fatal pulmonary hypoplasia of the fetus, have

been reported in pregnant women receiving trastuzumab. Also, the causal role of trastuzumab

cannot be excluded nor confirmed in two cases of interventricular septal defects reported in

infants exposed to trastuzumab in utero. In one of these two cases, spontaneous closure of the

defect occurred nine months postpartum. No follow up information regarding closure of the

defect was available in the second case. HER2 is known to be expressed in many embryonic

tissues. Women who become pregnant should be advised of the possibility of harm to the fetus.

If a pregnant woman is treated with HERZUMA

, close monitoring by a multidisciplinary team is

desirable.

Women using HERZUMA

during pregnancy should be monitored for oligohydramnios. If

oligohydramnios occurs, fetal testing should be done that is appropriate for gestational age and

consistent with community standards of care. Additional intravenous (IV) hydration has been

helpful when oligohydramnios has occurred following administration of other chemotherapy

agents; however, the effects of additional IV hydration with trastuzumab treatment are not

known.

Animal reproduction studies revealed no evidence of impaired fertility or harm to the fetus.

Because animal reproduction studies are not always predictive of human response, HERZUMA

should not be used during pregnancy unless the potential benefit for the mother outweighs the

potential risk to the fetus.

8.1.3

Breast-feeding

A study conducted in cynomolgus monkeys at doses 25 times the weekly human maintenance

dose of 2 mg/kg trastuzumab from days 120 to 150 of pregnancy

demonstrated that

trastuzumab is secreted in the milk postpartum. The exposure to trastuzumab in utero and the

presence of trastuzumab in the serum of infant monkeys was not associated with any adverse

effects on their growth or development from birth to 1 month of age. It is not known whether

trastuzumab is excreted in human milk. As human IgG is excreted in human milk, and the

potential for absorption and harm to the infant is unknown, a decision should be made whether

to discontinue nursing, or discontinue drug, taking into account the elimination half-life of

trastuzumab and the importance of the drug to the mother.

8.1.4

Pediatrics

The safety and effectiveness of trastuzumab in pediatric patients below the age of 18, have not

been established.

8.1.5

Geriatrics (> 65 years of age)

Trastuzumab has been administered in clinical studies to 386 patients who were 65 years of

age or over (253 in the adjuvant treatment and 133 in MBC treatment settings). The risk of

cardiac dysfunction was increased in geriatric patients as compared to younger patients in both

those receiving treatment for metastatic disease and those receiving adjuvant therapy in studies

NSABP B-31 and NCCTG N9831, and BCIRG-006. Age ≥ 60 years was associated with

increased risk of shorter time to first symptomatic cardiac event in study BCIRG-006 (based on

35 cardiac events in 2066 patients) (for the definition of cardiac events in each study see

page 27 / 117

WARNINGS AND PRECAUTIONS, Cardiotoxicity, Early Breast Cancer). Limitations in data

collection and differences in study design of the 4 studies of trastuzumab in adjuvant treatment

of breast cancer preclude a determination of whether the toxicity profile of trastuzumab in older

patients is different from younger patients. The reported clinical experience is not adequate to

determine whether the efficacy improvements (as measured by ORR, TTP, OS, and DFS) of

trastuzumab treatment in older patients differ from those observed in patients <65 years of age,

for either treatment of metastatic disease or adjuvant treatment of EBC.

In ToGA (BO18255) study in MGC, of the 294 patients treated with trastuzumab, 108 (37%)

were 65 years of age or older, while 13 (4.4%) were 75 and over. No overall differences in

safety or effectiveness were observed.

The risk of hematologic toxicities (leukopenia and thrombocytopenia) may be increased in

geriatric patients.

Data suggest that the disposition of trastuzumab is not altered based on age (see ACTION AND

CLINICAL PHARMACOLOGY: Pharmacokinetics). In clinical studies, geriatric patients (≥ 65

years of age) did not receive reduced doses of trastuzumab.

9

ADVERSE REACTIONS

The adverse drug reaction profiles reported in clinical studies that compared HERZUMA

to the

reference biologic drug were comparable. The description of adverse reactions in this section is

based on clinical experience with the reference biologic drug.

9.1

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates

observed in the clinical trials may not reflect the rates observed in practice and should not be

compared to the rates in the clinical trials of another drug. Adverse drug reaction information

from clinical trials is useful for identifying drug-related adverse events and for approximating

rates.

Early Breast Cancer (EBC)

HERA

(adjuvant sequential: use of trastuzumab following surgery and after chemotherapy)

Please see WARNINGS AND PRECAUTIONS: Cardiovascular/Cardiotoxicity/Early Breast

Cancer – Table 5~8 for a description of the absolute numbers and rates of cardiac endpoints in

HERA as well as the median time to return to baseline LVEF/ stabilizations of LVEF in the

HERA trial.

The HERA trial is a randomized, open label study in patients with HER2 positive EBC. Table 14

displays adverse events which were reported after 8 years of median follow up in ≥ 1% of

patients, by study treatment.

page 28 / 117

Table 14 Adverse Events Reported in ≥ 1% of HERA Study Patients, by Study Treatment

Final Analysis After 8 years of Median Follow Up According to MedDRA v 15.0

Classification

Adverse Event Term

Observation Only

trastuzumab

1 year

N = 1744

N = 1682

No. (%)

No. (%)

Blood and Lymphatic System Disorders

Anemia

4 (<1)

15 (<1)

Cardiac Disorders

Cardiac Failure Congestive

19 (1)

93 (6)*

Palpitations

20 (1)

73 (4)

Tachycardia

5 (<1)

25 (1)

Ear and Labyrinth Disorders

Vertigo

14 (<1)

33 (2)

Tinnitus

6 (<1)

7 (<1)

Eye Disorders

Conjunctivitis

7 (<1)

21 (1)

Vision blurred

6 (<1)

16 (<1)

Lacrimation Increased

1 (<1)

12 (<1)

Gastrointestinal Disorders

Diarrhea

23 (1)

156 (9)

Nausea

37 (2)

134 (8)

Vomiting

17 (<1)

76 (5)

Constipation

27 (2)

55 (3)

Abdominal Pain

25 (1)

60 (4)

Abdominal Pain Upper

30 (2)

45 (3)

Dyspepsia

14 (<1)

42 (2)

Stomatitis

1 (<1)

33 (2)

Gastritis

17 (<1)

27 (2)

Hemorrhoids

8 (<1)

18 (1)

Mouth Ulceration

2 (<1)

13 (<1)

General Disorders and Administration Site Conditions

Fatigue

83 (5)

198 (12)

Edema Peripheral

64 (4)

114 (7)

Pyrexia

12 (<1)

119 (7)

Asthenia

42 (2)

102 (6)

Chills

1 (<1)

101 (6)

Chest Pain

36 (2)

65 (4)

Influenza Like Illness

7 (<1)

51 (3)

Pain

24 (1)

23 (1)

Spinal Pain

21 (1)

21 (1)

Chest Discomfort

6 (<1)

27 (2)

Axillary Pain

17 (<1)

18 (1)

Edema

10 (<1)

23 (1)

Mucosal Inflammation

1 (<1)

18 (1)

Malaise

1 (<1)

18 (1)

Immune System Disorders

Seasonal Allergy

6 (<1)

14 (<1)

Infections and Infestations

#

Nasopharyngitis

65 (4)

192 (11)

Influenza

17 (<1)

95 (6)

Upper Respiratory Tract Inflection

31 (2)

53 (3)

Urinary Tract Infection

19 (1)

54 (3)

Rhinitis

11 (<1)

44 (3)

Bronchitis

25 (1)

36 (2)

Cystitis

15 (<1)

28 (2)

page 29 / 117

Adverse Event Term

Observation Only

trastuzumab

1 year

N = 1744

N = 1682

No. (%)

No. (%)

Sinusitis

7 (<1)

36 (2)

Pharyngitis

12 (<1)

33 (2)

Herpes Zoster

14 (<1)

31 (2)

Low er Respiratory Tract Infection

14 (<1)

17 (1)

Gastroenteritis

10 (<1)

9 (<1)

Oral Herpes

5 (<1)

15 (<1)

Cellulitis

6 (<1)

14 (<1)

Vaginal Infection

10 (<1)

13 (<1)

Ear Infection

6 (<1)

9 (<1)

Localised Infection

18 (1)

Injury, Poisoning and Procedural Complications

Confusion

12 (<1)

13 (<1)

Investigations

Ejection Fraction Decreased

11 (<1)

64 (4)

Weight Increased

23 (1)

42 (2)

Weight Decreased

10 (<1)

10 (<1)

Metabolism and Nutrition Disorders

Decreased Appetite

17 (<1)

25 (1)

Hypercholesterolemia

15 (<1)

16 (<1)

Musculoskeletal and Connective Tissue Disorders

Arthralgia

148 (8)

223 (13)

Back Pain

105 (6)

145 (9)

Pain in Extremity

73 (4)

94 (6)

Musculoskeletal Pain

66 (4)

75 (4)

Myalgia

28 (2)

86 (5)

Muscle Spasms

13 (<1)

68 (4)

Bone Pain

31 (2)

54 (3)

Musculoskeletal Chest Pain

37 (2)

43 (3)

Osteoporosis

29 (2)

30 (2)

Neck Pain

18 (1)

29 (2)

Osteoarthritis

18 (1)

28 (2)

Osteopenia

12 (<1)

19 (1)

Musculoskeletal Stiffness

8 (<1)

14 (<1)

Neoplasms Benign, Malignant and Unspecified (Incl Cysts And Polyps)

Contralateral Breast Cancer

10 (<1)

23 (1)

Uterine Letomyoma

7 (<1)

9 (<1)

Nervous System Disorders

Headache

73 (4)

199 (12)

Dizziness

39 (2)

80 (5)

Paraesthesia

21 (1)

42 (2)

Hypoaesthesia

15 (<1)

25 (1)

Lethargy

8 (<1)

20 (1)

Migraine

3 (<1)

15 (<1)

Peripheral Sensory Neuropathy

6 (<1)

14 (<1)

Pregnancy, Puerperium and Perinatal Conditions

Pregnancy

11 (<1)

22 (1)

Psychiatric Disorders

Depression

59 (3)

87 (5)

Insomnia

49 (3)

94 (6)

Anxiety

32 (2)

56 (3)

Sleep Disorder

5 (<1)

13 (<1)

Renal and Urinary Disorders

Dysuria

3 (<1)

20 (1)

page 30 / 117

Adverse Event Term

Observation Only

trastuzumab

1 year

N = 1744

N = 1682

No. (%)

No. (%)

Reproductive System and Breast Disorders

Breast Pain

26 (1)

36 (2)

Vaginal Haemorrhage

20 (1)

23 (1)

Vulvovaginal Dryness

16 (<1)

23 (1)

Breast Mass

22 (1)

17 (1)

Vaginal Discharge

9 (<1)

15 (<1)

Endometrial Hyperplasia

13 (<1)

17 (1)

Respiratory, Thoracic and Mediastinal Disorders

Cough

61 (3)

116 (7)

Dyspnea

46 (3)

81 (5)

Oropharnygeal Pain

14 (<1)

40 (2)

Epistaxis

3 (<1)

29 (2)

Dyspnea Exertional

16 (<1)

32 (2)

Rhinorrhoea

5 (<1)

27 (2)

Nasal Dryness

1 (<1)

25 (1)

Asthma

7 (<1)

9 (<1)

Skin and Subcutaneous Tissue Disorders

Rash

25 (1)

98 (6)

Onychoclasis

2 (<1)

53 (3)

Nail Disorder

2 (<1)

52 (3)

Pruritus

14 (<1)

58 (3)

Dry Skin

4 (<1)

22 (1)

Erythema

8 (<1)

39 (2)

Alopecia

6 (<1)

18 (1)

Scar Pain

18 (1)

21 (1)

Eczema

9 (<1)

19 (1)

Hyperhidrosis

10 (<1)

17 (1)

Urticaria

4 (<1)

13 (<1)

Acne

3 (<1)

17 (1)

Vascular Disorders

Hot Flush

129 (7)

163 (10)

Hypertension

61 (3)

104 (6)

Lymphoedema

69 (4)

80 (5)

Flushing

10 (<1)

14 (<1)

Hypotension

4 (<1)

14 (<1)

Multiple occurrences of the same adverse even in one individual counted only once.

* 69 out of the total 93 Cardiac Failure Congestive events reported in the 1-year trastuzumab arm occurred w ithin 365

days from randomization.

Serious adverse reactions of cellulitis and erysipelas w ere also reported in the HERA study.

In HERA, after a median follow-up of 12 months, 1 observation and 10 trastuzumab treated

patients experienced hypersensitivity. Eight out of the 10 events were considered related to

trastuzumab treatment.

In total, in the trastuzumab 1 year arm, 124 patients (7%) withdrew from trastuzumab treatment

due to adverse events, and 2 patients (<1%) withdrew from the post-treatment follow-up phase

due to adverse events, based on the withdrawal criteria in the HERA study protocol.

Please see

Table 7 and

page 31 / 117

Table 8 in WARNINGS AND PRECAUTIONS: Cardiovascular, Cardiotoxicity, Early Breast

Cancer for information on the median time to return to baseline

LVEF and stabilizations of LVEF

after 8 years of median follow up in the HERA trial.

Joint Analysis –NSABP Study B-31 and NCCTG Study N9831

(adjuvant concurrent: use of trastuzumab in combination with paclitaxel)

Cardiac failure/dysfunction, pulmonary events, and exacerbation of chemotherapy-induced

neutropenia were the most serious adverse reactions in the two randomized, controlled adjuvant

breast cancer studies (NSABP study B-31 and NCCTG study N9831, see CLINICAL STUDIES).

Please refer to WARNINGS AND PRECAUTIONS section for detailed description of these

reactions and for a description of the incidence and type of cardiac events seen in the Joint

Analysis.

Adverse events according to the National Cancer Institute - Common Terminology Criteria NCI-

CTC v 2.0 classification occurring at a frequency of ≥ 1% for NSABP-B31 and NCCTG N9831,

are summarized in Table 15 and

Table 16 respectively.

Table 15 Adverse Events of Any Grade with Incidence ≥ 1% in Study B-31 (Final Analysis

after Median Follow-up of 8.1 years in the AC - T+H Group) According to NCI-CTC v 2.0

Classification

Adverse Event Term

a

AC - T

(n = 885)

AC - T + H

(n = 1030)

Any

Grade

Grades

3–4

Grade 5

Any

Grade

Grades

3–4

Grade 5

Allergy/immunology

Allergic reaction*

33 (3.7%)

10 (1.1%)

(0.0%)

35 (3.4%)

12 (1.2%)

(0.0%)

Allergic rhinitis

11 (1.2%)

(0.0%)

(0.0%)

29 (2.8%)

(0.0%)

(0.0%)

Blood/bone marrow

Hemoglobin (HGB)*

156 (17.6%)

27 (3.1%)

(0.0%)

209 (20.3%)

33 (3.2%)

(0.0%)

Leukocytes (total WBC)

152 (17.2%)

95 (10.7%)

(0.0%)

201 (19.5%) 103 (10.0%)

(0.0%)

Lymphopenia

43 (4.9%)

27 (3.1%)

(0.0%)

54 (5.2%)

31 (3.0%)

(0.0%)

Neutrophils/granulocytes

112 (12.7%)

88 (9.9%)

(0.0%)

134 (13.0%) 107 (10.4%)

(0.0%)

Platelets

22 (2.5%)

11 (1.2%)

(0.0%)

23 (2.2%)

12 (1.2%)

(0.0%)

Cardiovascular (general)

Cardiac-left ventricular

function*

47 (5.3%)

7 (0.8%)

(0.0%)

151 (14.7%)

35 (3.4%)

(0.0%)

Edema

26 (2.9%)

1 (0.1%)

(0.0%)

50 (4.9%)

(0.0%)

(0.0%)

Hypertension

6 (0.7%)

4 (0.5%)

(0.0%)

25 (2.4%)

17 (1.7%)

(0.0%)

Thrombosis/embolism*

24 (2.7%)

23 (2.6%)

(0.0%)

39 (3.8%)

35 (3.4%)

(0.0%)

Constitutional symptoms

Fatigue*

323 (36.5%)

54 (6.1%)

(0.0%)

426 (41.4%)

58 (5.6%)

(0.0%)

Fever (in the absence of

neutropenia)*

21 (2.4%)

2 (0.2%)

(0.0%)

38 (3.7%)

7 (0.7%)

(0.0%)

Sw eating (diaphoresis)

10 (1.1%)

(0.0%)

(0.0%)

19 (1.8%)

(0.0%)

(0.0%)

Weight gain

5 (0.6%)

1 (0.1%)

(0.0%)

14 (1.4%)

3 (0.3%)

(0.0%)

Dermatology/skin

Alopecia

285 (32.2%)

3 (0.3%)

(0.0%)

354 (34.4%)

2 (0.2%)

(0.0%)

Nail changes

10 (1.1%)

(0.0%)

(0.0%)

30 (2.9%)

1 (0.1%)

(0.0%)

Pruritus

18 (2.0%)

1 (0.1%)

(0.0%)

18 (1.7%)

3 (0.3%)

(0.0%)

Radiation dermatitis

20 (2.3%)

3 (0.3%)

(0.0%)

31 (3.0%)

10 (1.0%)

(0.0%)

Rash/desquamation*

88 (9.9%)

12 (1.4%)

(0.0%)

130 (12.6%)

6 (0.6%)

(0.0%)

Skin-other

14 (1.6%)

2 (0.2%)

(0.0%)

25 (2.4%)

2 (0.2%)

(0.0%)

Wound-infectious

7 (0.8%)

4 (0.5%)

(0.0%)

15 (1.5%)

8 (0.8%)

(0.0%)

page 32 / 117

Adverse Event Term

a

AC - T

(n = 885)

AC - T + H

(n = 1030)

Any

Grade

Grades

3–4

Grade 5

Any

Grade

Grades

3–4

Grade 5

Endocrine

Hot flashes/flushes

157 (17.7%)

2 (0.2%)

(0.0%)

197 (19.1%)

(0.0%)

(0.0%)

Gastrointestinal

Anorexia*

71 (8.0%)

12 (1.4%)

(0.0%)

64 (6.2%)

11 (1.1%)

(0.0%)

Constipation*

81 (9.2%)

7 (0.8%)

(0.0%)

123 (11.9%)

5 (0.5%)

(0.0%)

Dehydration

22 (2.5%)

7 (0.8%)

(0.0%)

28 (2.7%)

5 (0.5%)

(0.0%)

Diarrhea w ithout prior

colostomy*

83 (9.4%)

23 (2.6%)

(0.0%)

112 (10.9%)

26 (2.5%)

(0.0%)

Dyspepsia

46 (5.2%)

2 (0.2%)

(0.0%)

51 (5.0%)

2 (0.2%)

(0.0%)

GI-other

14 (1.6%)

2 (0.2%)

(0.0%)

24 (2.3%)

4 (0.4%)

(0.0%)

Nausea*

309 (34.9%)

70 (7.9%)

(0.0%)

356 (34.6%)

69 (6.7%)

(0.0%)

Stomatitis/pharyngitis*

151 (17.1%)

6 (0.7%)

(0.0%)

179 (17.4%)

10 (1.0%)

(0.0%)

Taste disturbance (dysgeusia)

13 (1.5%)

(0.0%)

(0.0%)

25 (2.4%)

(0.0%)

(0.0%)

Vomiting*

232 (26.2%)

66 (7.5%)

(0.0%)

247 (24.0%)

64 (6.2%)

(0.0%)

Hemorrhage

Vaginal bleeding

4 (0.5%)

(0.0%)

(0.0%)

18 (1.8%)

(0.0%)

(0.0%)

Hepatic

SGOT (AST) (serum glutamic

oxaloacetic transaminase)*

18 (2.0%)

6 (0.7%)

(0.0%)

27 (2.6%)

5 (0.5%)

(0.0%)

SGPT (ALT) serum glutamic

pyruvic

transaminase *

26 (2.9%)

5 (0.6%)

(0.0%)

33 (3.2%)

5 (0.5%)

(0.0%)

Infection/febrile neutropenia

Febrile neutropenia*

42 (4.7%)

42 (4.7%)

(0.0%)

39 (3.8%)

39 (3.8%)

(0.0%)

Infection*

246 (27.8%) 124 (14.0%)

3 (0.3%)

341 (33.1%) 140 (13.6%)

(0.0%)

Lymphatics

Lymphatics

9 (1.0%)

(0.0%)

(0.0%)

25 (2.4%)

(0.0%)

(0.0%)

Metabolic/laboratory

Hyperglycemia

118 (13.3%)

46 (5.2%)

(0.0%)

139 (13.5%)

49 (4.8%)

(0.0%)

Hypoglycemia

6 (0.7%)

2 (0.2%)

(0.0%)

12 (1.2%)

6 (0.6%)

(0.0%)

Musculoskeletal

Joint, muscle, bone-other

11 (1.2%)

2 (0.2%)

(0.0%)

19 (1.8%)

2 (0.2%)

(0.0%)

Neurology

Ataxia (incoordination)

1 (0.1%)

(0.0%)

(0.0%)

11 (1.1%)

2 (0.2%)

(0.0%)

Dizziness/lightheadedness

30 (3.4%)

5 (0.6%)

(0.0%)

36 (3.5%)

6 (0.6%)

(0.0%)

Insomnia

35 (4.0%)

2 (0.2%)

(0.0%)

60 (5.8%)

6 (0.6%)

(0.0%)

Mood alteration-anxiety/agitation

44 (5.0%)

5 (0.6%)

(0.0%)

46 (4.5%)

9 (0.9%)

(0.0%)

Mood alteration-depression

56 (6.3%)

10 (1.1%)

(0.0%)

71 (6.9%)

11 (1.1%)

(0.0%)

Neuropathy-motor*

45 (5.1%)

17 (1.9%)

(0.0%)

51 (5.0%)

16 (1.6%)

(0.0%)

Neuropathy-sensory*

203 (22.9%)

59 (6.7%)

(0.0%)

235 (22.8%)

43 (4.2%)

(0.0%)

Syncope (fainting)

8 (0.9%)

8 (0.9%)

(0.0%)

12 (1.2%)

12 (1.2%)

(0.0%)

Ocular/visual

Dry Eye

13 (1.5%)

(0.0%)

(0.0%)

9 (0.9%)

(0.0%)

(0.0%)

Tearing (w atery eyes)

6 (0.7%)

(0.0%)

(0.0%)

12 (1.2%)

(0.0%)

(0.0%)

Vision-blurred vision

11 (1.2%)

(0.0%)

(0.0%)

22 (2.1%)

(0.0%)

(0.0%)

Pain

Abdominal pain or cramping

25 (2.8%)

12 (1.4%)

(0.0%)

24 (2.3%)

6 (0.6%)

(0.0%)

Arthralgia (joint pain)*

273 (30.8%)

57 (6.4%)

(0.0%)

329 (31.9%)

68 (6.6%)

(0.0%)

Bone pain

46 (5.2%)

14 (1.6%)

(0.0%)

60 (5.8%)

11 (1.1%)

(0.0%)

Chest pain

14 (1.6%)

4 (0.5%)

(0.0%)

36 (3.5%)

4 (0.4%)

(0.0%)

Headache*

80 (9.0%)

20 (2.3%)

(0.0%)

127 (12.3%)

30 (2.9%)

(0.0%)

Myalgia (muscle pain)*

293 (33.1%)

83 (9.4%)

(0.0%)

362 (35.1%)

65 (6.3%)

(0.0%)

Neuropathic pain

11 (1.2%)

4 (0.5%)

(0.0%)

20 (1.9%)

6 (0.6%)

(0.0%)

Pain-other

50 (5.6%)

10 (1.1%)

(0.0%)

78 (7.6%)

10 (1.0%)

(0.0%)

Pulmonary

Cough

9 (1.0%)

1 (0.1%)

(0.0%)

32 (3.0%)

2 (0.2%)

(0.0%)

page 33 / 117

Adverse Event Term

a

AC - T

(n = 885)

AC - T + H

(n = 1030)

Any

Grade

Grades

3–4

Grade 5

Any

Grade

Grades

3–4

Grade 5

Dyspnea (shortness of breath)

63 (7.1%)

21 (2.4%)

(0.0%)

144 (14.0%)

24 (2.3%)

(0.0%)

Pulmonary-other

7 (0.8%)

3 (0.3%)

(0.0%)

15 (1.5%)

4 (0.4%)

(0.0%)

Renal/genitourinary

Dysuria (painful urination)

9 (1.0%)

1 (0.1%)

(0.0%)

11 (1.1%)

1 (0.1%)

(0.0%)

Urinary frequency/urgency

7 (0.8%)

3 (0.3%)

(0.0%)

11 (1.1%)

2 (0.2%)

(0.0%)

Vaginitis (not due to infection)

10 (1.1%)

1 (0.1%)

(0.0%)

4 (0.4%)

1 (0.1%)

(0.0%)

Sexual/reproductive function

Irregular menses (change from

baseline)

35 (4.0%)

27 (3.1%)

(0.0%)

44 (4.3%)

37 (3.6%)

(0.0%)

Vaginal dryness

12 (1.4%)

(0.0%)

(0.0%)

26 (2.5%)

1 (0.1%)

(0.0%)

NCIC CTC terminology

A = doxorubicin; C = cyclophosphamide; GI = gastrointestinal; H = trastuzumab; T = paclitaxel; WBC = w hite blood

cell. Note: Only Grade 3–5 events, treatment-related Grade 2 events, Grade 2–5 cardiac left ventricular dysfunction,

and Grade 2–5 dyspnea w ere collected during and 3 months follow ing protocol treatment.

The term “febrile neutropenia” refers to febrile neutropenia w ith no evidence of infection; decreased neutrophils w ere

not intended to be collected.

* Adverse event term is itemized on the Adverse Event CRF.

Table 16 Adverse Events of Any Grade with Incidence ≥ 1% in Study N9831 (Final

Analysis after Median Follow-up of 8.1 years in the AC - T+H Group) According to NCI-

CTC v 2.0 Classification

Adverse Event Term

a

AC - T

(n = 766)

AC - T + H

(n = 969)

Any

Grade

Grades

3–4

Grade 5

Any

Grade

Grades

3–4 Grade 5

Allergy/immunology

Allergic reaction*

9 (1.2%)

9 (1.2%)

(0.0%)

3 (0.3%)

3 (0.3%)

(0.0%)

Blood/bone marrow

Leukocytes (total WBC)*

59 (7.7%)

58 (7.6%)

1 (0.1%)

82 (8.5%)

82 (8.5%)

(0.0%)

Neutrophils/granulocytes*

209 (27.3%)

208 (27.2%)

1 (0.1%)

286 (29.5%)

286 (29.5%)

(0.0%)

Cardiovascular (arrhythmia)

Palpitations

12 (1.6%)

(0.0%)

(0.0%)

15 (1.5%)

(0.0%)

(0.0%)

Cardiovascular (general)

Cardiac-ischemia/infarction*

9 (1.2%)

7 (0.9%)

(0.0%)

13 (1.3%)

7 (0.7%)

(0.0%)

Cardiac-left ventricular

function*

73 (9.5%)

1 (0.1%)

(0.0%)

219 (22.6%)

21 (2.2%)

(0.0%)

Edema

8 (1.0%)

(0.0%)

(0.0%)

15 (1.5%)

(0.0%)

(0.0%)

Hypertension

7 (0.9%)

3 (0.4%)

(0.0%)

12 (1.2%)

6 (0.6%)

(0.0%)

Thrombosis/embolism*

22 (2.9%)

20 (2.6%)

2 (0.3%)

18 (1.9%)

18 (1.9%)

(0.0%)

Constitutional symptoms

Fatigue*

34 (4.4%)

34 (4.4%)

(0.0%)

41 (4.2%)

41 (4.2%)

(0.0%)

Dermatology/skin

Nail changes*

50 (6.5%)

(0.0%)

(0.0%)

116 (12.0%)

(0.0%)

(0.0%)

Gastrointestinal

Diarrhea w ithout prior

colostomy*

5 (0.7%)

5 (0.7%)

(0.0%)

33 (3.4%)

33 (3.4%)

(0.0%)

Nausea*

40 (5.2%)

40 (5.2%)

(0.0%)

53 (5.5%)

53 (5.5%)

(0.0%)

Vomiting*

39 (5.1%)

39 (5.1%)

(0.0%)

36 (3.7%)

36 (3.7%)

(0.0%)

Infection/febrile neutropenia

Febrile neutropenia*

33 (4.3%)

32 (4.2%)

1 (0.1%)

57 (5.9%)

57 (5.9%)

(0.0%)

Infection*

38 (5.0%)

38 (5.0%)

(0.0%)

71 (7.3%)

70 (7.2%)

1 (0.1%)

Metabolic/laboratory

Hyperglycemia

14 (1.8%)

14 (1.8%)

(0.0%)

9 (0.9%)

9 (0.9%)

(0.0%)

Neurology

page 34 / 117

Adverse Event Term

a

AC - T

(n = 766)

AC - T + H

(n = 969)

Any

Grade

Grades

3–4

Grade 5

Any

Grade

Grades

3–4 Grade 5

Neuropathy-motor*

38 (5.0%)

8 (1.0%)

(0.0%)

42 (4.3%)

13 (1.3%)

(0.0%)

Neuropathy-sensory*

132 (17.2%)

29 (3.8%)

(0.0%)

174 (18.0%)

46 (4.7%)

(0.0%)

Pain

Arthralgia (joint pain)*

75 (9.8%)

10 (1.3%)

(0.0%)

133 (13.7%)

18 (1.9%)

(0.0%)

Chest pain

5 (0.7%)

1 (0.1%)

(0.0%)

13 (1.3%)

5 (0.5%)

(0.0%)

Myalgia (muscle pain)*

62 (8.1%)

10 (1.3%)

(0.0%)

110 (11.4%)

10 (1.0%)

(0.0%)

Pulmonary

Dyspnea (shortness of

breath)

3 (0.4%)

3 (0.4%)

(0.0%)

29 (3.0%)

24 (2.5%)

(0.0%)

Pneumonitis/Pulmonary

infiltrates*

8 (1.0%)

7 (0.9%)

1 (0.1%)

10 (1.0%)

9 (0.9%)

(0.0%)

NCIC CTC terminology

A = doxorubicin; AE = adverse event; C = cyclophosphamide; H = trastuzumab; T = paclitaxel; WBC = w hite blood cell.

Note: Only treatment-related Grade 4 and 5 hematologic toxicities, Grade 3–5 non-hematologic toxicities, Grade 1–5

cardiac toxicities, as w ell as Grade 2–5 arthralgia, myalgia, nail changes, neuropathy–motor, and neuropathy–sensory

adverse events w ere collected during the treatment period. During the post-treatment follow -up period, only Grade 3–5

cardiac ischemia/infarction, thrombosis/embolism,

pneumonitis/pulmonary infiltrates, and lymphatic events w ere

collected.

*Adverse event term is itemized on the Adverse Event CRF.

BCIRG-006

(adjuvant concurrent: use of trastuzumab in combination with docetaxel)

Adverse events according to the National Cancer Institute - Common Terminology Criteria NCI-

CTC v 2.0 classification occurring at a frequency of ≥ 1% for study BCIRG-006 are summarized

in Table 17. For adverse events that could not be classified according to the NCI-CTC, the

Coding Symbols for Thesaurus of Adverse Reaction Terms (COSTART) coding dictionary was

used (see Table 18).

Table 17 Adverse Events of Any Grade with Incidence ≥ 1% in Study BCIRG-006 (5 Year

Follow Up) According to NCI-CTC v 2.0 Classification

Any

Grade

Grade

3 or 4

Any

Grade

Grade

3 or 4

Any

Grade

Grade

3 or 4

NCI-CTC term

AC->T

(n=10 4 1 )

AC->T

(n=10 4 1 )

AC->TH

(n=10 7 7 )

AC->TH

(n=10 7 7 )

TCH

(n=10 5 6 )

TCH

(n=10 5 6 )

Allergy/immunology

Allergic reaction/

hypersensitivity (including

drug fever)

(9.4%)

(1.2%)

(12.3%)

(1.8%)

(14.9%)

(2.7%)

Allergic rhinitis (including

sneezing, nasal stuffiness,

postnasal drip)

(8.0%)

(0.0%)

(12.8%)

(0.0%)

(9.2%)

(0.0%)

Auditory/hearing

Earache (otalgia)

(3.1%)

(0.0%)

(2.8%)

(0.0%)

(1.6%)

(0.0%)

Inner ear/hearing

(2.5%)

(0.1%)

(3.1%)

(0.0%)

(3.2%)

(0.1%)

Blood/bone marrow

Neutrophils/granulocytes

(ANC/AGC)

(2.2%)

(2.0%)

(3.2%)

(2.2%)

(1.9%)

(1.8%)

Cardiovascular (general)

Cardiac left ventricular

function

(2.9%)

(0.6%)

(7.5%)

(2.0%)

(2.6%)

(0.1%)

Edema

(0.0%)

(0.0%)

page 35 / 117

Any

Grade

Grade

3 or 4

Any

Grade

Grade

3 or 4

Any

Grade

Grade

3 or 4

NCI-CTC term

AC->T

(n=10 4 1 )

AC->T

(n=10 4 1 )

AC->TH

(n=10 7 7 )

AC->TH

(n=10 7 7 )

TCH

(n=10 5 6 )

TCH

(n=10 5 6 )

(2.9%)

(3.4%)

(3.1%)

(0.1%)

Hypertension

(3.6%)

(1.2%)

(4.8%)

(2.1%)

(5.8%)

(3.1%)

Hypotension

(1.9%)

(0.1%)

(2.9%)

(0.0%)

(1.8%)

(0.2%)

Pericardial effusion/

pericarditis

(1.3%)

(0.0%)

(1.8%)

(0.0%)

(1.6%)

(0.1%)

Phlebitis (superficial)

(1.3%)

(0.0%)

(2.0%)

(0.0%)

(0.9%)

(0.0%)

Thrombosis/embolism

(1.6%)

(1.5%)

(1.9%)

(1.8%)

(2.8%)

(2.7%)

Cardio vascular

(arrhythmia)

Palpitations

(7.0%)

(0.0%)

(8.2%)

(0.0%)

(9.1%)

(0.0%)

Sinus tachycardia

(4.4%)

(0.4%)

(4.1%)

(0.1%)

(5.2%)

(0.0%)

Supraventricular

arrhythmias

(SVT/atrial

fibrillation/ flutter)

(1.1%)

(0.5%)

(0.7%)

(0.4%)

(0.9%)

(0.5%)

Constitutional symptoms

Fatigue (lethargy, malaise,

asthenia)

(82.4%)

(6.7%)

(84.0%)

(7.4%)

(83.2%)

(7.2%)

Fever (in the absence of

neutropenia, w here

neutropenia is defined as

AGC < 1.0 x 109/l)

(13.8%)

(0.2%)

(15.8%)

(0.5%)

(10.9%)

(0.6%)

Rigors, chills

(5.1%)

(0.0%)

(8.0%)

(0.0%)

(7.1%)

(0.0%)

Sw eating (diaphoresis)

(6.5%)

(0.0%)

(6.1%)

(0.0%)

(6.8%)

(0.0%)

Weight gain

(19.7%)

(1.0%)

(23.5%)

(0.6%)

(24.1%)

(0.9%)

Weight loss

(7.9%)

(0.2%)

(9.3%)

(0.2%)

(6.5%)

(0.3%)

Dermatology/skin

Alopecia

1025

(98.5%)

(0.0%)

1060

(98.4%)

(0.0%)

1016

(96.2%)

(0.2%)

Bruising (in absence of

grade

3 or 4

thrombocytopenia)

(1.6%)

(0.0%)

(1.6%)

(0.0%)

(2.4%)

(0.0%)

Dry skin

(7.1%)

(0.0%)

(8.9%)

(0.0%)

(5.7%)

(0.0%)

Flushing

(4.4%)

(0.0%)

(5.2%)

(0.0%)

(7.2%)

(0.0%)

Hand-foot skin reaction

(8.2%)

(1.9%)

(7.1%)

(1.4%)

(2.8%)

(0.0%)

Injection site reaction

(6.1%)

(0.3%)

(5.7%)

(0.1%)

(7.4%)

(0.2%)

Nail changes

(49.2%)

(0.0%)

(43.8%)

(0.0%)

(28.6%)

(0.0%)

Pigmentation changes

(e.g.,

vitiligo)

(6.2%)

(0.0%)

(6.2%)

(0.0%)

(4.5%)

(0.0%)

Pruritus

(2.8%)

(0.0%)

(3.2%)

(0.1%)

(4.8%)

(0.1%)

page 36 / 117

Any

Grade

Grade

3 or 4

Any

Grade

Grade

3 or 4

Any

Grade

Grade

3 or 4

NCI-CTC term

AC->T

(n=10 4 1 )

AC->T

(n=10 4 1 )

AC->TH

(n=10 7 7 )

AC->TH

(n=10 7 7 )

TCH

(n=10 5 6 )

TCH

(n=10 5 6 )

Radiation dermatitis

(18.0%)

(0.5%)

(17.8%)

(0.8%)

(22.9%)

(0.8%)

Rash/desquamation

(28.3%)

(1.7%)

(34.3%)

(1.3%)

(33.0%)

(0.9%)

Wound- infectious

(2.1%)

(0.4%)

(3.1%)

(0.6%)

(3.6%)

(0.9%)

Wound

Non-infectious

(0.6%)

(0.0%)

(1.0%)

(0.0%)

(1.6%)

(0.0%)

Gastrointestinal

Anorexia

(21.3%)

(0.6%)

(20.8%)

(0.5%)

(22.5%)

(0.6%)

Constipation

(38.0%)

(0.8%)

(36.1%)

(1.4%)

(33.2%)

(0.6%)

Dehydration

(2.9%)

(0.5%)

(3.6%)

(0.4%)

(4.0%)

(0.5%)

Diarrhea patients w ithout

colostomy:

(42.9%)

(3.1%)

(50.9%)

(5.6%)

(62.5%)

(5.4%)

Dyspepsia/

heartburn

(19.7%)

(0.5%)

(24.3%)

(0.3%)

(24.1%)

(0.5%)

Dysphagia, esophagitis,

odynophagia (painful

sw allow ing)

(4.3%)

(0.2%)

(4.2%)

(0.0%)

(3.5%)

(0.1%)

Flatulence

(1.8%)

(0.0%)

(2.1%)

(0.0%)

(1.9%)

(0.0%)

Gastritis

(1.6%)

(0.0%)

(3.2%)

(0.1%)

(2.1%)

(0.0%)

Mouth dryness

(8.2%)

(0.0%)

(5.0%)

(0.0%)

(3.5%)

(0.0%)

Mucositis

(2.1%)

(0.1%)

(2.4%)

(0.2%)

(2.0%)

(0.1%)

Nausea

(87.5%)

(6.0%)

(87.8%)

(5.7%)

(81.8%)

(4.8%)

Proctitis

(2.8%)

(0.0%)

(3.2%)

(0.0%)

(3.7%)

(0.0%)

Salivary gland changes

(1.1%)

(0.0%)

(0.8%)

(0.0%)

(0.7%)

(0.0%)

Sense of smell

(1.3%)

(0.0%)

(1.7%)

(0.0%)

(0.8%)

(0.0%)

Stomatitis/pharyngitis

(oral/pharyngeal

mucositis)

(65.4%)

(3.6%)

(66.6%)

(2.9%)

(53.2%)

(1.4%)

Taste disturbance

(dysgeusia)

(28.6%)

(0.0%)

(28.2%)

(0.0%)

(30.3%)

(0.0%)

Vomiting

(55.4%)

(6.2%)

(57.2%)

(6.7%)

(41.1%)

(3.5%)

Hemorrhage

Epistaxis

(6.1%)

(0.0%)

(13.0%)

(0.0%)

(16.1%)

(0.4%)

Rectal

bleeding/hematochezia

(2.2%)

(0.0%)

(3.3%)

(0.1%)

(2.7%)

(0.1%)

Vaginal bleeding

(3.3%)

(0.2%)

(2.2%)

(0.2%)

(2.3%)

(0.1%)

Endocrine

page 37 / 117

Any

Grade

Grade

3 or 4

Any

Grade

Grade

3 or 4

Any

Grade

Grade

3 or 4

NCI-CTC term

AC->T

(n=10 4 1 )

AC->T

(n=10 4 1 )

AC->TH

(n=10 7 7 )

AC->TH

(n=10 7 7 )

TCH

(n=10 5 6 )

TCH

(n=10 5 6 )

Hot flashes/flushes

(34.2%)

(0.1%)

(35.2%)

(0.2%)

(33.0%)

(0.0%)

Infection/febrile

neutropenia

Catheter-related infection

(1.7%)

(0.7%)

(2.8%)

(1.3%)

(2.5%)

(0.8%)

Febrile neutropenia (fever

unknow n origin w ithout

clinically or

microbiologically

documented infection)

(ANC

< 1.0 x 109/l, fever

38.5°c)

(9.3%)

(9.2%)

(10.9%)

(10.9%)

(9.5%)

(9.5%)

Infection (documented

clinically or

microbiologically)

w ith

grade 3 or 4 neutropenia

(11.4%)

(11.1%)

(12.2%)

(12.0%)

(11.2%)

(11.2%)

Infection w ith unknow n

(11.7%)

(11.5%)

(11.1%)

(10.9%)

(8.2%)

(8.1%)

Infection w ithout

neutropenia

(23.2%)

(3.2%)

(30.3%)

(4.6%)

(23.5%)

(3.5%)

Lymphatics

Lymphatics

(6.5%)

(0.0%)

(6.6%)

(0.3%)

(7.7%)

(0.2%)

Metabolic/laboratory

Hyperglycemia

(7.7%)

(1.7%)

(7.5%)

(1.1%)

(7.5%)

(1.9%)

Hypokalemia

(1.6%)

(0.2%)

(2.0%)

(0.4%)

(2.3%)

(0.6%)

Hypomagnesemia

(0.5%)

(0.0%)

(0.0%)

(0.0%)

(1.1%)

(0.1%)

Musculoskeletal

Muscle w eakness (not due

neuropathy)

(3.5%)

(0.2%)

(3.3%)

(0.3%)

(2.8%)

(0.0%)

Neurology

Cognitive disturbance/

learning problems

(1.0%)

(0.0%)

(0.7%)

(0.0%)

(0.3%)

(0.0%)

Confusion

(1.0%)

(0.0%)

(0.8%)

(0.2%)

(0.6%)

(0.0%)

Dizziness/lightheadedness

(10.9%)

(0.6%)

(14.0%)

(0.6%)

(12.2%)

(0.4%)

Insomnia

(22.5%)

(0.1%)

(25.8%)

(0.5%)

(23.9%)

(0.3%)

Memory loss

(3.6%)

(0.0%)

(3.2%)

(0.1%)

(2.9%)

(0.1%)

Mood alteration- anxiety

agitation

(12.8%)

(0.8%)

(11.7%)

(0.5%)

(9.6%)

(0.4%)

Mood alteration-

depression

(10.4%)

(0.4%)

(12.5%)

(1.2%)

(11.6%)

(0.6%)

Neuropathy-motor

(5.3%)

(0.4%)

(6.3%)

(0.7%)

(4.3%)

(0.3%)

Neuropathy-sensory

(49.1%)

(2.4%)

(50.3%)

(2.3%)

(36.4%)

(0.8%)

Syncope (fainting)

(1.9%)

(1.9%)

(1.9%)

(1.9%)

(1.8%)

(1.8%)

Vertigo

(0.0%)

page 38 / 117

Any

Grade

Grade

3 or 4

Any

Grade

Grade

3 or 4

Any

Grade

Grade

3 or 4

NCI-CTC term

AC->T

(n=10 4 1 )

AC->T

(n=10 4 1 )

AC->TH

(n=10 7 7 )

AC->TH

(n=10 7 7 )

TCH

(n=10 5 6 )

TCH

(n=10 5 6 )

(1.5%)

(3.4%)

(0.3%)

(2.7%)

(0.6%)

Pain

Abdominal pain or

cramping

(17.7%)

(0.7%)

(20.0%)

(0.7%)

(22.4%)

(0.8%)

Arthralgia (joint pain)

(41.9%)

(3.3%)

(46.1%)

(3.2%)

(29.6%)

(1.4%)

Bone pain

(18.1%)

(1.6%)

(20.8%)

(0.9%)

(13.4%)

(0.3%)

Chest pain (non-cardiac

non-pleuritic)

(5.7%)

(0.1%)

(7.3%)

(0.6%)

(6.8%)

(0.3%)

Headache

(29.5%)

(1.1%)

(29.3%)

(1.5%)

(28.8%)

(0.7%)

Myalgia (muscle pain)

(52.9%)

(5.2%)

(55.7%)

(5.3%)

(39.0%)

(1.8%)

Neuropathic pain (e.g.,

pain, neurologic pain,

phantom limb pain, post-

infectious neuralgia, or

painful

neuropathies)

(1.7%)

(0.1%)

(1.5%)

(0.2%)

(0.9%)

(0.1%)

Pulmonary

Cough

(18.2%)

(0.3%)

(18.9%)

(0.3%)

(13.5%)

(0.0%)

Dyspnea (shortness of

breath)

(22.0%)

(1.2%)

(24.5%)

(2.8%)

(21.5%)

(2.2%)

Voice

changes/stridor/larynx

(e.g., hoarseness, loss of

voice, laryngitis)

(1.0%)

(0.1%)

(1.1%)

(0.1%)

(1.0%)

(0.1%)

Ocular/visual

Conjunctivitis

(9.0%)

(0.5%)

(10.4%)

(0.1%)

(4.1%)

(0.0%)

Dry eye

(4.2%)

(0.0%)

(4.9%)

(0.0%)

(2.8%)

(0.0%)

Tearing (w atery eyes)

(20.5%)

(0.0%)

(24.0%)

(0.3%)

(11.7%)

(0.0%)

Vision- blurred vision

(3.4%)

(0.0%)

(4.7%)

(0.2%)

(5.2%)

(0.0%)

Renal/genitourinary

Dysuria (painful urination)

(2.4%)

(0.0%)

(4.5%)

(0.0%)

(5.3%)

(0.1%)

Incontinence

(0.3%)

(0.0%)

(0.9%)

(0.1%)

(1.4%)

(0.0%)

Urinary

frequency/urgency

(2.5%)

(0.0%)

(3.2%)

(0.0%)

(2.4%)

(0.0%)

Vaginitis (not due to

infection)

(1.6%)

(0.0%)

(1.5%)

(0.0%)

(1.3%)

1 (0.1%)

Sexual/reproductive

function

Irregular menses (change

from baseline)

(35.7%)

(27.2%)

(32.4%)

(24.3%)

(36.3%)

(26.8%)

Libido

(0.6%)

(0.0%)

(0.8%)

(0.0%)

(1.0%)

(0.0%)

Vaginal dryness

(3.2%)

(0.0%)

(4.1%)

(0.0%)

(4.6%)

(0.0%)

page 39 / 117

Any

Grade

Grade

3 or 4

Any

Grade

Grade

3 or 4

Any

Grade

Grade

3 or 4

NCI-CTC term

AC->T

(n=10 4 1 )

AC->T

(n=10 4 1 )

AC->TH

(n=10 7 7 )

AC->TH

(n=10 7 7 )

TCH

(n=10 5 6 )

TCH

(n=10 5 6 )

A=doxorubicin; C=cyclophosphamide;

H=trastuzumab; T =docetaxel; C (in TCH)=carboplatin

Note: In the BCIRG-006

study, all grade hematological

and non-hematological

AEs, and cardiac AEs w ere collected,

as w ell as laboratory data.

Table 18 Adverse Events of Any Grade with Incidence ≥ 1% in Study BCIRG-006 (5 Year

Follow Up) According to COSTART Classification

Any

Grade

Grade 3

or 4

Any

Grade

Grade 3

or 4

Any

Grade

Grade 3

or 4

COSTART term

AC->T

(n=10 4 1 )

AC->T

(n=10 4 1 )

AC->TH

(n=10 7 7 )

AC->TH

(n=10 7 7 )

TCH

(n=10 5 6 )

TCH

(n=10 5 6 )

Body as a whole

Accidental injury

19 (1.8%)

2 (0.2%)

18 (1.7%)

1 (0.1%)

20 (1.9%)

3 (0.3%)

Back pain

83 (8.0%)

3 (0.3%)

133 (12.3%)

12 (1.1%)

97 (9.2%)

5 (0.5%)

Chest pain

13 (1.2%)

1 (0.1%)

14 (1.3%)

(0.0%)

10 (0.9%)

1 (0.1%)

Cyst

13 (1.2%)

1 (0.1%)

12 (1.1%)

1 (0.1%)

13 (1.2%)

1 (0.1%)

Face edema

12 (1.2%)

(0.0%)

16 (1.5%)

(0.0%)

12 (1.1%)

(0.0%)

Fever

32 (3.1%)

7 (0.7%)

30 (2.8%)

2 (0.2%)

22 (2.1%)

4 (0.4%)

Flu syndrome

33 (3.2%)

(0.0%)

33 (3.1%)

(0.0%)

29 (2.7%)

(0.0%)

Injection site pain

23 (2.2%)

(0.0%)

39 (3.6%)

(0.0%)

40 (3.8%)

1 (0.1%)

Neck pain

14 (1.3%)

1 (0.1%)

13 (1.2%)

(0.0%)

16 (1.5%)

(0.0%)

Pain

228 (21.9%)

5 (0.5%)

257 (23.9%)

8 (0.7%)

208 (19.7%)

3 (0.3%)

Cardiac adverse events

(body

as a whole)

Chest pain

7 (0.7%)

(0.0%)

16 (1.5%)

(0.0%)

16 (1.5%)

(0.0%)

Cardiac adverse events

(cardiovascular

system)

Cardiomegaly

7 (0.7%)

(0.0%)

18 (1.7%)

(0.0%)

9 (0.9%)

(0.0%)

Cardiovascular disorder

16 (1.5%)

1 (0.1%)

25 (2.3%)

(0.0%)

16 (1.5%)

1 (0.1%)

Hemorrhage

19 (1.8%)

(0.0%)

11 (1.0%)

2 (0.2%)

9 (0.9%)

2 (0.2%)

Tachycardia

7 (0.7%)

(0.0%)

18 (1.7%)

(0.0%)

14 (1.3%)

2 (0.2%)

Digestive system

Anorexia

14 (1.3%)

(0.0%)

12 (1.1%)

(0.0%)

16 (1.5%)

(0.0%)

Dyspepsia

7 (0.7%)

(0.0%)

10 (0.9%)

(0.0%)

17 (1.6%)

(0.0%)

Esophagitis

20 (1.9%)

2 (0.2%)

8 (0.7%)

(0.0%)

12 (1.1%)

(0.0%)

Flatulence

16 (1.5%)

(0.0%)

24 (2.2%)

(0.0%)

22 (2.1%)

(0.0%)

Gum hemorrhage

1 (0.1%)

(0.0%)

14 (1.3%)

(0.0%)

5 (0.5%)

(0.0%)

Rectal disorder

17 (1.6%)

(0.0%)

23 (2.1%)

1 (0.1%)

28 (2.7%)

2 (0.2%)

Hemic and lymphatic system

Lymphedema

21 (2.0%)

(0.0%)

23 (2.1%)

1 (0.1%)

28 (2.7%)

(0.0%)

Metabolic and nutritional

disorders

Edema

4 (0.4%)

(0.0%)

6 (0.6%)

(0.0%)

13 (1.2%)

(0.0%)

Peripheral edema

349 (33.5%)

4 (0.4%)

395 (36.7%)

4 (0.4%)

346 (32.8%)

2 (0.2%)

Musculoskeletal system

Arthralgia

19 (1.8%)

(0.0%)

20 (1.9%)

(0.0%)

24 (2.3%)

1 (0.1%)

Joint disorder

9 (0.9%)

(0.0%)

7 (0.6%)

1 (0.1%)

10 (0.9%)

1 (0.1%)

Osteoporosis

6 (0.6%)

(0.0%)

11 (1.0%)

1 (0.1%)

12 (1.1%)

1 (0.1%)

Nervous system

Hypertonia

6 (0.6%)

(0.0%)

11 (1.0%)

(0.0%)

16 (1.5%)

(0.0%)

Leg cramps

8 (0.8%)

(0.0%)

13 (1.2%)

(0.0%)

7 (0.7%)

(0.0%)

Neuropathy

8 (0.8%)

1 (0.1%)

10 (0.9%)

(0.0%)

9 (0.9%)

2 (0.2%)

Tw itching

7 (0.7%)

(0.0%)

13 (1.2%)

(0.0%)

26 (2.5%)

(0.0%)

Respiratory system

page 40 / 117

Any

Grade

Grade 3

or 4

Any

Grade

Grade 3

or 4

Any

Grade

Grade 3

or 4

COSTART term

AC->T

(n=10 4 1 )

AC->T

(n=10 4 1 )

AC->TH

(n=10 7 7 )

AC->TH

(n=10 7 7 )

TCH

(n=10 5 6 )

TCH

(n=10 5 6 )

Pharyngitis

71 (6.8%)

(0.0%)

83 (7.7%)

(0.0%)

55 (5.2%)

2 (0.2%)

Rhinitis

111 (10.7%)

1 (0.1%)

142 (13.2%)

1 (0.1%)

108 (10.2%)

(0.0%)

Sinusitis

18 (1.7%)

(0.0%)

21 (1.9%)

1 (0.1%)

22 (2.1%)

1 (0.1%)

Skin and appendages

Acne

11 (1.1%)

(0.0%)

28 (2.6%)

(0.0%)

33 (3.1%)

(0.0%)

Herpes simplex

20 (1.9%)

1 (0.1%)

27 (2.5%)

4 (0.4%)

19 (1.8%)

1 (0.1%)

Nail disorder

11 (1.1%)

(0.0%)

5 (0.5%)

(0.0%)

3 (0.3%)

(0.0%)

Pruritus

10 (1.0%)

(0.0%)

16 (1.5%)

1 (0.1%)

16 (1.5%)

(0.0%)

Skin and appendages

Rash

38 (3.7%)

1 (0.1%)

55 (5.1%)

(0.0%)

42 (4.0%)

1 (0.1%)

Skin disorder

6 (0.6%)

(0.0%)

13 (1.2%)

(0.0%)

11 (1.0%)

(0.0%)

Special senses

Abnormal vision

9 (0.9%)

(0.0%)

14 (1.3%)

(0.0%)

13 (1.2%)

(0.0%)

Conjunctivitis

17 (1.6%)

(0.0%)

10 (0.9%)

(0.0%)

2 (0.2%)

(0.0%)

Eye pain

16 (1.5%)

(0.0%)

15 (1.4%)

(0.0%)

16 (1.5%)

(0.0%)

Urogenital system

Breast pain

53 (5.1%)

(0.0%)

57 (5.3%)

1 (0.1%)

61 (5.8%)

2 (0.2%)

Leukorrhea

16 (1.5%)

(0.0%)

26 (2.4%)

(0.0%)

19 (1.8%)

(0.0%)

The toxicity profile of trastuzumab in all four adjuvant trials appears to be similar. Cardiac

dysfunction is the main concern with trastuzumab treatment (see WARNINGS AND

PRECAUTIONS).

Metastatic Breast Cancer (MBC)

In clinical trials conducted prior to marketing, a total of 958 patients received trastuzumab alone

or in combination with chemotherapy. Data in

Table 20 are based on the experience with the recommended dosing regimen for trastuzumab in

the randomized controlled clinical trial in 234 patients who received trastuzumab in combination

with chemotherapy and the open-label study of trastuzumab as a single agent in 213 patients

with HER2-overexpressing MBC.

Table 19 Adverse Events Occurring in ≥ 1% of Patients in Study H0649g

(up to First

Disease Progression on Study)

Adverse event term

Single Agent

(n=213)

Body as a whole

Abdomen enlarged

3 (1.4%)

Abdominal pain

47 (22.1%)

Accidental injury

12 (5.6%)

Allergic reaction

4 (1.9%)

Ascites

9 (4.2%)

Asthenia

100 (46.9%)

Back pain

44 (20.7%)

Carcinoma

9 (4.2%)

Cellulitis

3 (1.4%)

Chest pain

46 (21.6%)

Chills

76 (35.7%)

Chills and fever

7 (3.3%)

Face edema

4 (1.9%)

Fever

83 (39.0%)

page 41 / 117

Adverse event term

Single Agent

(n=213)

Flu syndrome

24 (11.3%)

Headache

56 (26.3%)

Infection

42 (19.7%)

Injection site inflammation

3 (1.4%)

Injection site pain

4 (1.9%)

Malaise

7 (3.3%)

Moniliasis

4 (1.9%)

Mucous membrane disorder

4 (1.9%)

Neck pain

11 (5.2%)

Neoplasm

4 (1.9%)

Pain

105 (49.3%)

Pelvic pain

8 (3.8%)

Procedure

4 (1.9%)

Sepsis

3 (1.4%)

Cardiovascular

Cardiovascular disorder

3 (1.4%)

Congestive heart failure

4 (1.9%)

Heart arrest

3 (1.4%)

Hemorrhage

3 (1.4%)

Hypertension

4 (1.9%)

Hypotension

5 (2.3%)

Migraine

4 (1.9%)

Palpitation

4 (1.9%)

Tachycardia

13 (6.1%)

Vascular disorder

8 (3.8%)

Vasodilatation

16 (7.5%)

Digestive

Anorexia

28 (13.1%)

Constipation

27 (12.7%)

Diarrhea

57 (26.8%)

Dry mouth

6 (2.8%)

Dyspepsia

17 (8.0%)

Dysphagia

5 (2.3%)

Flatulence

10 (4.7%)

Gastroenteritis

3 (1.4%)

Gastrointestinal disorder

4 (1.9%)

Hepatic failure

4 (1.9%)

Jaundice

6 (2.8%)

Liver tenderness

7 (3.3%)

Mouth ulceration

4 (1.9%)

Nausea

79 (37.1%)

Nausea and vomiting

16 (7.5%)

Oral moniliasis

4 (1.9%)

Rectal disorder

4 (1.9%)

Stomatitis

9 (4.2%)

Vomiting

60 (28.2%)

Hemic and lymphatic

Anemia

9 (4.2%)

Ecchymosis

7 (3.3%)

Hypochromic anemia

3 (1.4%)

Leukopenia

7 (3.3%)

Lymphadenopathy

3 (1.4%)

Lymphedema

4 (1.9%)

Metabolic and nutritional disorders

Dehydration

5 (2.3%)

page 42 / 117

Adverse event term

Single Agent

(n=213)

Edema

17 (8.0%)

Hypercalcemia

3 (1.4%)

Hypokalemia

8 (3.8%)

Hypomagnesemia

3 (1.4%)

Peripheral edema

21 (9.9%)

Serum glutamic pyruvic transaminase (SGPT) increased

3 (1.4%)

Weight gain

4 (1.9%)

Weight loss

7 (3.3%)

Musculoskeletal

Arthralgia

13 (6.1%)

Bone pain

18 (8.5%)

Joint disorder

3 (1.4%)

Leg cramps

14 (6.6%)

Myalgia

16 (7.5%)

Myasthenia

6 (2.8%)

Nervous

Abnormal gait

5 (2.3%)

Amnesia

3 (1.4%)

Anxiety

28 (13.1%)

Circumoral paresthesia

3 (1.4%)

Confusion

4 (1.9%)

Convulsion

4 (1.9%)

Depression

16 (7.5%)

Dizziness

28 (13.1%)

Hypertonia

9 (4.2%)

Insomnia

35 (16.4%)

Nervousness

6 (2.8%)

Neuropathy

4 (1.9%)

Paralysis

3 (1.4%)

Paresthesia

19 (8.9%)

Peripheral neuritis

4 (1.9%)

Somnolence

15 (7.0%)

Speech disorder

3 (1.4%)

Thinking abnormal

3 (1.4%)

Tremor

4 (1.9%)

Vertigo

3 (1.4%)

Respiratory

Asthma

13 (6.1%)

Bronchitis

7 (3.3%)

Cough increased

60 (28.2%)

Dyspnea

49 (23.0%)

Epistaxis

12 (5.6%)

Laryngitis

3 (1.4%)

Lung disorder

17 (8.0%)

Pharyngitis

28 (13.1%)

Pleural effusion

19 (8.9%)

Pneumonia

3 (1.4%)

Pneumothorax

4 (1.9%)

Rhinitis

33 (15.5%)

Sinusitis

25 (11.7%)

Voice alteration

6 (2.8%)

Skin and appendages

Acne

4 (1.9%)

Alopecia

3 (1.4%)

Dry skin

4 (1.9%)

page 43 / 117

Adverse event term

Single Agent

(n=213)

Herpes simplex

5 (2.3%)

Herpes zoster

4 (1.9%)

Nail disorder

4 (1.9%)

Pruritus

24 (11.3%)

Rash

30 (14.1%)

Skin benign neoplasm

3 (1.4%)

Skin ulcer

3 (1.4%)

Sw eating

8 (3.8%)

Urticarial

4 (1.9%)

Special senses

Abnormal vision

3 (1.4%)

Amblyopia

9 (4.2%)

Conjunctivitis

5 (2.3%)

Diplopia

4 (1.9%)

Ear disorder

5 (2.3%)

Ear pain

5 (2.3%)

Taste perversion

5 (2.3%)

Urogenital

Breast carcinoma

11 (5.2%)

Breast pain

15 (7.0%)

Dysuria

8 (3.8%)

Hematuria

3 (1.4%)

Urinary frequency

7 (3.3%)

Urinary tract infection

7 (3.3%)

Vaginitis

4 (1.9%)

Table 20 Adverse Events Occurring in ≥ 1% of Patients in Study H0648g (up to First

Disease Progression on Study)

Adverse Event

Term

Trastuzumab

+ AC

AC Alone

Trastuzumab

+ Paclitaxel

Paclitaxel

Alone

(N=143)

(N=135)

(N=91)

(N=95)

Body as a whole

Abdomen enlarged

2 (1.4%)

1 (0.7%)

1 (1.1%)

1 (1.1%)

Abdominal pain

33 (23.1%)

25 (18.5%)

31 (34.1%)

21 (22.1%)

Abscess

2 (1.4%)

1 (0.7%)

(0.0%)

(0.0%)

Accidental injury

13 (9.1%)

6 (4.4%)

12 (13.2%)

3 (3.2%)

Allergic reaction

6 (4.2%)

3 (2.2%)

7 (7.7%)

2 (2.1%)

Anaphylactoid

reaction

(0.0%)

(0.0%)

1 (1.1%)

(0.0%)

Ascites

3 (2.1%)

6 (4.4%)

(0.0%)

3 (3.2%)

Asthenia

78 (54.5%)

74 (54.8%)

56 (61.5%)

54 (56.8%)

Back pain

39 (27.3%)

21 (15.6%)

33 (36.3%)

29 (30.5%)

Carcinoma

6 (4.2%)

12 (8.9%)

7 (7.7%)

6 (6.3%)

Cellulitis

2 (1.4%)

3 (2.2%)

3 (3.3%)

5 (5.3%)

Chest pain

29 (20.3%)

28 (20.7%)

27 (29.7%)

26 (27.4%)

Chest pain

substernal

3 (2.1%)

(0.0%)

(0.0%)

1 (1.1%)

Chills

50 (35.0%)

15 (11.1%)

38 (41.8%)

4 (4.2%)

Chills and fever

3 (2.1%)

1 (0.7%)

5 (5.5%)

4 (4.2%)

Cyst

2 (1.4%)

(0.0%)

1 (1.1%)

(0.0%)

Face edema

2 (1.4%)

(0.0%)

4 (4.4%)

6 (6.3%)

Facial pain

1 (0.7%)

(0.0%)

1 (1.1%)

(0.0%)

Fever

80 (55.9%)

45 (33.3%)

43 (47.3%)

22 (23.2%)

Flu syndrome

17 (11.9%)

8 (5.9%)

11 (12.1%)

5 (5.3%)

Headache

63 (44.1%)

42 (31.1%)

33 (36.3%)

27 (28.4%)

Hydrocephalus

(0.0%)

(0.0%)

(0.0%)

1 (1.1%)

Hypothermia

(0.0%)

(0.0%)

1 (1.1%)

(0.0%)

page 44 / 117

Adverse Event

Term

Trastuzumab

+ AC

AC Alone

Trastuzumab

+ Paclitaxel

Paclitaxel

Alone

(N=143)

(N=135)

(N=91)

(N=95)

Immune system

disorder

1 (0.7%)

(0.0%)

(0.0%)

(0.0%)

Infection

67 (46.9%)

41 (30.4%)

42 (46.2%)

26 (27.4%)

Infection site edema

3 (2.1%)

1 (0.7%)

2 (2.2%)

(0.0%)

Injection site

hemorrhage

1 (0.7%)

1 (0.7%)

1 (1.1%)

(0.0%)

Injection site

hyperse ns itiv ity

1 (0.7%)

(0.0%)

(0.0%)

1 (1.1%)

Injection site

inflammation

12 (8.4%)

3 (2.2%)

3 (3.3%)

2 (2.1%)

Injection site pain

8 (5.6%)

4 (3.0%)

4 (4.4%)

5 (5.3%)

Injection site

reaction

6 (4.2%)

1 (0.7%)

6 (6.6%)

1 (1.1%)

Lab test abnormal

(0.0%)

(0.0%)

(0.0%)

1 (1.1%)

Le syndrome

1 (0.7%)

(0.0%)

(0.0%)

(0.0%)

Malaise

4 (2.8%)

7 (5.2%)

3 (3.3%)

4 (4.2%)

Moniliasis

3 (2.1%)

3 (2.2%)

1 (1.1%)

1 (1.1%)

Mucous membrane

disorder

31 (21.7%)

25 (18.5%)

10 (11.0%)

7 (7.4%)

Neck pain

15 (10.5%)

11 (8.1%)

8 (8.8%)

5 (5.3%)

Neck rigidity

3 (2.1%)

(0.0%)

(0.0%)

3 (3.2%)

Necrosis

1 (0.7%)

(0.0%)

(0.0%)

(0.0%)

Neoplasm

5 (3.5%)

3 (2.2%)

3 (3.3%)

1 (1.1%)

Pain

82 (57.3%)

56 (41.5%)

55 (60.4%)

58 (61.1%)

Pelvic pain

1 (0.7%)

2 (1.5%)

4 (4.4%)

2 (2.1%)

Photosensitivity

reaction

2 (1.4%)

(0.0%)

(0.0%)

(0.0%)

Procedure

11 (7.7%)

5 (3.7%)

5 (5.5%)

2 (2.1%)

Radiation injury

(0.0%)

2 (1.5%)

1 (1.1%)

2 (2.1%)

Reaction

unevaluable

14 (9.8%)

9 (6.7%)

4 (4.4%)

2 (2.1%)

Sepsis

10 (7.0%)

9 (6.7%)

4 (4.4%)

1 (1.1%)

Sudden death

(0.0%)

1 (0.7%)

(0.0%)

(0.0%)

Angina pectoris

3 (2.14%)

(0.0%)

(0.0%)

(0.0%)

Arrhythmia

1 (0.7%)

2 (1.5%)

(0.0%)

2 (2.1%)

Atrial fibrillation

(0.0%)

1 (0.7%)

1 (1.1%)

2 (2.1%)

Atrial flutter

(0.0%)

1 (0.7%)

(0.0%)

(0.0%)

Bradycardia

1 (0.7%)

1 (0.7%)

(0.0%)

(0.0%)

Cardiomegaly

2 (1.4%)

1 (0.7%)

(0.0%)

(0.0%)

Cardiomyopathy

10 (7.0%)

2 (1.5%)

1 (1.1%)

(0.0%)

Cardiovascular

disorder

3 (2.1%)

7 (5.2%)

3 (3.3%)

1 (1.1%)

Cerebrovascular

accident

1 (0.7%)

1 (0.7%)

(0.0%)

(0.0%)

Congestive heart

failure

17 (11.9%)

2 (1.5%)

2 (2.2%)

1 (1.1%)

Deep

thrombophlebitis

4 (2.8%)

1 (0.7%)

1 (1.1%)

1 (1.1%)

Electroc ardiogram

abnormal

1 (0.7%)

(0.0%)

(0.0%)

(0.0%)

Endocarditis

(0.0%)

(0.0%)

(0.0%)

1 (1.1%)

Heart arrest

(0.0%)

1 (0.7%)

1 (1.1%)

2 (2.1%)

Heart failure

1(0.7%)

1 (0.7%)

2 (2.2%)

(0.0%)

Hemorrhage

2 (1.4%)

1 (0.7%)

3 (3.3%)

(0.0%)

Hypertension

5 (3.5%)

4 (3.0%)

5 (5.5%)

4 (4.2%)

Hypotension

10 (7.0%)

5 (3.7%)

2 (2.2%)

3 (3.2%)

Left heart failure

14 (9.8%)

7 (5.2%)

5 (5.5%)

(0.0%)

Migraine

(0.0%)

2 (1.5%)

1 (1.1%)

3 (3.2%)

page 45 / 117

Adverse Event

Term

Trastuzumab

+ AC

AC Alone

Trastuzumab

+ Paclitaxel

Paclitaxel

Alone

(N=143)

(N=135)

(N=91)

(N=95)

Myocardial ischemia

(0.0%)

(0.0%)

1 (1.1%)

(0.0%)

Pallor

7 (4.9%)

2 (1.5%)

1 (1.1%)

2 (2.1%)

Palpitation

8 (5.6%)

5 (3.7%)

4 (4.4%)

2 (2.1%)

Pericardial effusion

1 (0.7%)

1 (0.7%)

(0.0%)

(0.0%)

Peripheral vascular

disorder

(0.0%)

(0.0%)

2 (2.2%)

3 (3.2%)

Phlebitis

3 (2.1%)

1 (0.7%)

1 (1.1%)

1 (1.1%)

Postural hypotension

4 (2.8%)

2 (1.5%)

1 (1.1%)

1 (1.1%)

Pulmonary embolus

(0.0%)

(0.0%)

1 (1.1%)

(0.0%)

Shock

(0.0%)

(0.0%)

(0.0%)

1 (1.1%)

Sinus bradycardia

(0.0%)

1 (0.7%)

(0.0%)

(0.0%)

Syncope

4 (2.8%)

3 (2.2%)

4 (4.4%)

3 (3.2%)

Tachycardia

14 (9.8%)

7 (5.2%)

11 (12.1%)

4 (4.2%)

Thrombophlebitis

2 (1.4%)

2 (1.5%)

(0.0%)

(0.0%)

Thrombosis

3 (2.1%)

(0.0%)

2 (2.2%)

(0.0%)

Varicose vein

(0.0%)

1 (0.7%)

(0.0%)

(0.0%)

Vascular disorder

9 (6.3%)

7 (5.2%)

2 (2.2%)

2 (2.1%)

Vasodilatation

25 (17.5%)

22 (16.3%)

20 (22.0%)

19 (20.0%)

Ventricular

fibrillation

(0.0%)

1 (0.7%)

(0.0%)

(0.0%)

Ventricular

tachycardia

1 (0.7%)

(0.0%)

(0.0%)

(0.0%)

Digestive

Abnormal stools

2 (1.4%)

1 (0.7%)

2 (2.2%)

(0.0%)

Anorexia

44 (30.8%)

35 (25.9%)

22 (24.2%)

15 (15.8%)

Cheilitis

1 (0.7%)

1 (0.7%)

1 (1.1%)

(0.0%)

Cholelithiasis

1 (0.7%)

(0.0%)

(0.0%)

(0.0%)

Cirrhosis of liver

(0.0%)

1 (0.7%)

(0.0%)

(0.0%)

Colitis

3 (2.1%)

(0.0%)

(0.0%)

1 (1.1%)

Constipation

51 (35.7%)

38 (28.1%)

23 (25.3%)

26 (27.4%)

Diarrhea

64 (44.8%)

34 (25.2%)

41 (45.1%)

28 (29.5%)

Dry mouth

9 (6.3%)

12 (8.9%)

7 (7.7%)

5 (5.3%)

Dyspepsia

32 (22.4%)

27 (20.0%)

16 (17.6%)

15 (15.8%)

Dysphagia

11 (7.7%)

5 (3.7%)

3 (3.3%)

2 (2.1%)

Eructation

2 (1.4%)

(0.0%)

(0.0%)

(0.0%)

Esophageal stenosis

1 (0.7%)

(0.0%)

(0.0%)

(0.0%)

Esophageal ulcer

1 (0.7%)

(0.0%)

(0.0%)

1 (1.1%)

Esophagitis

2 (1.4%)

8 (5.9%)

(0.0%)

2 (2.1%)

Fecal impaction

(0.0%)

1 (0.7%)

(0.0%)

(0.0%)

Fecal incontinence

(0.0%)

1 (0.7%)

3 (3.3%)

(0.0%)

Flatulence

5 (3.5%)

8 (5.9%)

1 (1.1%)

5 (5.3%)

Gastritis

3 (2.1%)

4 (3.0%)

3 (3.3%)

(0.0%)

Gastroenteritis

2 (1.4%)

5 (3.7%)

2 (2.2%)

(0.0%)

Gastrointestinal

carcinoma

(0.0%)

1 (0.7%)

(0.0%)

(0.0%)

Gastrointestinal

disorder

7 (4.9%)

5 (3.7%)

5 (5.5%)

2 (2.1%)

Gastrointestinal

hemorrhage

3 (2.1%)

2 (1.5%)

2 (2.2%)

2 (2.1%)

Gingivitis

4 (2.8%)

2 (1.5%)

2 (2.2%)

(0.0%)

Glossitis

3 (2.1%)

2 (1.5%)

(0.0%)

(0.0%)

Gum hemorrhage

3 (2.1%)

(0.0%)

(0.0%)

(0.0%)

Hematemesis

1 (0.7%)

1 (0.7%)

1 (1.1%)

1 (1.1%)

Hepatic failure

(0.0%)

1 (0.7%)

1 (1.1%)

3 (3.2%)

Hepatic neoplasia

(0.0%)

1 (0.7%)

(0.0%)

(0.0%)

Hepatitis

1 (0.7%)

(0.0%)

1 (1.1%)

(0.0%)

Hepatomegaly

2 (1.4%)

1 (0.7%)

3 (3.3%)

1 (1.1%)

page 46 / 117

Adverse Event

Term

Trastuzumab

+ AC

AC Alone

Trastuzumab

+ Paclitaxel

Paclitaxel

Alone

(N=143)

(N=135)

(N=91)

(N=95)

Hepatosplenomegaly

(0.0%)

1 (0.7%)

(0.0%)

(0.0%)

Ileus

(0.0%)

(0.0%)

(0.0%)

1 (1.1%)

Increased appetite

(0.0%)

(0.0%)

2 (2.2%)

1 (1.1%)

Increased salivation

3 (2.1%)

(0.0%)

(0.0%)

(0.0%)

Intestinal

obstructio n

(0.0%)

1 (0.7%)

(0.0%)

1 (1.1%)

Jaundice

(0.0%)

1 (0.7%)

1 (1.1%)

4 (4.2%)

Liver damage

(0.0%)

(0.0%)

(0.0%)

1 (1.1%)

Liver function tests

abnormal

2 (1.4%)

(0.0%)

(0.0%)

1 (1.1%)

Liver tenderness

1 (0.7%)

2 (1.5%)

2 (2.2%)

1 (1.1%)

Melena

(0.0%)

1 (0.7%)

1 (1.1%)

1 (1.1%)

Mouth ulceration

17 (11.9%)

19 (14.1%)

4 (4.4%)

1 (1.1%)

Nausea

109 (76.2%)

107 (79.3%)

46 (50.5%)

46 (48.4%)

Nausea and

vomiting

26 (18.2%)

12 (8.9%)

13 (14.3%)

11 (11.6%)

Oral moniliasis

5 (3.5%)

6 (4.4%)

4 (4.4%)

6 (6.3%)

Periodontal abscess

1 (0.7%)

(0.0%)

3 (3.3%)

(0.0%)

Pseudomembranous

colitis

1 (0.7%)

(0.0%)

(0.0%)

(0.0%)

Rectal disorder

10 (7.0%)

8 (5.9%)

6 (6.6%)

(0.0%)

Rectal hemorrhage

6 (4.2%)

1 (0.7%)

4 (4.4%)

1 (1.1%)

Stomach ulcer

1 (0.7%)

(0.0%)

1 (1.1%)

(0.0%)

Stomatitis

43 (30.1%)

42 (31.1%)

9 (9.9%)

7 (7.4%)

Tenesmus

4 (2.8%)

1 (0.7%)

(0.0%)

(0.0%)

Thirst

3 (2.1%)

1 (0.7%)

(0.0%)

1 (1.1%)

Tongue

discolor ati o n

1 (0.7%)

(0.0%)

(0.0%)

(0.0%

Tongue disorder

2 (1.4%)

7 (5.2%)

1 (1.1%)

(0.0%)

Tooth discoloration

(0.0%)

(0.0%)

1 (1.1%)

(0.0%)

Tooth disorder

2 (1.4%)

1 (0.7%)

1 (1.1%)

(0.0%)

Ulcerative stomatitis

1 (0.7%)

2 (1.5%)

(0.0%)

2 (2.1%)

Vomiting

76 (53.1%)

66 (48.9%)

34 (37.4%)

27 (28.4%)

Endocrine

Cushings syndrome

1 (0.7%)

4 (3.0%)

(0.0%)

1 (1.1%)

Diabetes mellitus

1 (0.7%)

1 (0.7%)

(0.0%)

(0.0%)

Goiter

1 (0.7%)

(0.0%)

(0.0%)

(0.0%)

Hyperthyroidism

1 (0.7%)

(0.0%)

(0.0%)

(0.0%)

Hypothyroidism

3 (2.1%)

1 (0.7%)

(0.0%)

(0.0%)

Thyroiditis

(0.0%)

1 (0.7%)

(0.0%)

(0.0%)

Hemic and

lymphatic

Acute leukemia

1 (0.7%)

(0.0%)

(0.0%)

(0.0%)

Anemia

50 (35.0%)

34 (25.2%)

13 (14.3%)

9 (9.5%)

Bleeding time

increased

(0.0%)

(0.0%)

1 (1.1%)

(0.0%)

Coagulation disorder

(0.0%)

(0.0%)

1 (1.1%)

1 (1.1%)

Ecchymosis

9 (6.3%)

3 (2.2%)

7 (7.7%)

2 (2.1%)

Hemolytic anemia

(0.0%)

1 (0.7%)

(0.0%)

(0.0%)

Hypochromic

anemia

8 (5.6%)

1 (0.7%)

2 (2.2%)

2 (2.1%)

Leukocytosis

1 (0.7%)

(0.0%)

(0.0%)

(0.0%)

Leukopenia

74 (51.7%)

45 (33.3%)

22 (24.2%)

16 (16.8%)

Lymphadenopathy

6 (4.2%)

4 (3.0%)

2 (2.2%)

1 (1.1%)

Lymphangitis

1 (0.7%)

(0.0%)

(0.0%)

1 (1.1%)

Lymphedema

8 (5.6%)

4 (3.0%)

3 (3.3%)

1 (1.1%)

Marrow depression

1 (0.7%)

(0.0%)

(0.0%)

(0.0%)

Myeloid maturation

arrest

1 (0.7%)

(0.0%)

(0.0%)

(0.0%)

Pancytopenia

5 (3.5%)

3 (2.2%)

2 (2.2%)

1 (1.1%)

page 47 / 117

Adverse Event

Term

Trastuzumab

+ AC

AC Alone

Trastuzumab

+ Paclitaxel

Paclitaxel

Alone

(N=143)

(N=135)

(N=91)

(N=95)

Petechia

3 (2.1%)

1 (0.7%)

1 (1.1%)

(0.0%)

Purpura

(0.0%)

1 (0.7%)

(0.0%)

(0.0%)

Thrombocythemia

1 (0.7%)

(0.0%)

(0.0%)

(0.0%)

Thrombocytopenia

16 (11.2%)

12 (8.9%)

3 (3.3%)

3 (3.2%)

Thromboplast in

increased

(0.0%)

(0.0%)

1 (1.1%)

(0.0%)

Metabolic and

nutritional

disorders

Acidosis

(0.0%)

(0.0%)

(0.0%)

1 (1.1%)

Alkaline

phosphatase

increased

1 (0.7%)

(0.0%)

(0.0%)

1 (1.1%)

Bilirubinemia

(0.0%)

1 (0.7%)

1 (1.1%)

(0.0%)

Cachexia

(0.0%)

(0.0%)

1 (1.1%)

(0.0%)

Creatinine increased

1 (0.7%)

(0.0%)

1 (1.1%)

(0.0%)

Dehydration

15 (10.5%)

5 (3.7%)

8 (8.8%)

9 (9.5%)

Edema

16 (11.2%)

7 (5.2%)

9 (9.9%)

8 (8.4%)

Electrolyte

abnorm alit y

(0.0%)

2 (1.5%)

(0.0%)

(0.0%)

Glucose tolerance

decreased

(0.0%)

1 (0.7%)

(0.0%)

(0.0%)

Gout

1 (0.7%)

1 (0.7%)

(0.0%)

(0.0%)

Grow th retarded

(0.0%)

1 (0.7%)

(0.0%)

(0.0%)

Healing abnormal

4 (2.8%)

(0.0%)

1 (1.1%)

2 (2.1%)

Hypercalcemia

(0.0%)

1 (0.7%)

3 (3.3%)

6 (6.3%)

Hypercholesteremia

1 (0.7%)

1 (0.7%)

(0.0%)

(0.0%)

Hyperglycemia

2 (1.4%)

4 (3.0%)

2 (2.2%)

2 (2.14%)

Hyperkalemia

(0.0%)

(0.0%)

3 (3.3%)

2 (2.1%)

Hypernatremia

(0.0%)

(0.0%)

1 (1.1%)

1 (1.1%)

Hyperuricemia

1 (0.7%)

(0.0%)

(0.0%)

(0.0%)

Hypervolemia

(0.0%)

2 (1.5%)

(0.0%)

(0.0%)

Hypocalcemia

2 (1.4%)

1 (0.7%)

1 (1.1%)

(0.0%)

Hypoglycemia

1 (0.7%)

1 (0.7%)

(0.0%)

3 (3.2%)

Hypokalemia

18 (12.6%)

6 (4.4%)

2 (2.2%)

3 (3.2%)

Hypomagnesemia

3 (2.1%)

1 (0.7%)

1 (1.1%)

(0.0%)

Hyponatremia

1 (0.7%)

(0.0%)

1 (1.1%)

(0.0%)

Hypophosphatemia

(0.0%)

(0.0%)

(0.0%)

1 (1.1%)

Hypoproteinemia

1 (0.7%)

(0.0%)

1 (1.1%)

(0.0%)

Lactic

dehydrogenase

increased

1 (0.7%)

(0.0%)

(0.0%)

(0.0%)

NPN increased

(0.0%)

(0.0%)

(0.0%)

1 (1.1%)

Peripheral edema

29 (20.3%)

23 (17.0%)

20 (22.0%)

19 (20.0%)

SGOT (serum

glutamic

oxaloacetic

transaminase)

increased

(0.0%)

1 (0.7%)

2 (2.2%)

3 (3.2%)

serum glutamic

pyruvic

transaminase

(SGPT)

increased

(0.0%)

(0.0%)

2 (2.2%)

1 (1.1%)

Weight gain

4 (2.8%)

3 (2.2%)

2 (2.2%)

2 (2.1%)

Weight loss

12 (8.4%)

8 (5.9%)

7 (7.7%)

5 (5.3%)

Musculoskeletal

Arthralgia

12 (8.4%)

13 (9.6%)

34 (37.4%)

20 (21.1%)

Arthritis

3 (2.1%)

(0.0%)

4 (4.4%)

1 (1.1%)

Bone disorder

(0.0%)

1 (0.7%)

1 (1.1%)

(0.0%)

Bone necrosis

1 (0.7%)

(0.0%)

1 (1.1%)

(0.0%)

Bone pain

10 (7.0%)

9 (6.7%)

22 (24.2%)

17 (17.9%)

page 48 / 117

Adverse Event

Term

Trastuzumab

+ AC

AC Alone

Trastuzumab

+ Paclitaxel

Paclitaxel

Alone

(N=143)

(N=135)

(N=91)

(N=95)

Joint disorder

5 (3.5%)

2 (1.5%)

2 (2.2%)

3 (3.2%)

Leg cramps

6 (4.2%)

3 (2.2%)

5 (5.5%)

2 (2.1%)

Myalgia

19 (13.3%)

17 (12.6%)

35 (38.5%)

34 (35.8%)

Myasthenia

4 (2.8%)

8 (5.9%)

6 (6.6%)

8 (8.4%)

Myopathy

(0.0%)

(0.0%)

(0.0%)

1 (1.1%)

Myositis

(0.0%)

(0.0%)

1 (1.1%)

(0.0%)

Osteoporosis

1 (0.7%)

(0.0%)

(0.0%)

(0.0%)

Pathological fracture

1 (0.7%)

(0.0%)

1 (1.1%)

(0.0%)

Rheumatoid arthritis

1 (0.7%)

(0.0%)

(0.0%)

(0.0%)

Tendinous

contracture

1 (0.7%)

(0.0%)

(0.0%)

(0.0%)

Tenosynovitis

(0.0%)

(0.0%)

2 (2.2%)

(0.0%)

Tw itching

1 (0.7%)

1 (0.7%)

(0.0%)

2 (2.1%)

Nervous

Abnormal dreams

(0.0%)

1 (0.7%)

(0.0%)

(0.0%)

Abnormal gait

3 (2.1%)

4 (3.0%)

7 (7.7%)

4 (4.2%)

Agitation

2 (1.4%)

2 (1.5%)

(0.0%)

(0.0%)

Amnesia

3 (2.1%)

4 (3.0%)

2 (2.2%)

1 (1.1%)

Anxiety

26 (18.2%)

19 (14.1%)

17 (18.7%)

14 (14.7%)

Ataxia

2 (1.4%)

3 (2.2%)

6 (6.6%)

4 (4.2%)

Brain edema

2 (1.4%)

2 (1.5%)

1 (1.1%)

(0.0%)

Circumoral

paresthesia

1 (0.7%)

1 (0.7%)

2 (2.2%)

1 (1.1%)

Coma

1 (0.7%)

(0.0%)

1 (1.1%)

(0.0%)

Confusion

8 (5.6%)

(0.0%)

3 (3.3%)

6 (6.3%)

Convulsion

1 (0.7%)

(0.0%)

2 (2.2%)

3 (3.2%)

Depression

28 (19.6%)

16 (11.9%)

11 (12.1%)

12 (12.6%)

Dizziness

34 (23.8%)

24 (17.8%)

20 (22.0%)

23 (24.2%)

Dystonia

2 (1.4%)

(0.0%)

(0.0%)

(0.0%)

Emotional lability

3 (2.1%)

1 (0.7%)

2 (2.2%)

(0.0%)

Euphoria

1 (0.7%)

(0.0%)

1 (1.1%)

(0.0%)

Extraphyramidal

syndrome

1 (0.7%)

(0.0%)

(0.0%)

(0.0%)

Foot drop

1 (0.7%)

(0.0%)

(0.0%)

(0.0%)

Guillain barre

syndrome

(0.0%)

(0.0%)

(0.0%)

1 (1.1%)

Hallucinations

2 (1.4%)

(0.0%)

1 (1.1%)

2 (2.1%)

Hyperesthesia

3 (2.1%)

(0.0%)

2 (2.2%)

3 (3.2%)

Hyperkinesia

2 (1.4%)

(0.0%)

3 (3.3%)

2 (2.1%)

Hypertonia

11 (7.7%)

3 (2.2%)

10 (11.0%)

3 (3.2%)

Hypesthesia

1 (0.7%)

1 (0.7%)

1 (1.1%)

3 (3.2%)

Hypokinesia

(0.0%)

1 (0.7%)

2 (2.2%)

(0.0%)

Incoordination

2 (1.4%)

(0.0%)

1 (1.1%)

3 (3.2%)

Insomnia

42 (29.4%)

21 (15.6%)

23 (25.3%)

12 (12.6%)

Meningitis

(0.0%)

(0.0%)

(0.0%)

1 (1.1%)

Movement disorder

(0.0%)

3 (2.2%)

1 (1.1%)

1 (1.1%)

Nervousness

6 (4.2%)

5 (3.7%)

4 (4.4%)

2 (2.1%)

Neuralgia

3 (2.1%)

1 (0.7%)

1 (1.1%)

2 (2.1%)

Neuropathy

5 (3.5%)

6 (4.4%)

12 (13.2%)

5 (5.3%)

Neurosis

1 (0.7%)

1 (0.7%)

(0.0%)

(0.0%)

Nystagmus

(0.0%)

(0.0%)

1 (1.1%)

(0.0%)

Paranoid reaction

1 (0.7%)

(0.0%)

(0.0%)

(0.0%)

Paraplegia

1 (0.7%)

(0.0%)

(0.0%)

(0.0%)

Parasthesia

24 (16.8%)

15 (11.1%)

43 (47.3%)

37 (38.9%)

Peripheral neuritis

3 (2.1%)

3 (2.2%)

21 (23.1%)

15 (15.8%)

Reflexes decreased

(0.0%)

1 (0.7%)

3 (3.3%)

1 (1.1%)

page 49 / 117

Adverse Event

Term

Trastuzumab

+ AC

AC Alone

Trastuzumab

+ Paclitaxel

Paclitaxel

Alone

(N=143)

(N=135)

(N=91)

(N=95)

Reflexes increased

1 (0.7%)

(0.0%)

(0.0%)

(0.0%)

Sleep disorder

2 (1.4%)

1 (0.7%)

1 (1.1%)

(0.0%)

Somnolence

15 (10.5%)

20 (14.8%)

9 (9.9%)

9 (9.5%)

Speech disorder

3 (2.1%)

1 (0.7%)

2 (2.2%)

2 (2.1%)

Thinking abnormal

5 (3.5%)

1 (0.7%)

3 (3.3%)

1 (1.1%)

Tremor

5 (3.5%)

2 (1.5%)

4 (4.4%)

4 (4.2%)

Vertigo

4 (2.8%)

3 (2.2%)

3 (3.3%)

2 (2.1%)

Weakness

(0.0%)

2 (1.5%)

(0.0%)

1 (1.1%)

Respiratory

Apnea

1 (0.7%)

(0.0%)

1 (1.1%)

(0.0%)

Asthma

6 (4.2%)

5 (3.7%)

5 (5.5%)

2 (2.1%)

Bronchitis

2 (1.4%)

5 (3.7%)

6 (6.6%)

2 (2.1%)

Carcinoma of lung

(0.0%)

1 (0.7%)

(0.0%)

(0.0%)

Cough increased

62 (43.4%)

38 (28.1%)

38 (41.8%)

21 (22.1%)

Dry nasal

1 (0.7%)

(0.0%)

1 (1.1%)

(0.0%)

Dyspnea

60 (42.0%)

33 (24.4%)

25 (27.5%)

25 (26.3%)

Epistaxis

10 (7.0%)

8 (5.9%)

16 (17.6%)

4 (4.2%)

Hemoptysis

1 (0.7%)

(0.0%)

2 (2.2%)

(0.0%)

Hiccup

4 (2.8%)

1 (0.7%)

(0.0%)

(0.0%)

Hyperventilation

3 (2.1%)

1 (0.7%)

1 (1.1%)

(0.0%)

Hypoxia

4 (2.8%)

1 (0.7%)

(0.0%)

5 (5.3%)

Laryngismus

(0.0%)

(0.0%)

1 (1.1%)

(0.0%)

Laryngitis

(0.0%)

(0.0%)

3 (3.3%)

1 (1.1%)

Larynx edema

(0.0%)

1 (0.7%)

(0.0%)

(0.0%)

Lung disorder

12 (8.4%)

4 (3.0%)

7 (7.7%)

7 (7.4%)

Lung edema

1 (0.7%)

(0.0%)

(0.0%)

(0.0%)

Pharyngitis

43 (30.1%)

25 (18.5%)

20 (22.0%)

13 (13.7%)

Pleural disorder

(0.0%)

(0.0%)

2 (2.2%)

1 (1.1%)

Pleural effusion

9 (6.3%)

4 (3.0%)

6 (6.6%)

5 (5.3%)

Pneumonia

9 (6.3%)

4 (3.0%)

2 (2.2%)

2 (2.1%)

Pneumothorax

2 (1.4%)

2 (1.5%)

(0.0%)

(0.0%)

Respiratory disorder

3 (2.1%)

(0.0%)

1 (1.1%)

(0.0%)

Rhinitis

31 (21.7%)

21 (15.6%)

20 (22.0%)

5 (5.3%)

Sinusitis

18 (12.6%)

8 (5.9%)

19 (20.9%)

7 (7.4%)

Sputum change

1 (0.7%)

(0.0%)

(0.0%)

(0.0%)

Sputum increased

1 (0.7%)

2 (1.5%)

(0.0%)

1 (1.1%)

Vocal cord paralysis

(0.0%)

(0.0%)

(0.0%)

1 (1.1%)

Voice alteration

5 (3.5%)

(0.0%)

4 (4.4%)

3 (3.2%)

Skin and

appen dag es

Acne

4 (2.8%)

1 (0.7%)

10 (11.0%)

3 (3.2%)

Alopecia

83 (58.0%)

80 (59.3%)

51 (56.0%)

53 (55.8%)

Contact dermatitis

(0.0%)

(0.0%)

2 (2.2%)

1 (1.1%)

Cutaneous

moniliasis

(0.0%)

1 (0.7%)

(0.0%)

(0.0%)

Dry skin

1 (0.7%)

7 (5.2%)

4 (4.4%)

4 (4.2%)

Eczema

2 (1.4%)

(0.0%)

(0.0%)

(0.0%)

Exf oliative

dermatitis

2 (1.4%)

1 (0.7%)

3 (3.3%)

2 (2.1%)

Fungal dermatitis

6 (4.2%)

5 (3.7%)

3 (3.3%)

(0.0%)

Furunculosis

(0.0%)

1 (0.7%)

(0.0%)

(0.0%)

Herpes simplex

10 (7.0%)

11 (8.1%)

11 (12.1%)

3 (3.2%)

Herpes zoster

4 (2.8%)

4 (3.0%)

4 (4.4%)

2 (2.1%)

Maculopapular rash

2 (1.4%)

3 (2.2%)

3 (3.3%)

1 (1.1%)

Melanosis

1 (0.7%)

(0.0%)

(0.0%)

(0.0%)

Nail disorder

6 (4.2%)

5 (3.7%)

4 (4.4%)

1 (1.1%)

Pruritus

11 (7.7%)

8 (5.9%)

13 (14.3%)

12 (12.6%)

page 50 / 117

Adverse Event

Term

Trastuzumab

+ AC

AC Alone

Trastuzumab

+ Paclitaxel

Paclitaxel

Alone

(N=143)

(N=135)

(N=91)

(N=95)

Psoriasis

1 (0.7%)

2 (1.5%)

(0.0%)

(0.0%)

Purpuric rash

(0.0%)

(0.0%)

1 (1.1%)

(0.0%)

Pustular rash

1 (0.7%)

(0.0%)

(0.0%)

1 (1.1%)

Rash

38 (26.6%)

23 (17.0%)

35 (38.5%)

17 (17.9%)

Seborrhea

1 (0.7%)

(0.0%)

(0.0%)

(0.0%)

Skin discoloration

7 (4.9%)

3 (2.2%)

2 (2.2%)

1 (1.1%)

Skin disorder

3 (2.1%)

1 (0.7%)

2 (2.2%)

1 (1.1%)

Skin hypertrophy

1 (0.7%)

(0.0%)

(0.0%)

(0.0%)

Skin melanoma

1 (0.7%)

(0.0%)

(0.0%)

(0.0%)

Skin nodule

(0.0%)

1 (0.7%)

(0.0%)

(0.0%)

Skin ulcer

8 (5.6%)

6 (4.4%)

3 (3.3%)

1 (1.1%)

Subcutaneous

nodule

1 (0.7%)

1 (0.7%)

(0.0%)

(0.0%)

Sw eating

13 (9.1%)

10 (7.4%)

7 (7.7%)

3 (3.2%)

Urticaria

2 (1.4%)

(0.0%)

1 (1.1%)

1 (1.1%)

Vesiculobullous rash

1 (0.7%)

1 (0.7%)

3 (3.3%)

1 (1.1%)

Special senses

Abnormal vision

11 (7.7%)

3 (2.2%)

6 (6.6%)

3 (3.2%)

Amblyopia

8 (5.6%)

5 (3.7%)

5 (5.5%)

6 (6.3%)

Blepharitis

(0.0%)

2 (1.5%)

(0.0%)

(0.0%)

Blindness

1 (0.7%)

(0.0%)

(0.0%)

(0.0%)

Cataract specified

1 (0.7%)

(0.0%)

1 (1.1%)

(0.0%)

Conjunctivitis

12 (8.4%)

9 (6.7%)

6 (6.6%)

2 (2.1%)

Corneal lesion

(0.0%)

2 (1.5%)

1 (1.1%)

(0.0%)

Deafness

2 (1.4%)

3 (2.2%)

(0.0%)

2 (2.1%)

Diplopia

1 (0.7%)

2 (1.5%)

1 (1.1%)

2 (2.1%)

Dry eyes

3 (2.1%)

1 (0.7%)

1 (1.1%)

1 (1.1%)

Ear disorder

2 (1.4%)

2 (1.5%)

1 (1.1%)

1 (1.1%)

Ear pain

4 (2.8%)

1 (0.7%)

3 (3.3%)

1 (1.1%)

Eye disorder

1 (0.7%)

2 (1.5%)

(0.0%)

(0.0%)

Eye hemorrhage

1 (0.7%)

1 (0.7%)

(0.0%)

1 (1.1%)

Eye pain

1 (0.7%)

2 (1.5%)

2 (2.2%)

(0.0%)

Glaucoma

(0.0%)

1 (0.7%)

1 (1.1%)

(0.0%)

Hyperacusis

(0.0%)

(0.0%)

1 (1.1%)

(0.0%)

Keratitis

(0.0%)

(0.0%)

1 (1.1%)

(0.0%)

Lacrimation disorder

7 (4.9%)

12 (8.9%)

3 (3.3%)

(0.0%)

Otitis media

3 (2.1%)

2 (1.5%)

3 (3.3%)

(0.0%)

Parosmia

1 (0.7%)

2 (1.5%)

1 (1.1%)

(0.0%)

Photophobia

(0.0%)

2 (1.5%)

1 (1.1%)

(0.0%)

Ptosis

(0.0%)

(0.0%)

(0.0%)

1 (1.1%)

Retinal artery

occlusion

1 (0.7%)

(0.0%)

(0.0%)

(0.0%)

Retinal disorder

1 (0.7%)

1 (0.7%)

(0.0%)

(0.0%)

Strabismus

(0.0%)

1 (0.7%)

(0.0%)

(0.0%)

Taste loss

2 (1.4%)

(0.0%)

(0.0%)

3 (3.2%)

Taste perversion

16 (11.2%)

18 (13.3%)

5 (5.5%)

3 (3.2%)

Tinnitus

2 (1.4%)

2 (1.5%)

2 (2.2%)

2 (2.1%)

Vestibular disorder

(0.0%)

1 (0.7%)

(0.0%)

(0.0%)

Visual field defect

1 (0.7%)

(0.0%)

3 (3.3%)

(0.0%)

Vitreous disorder

2 (1.4%)

(0.0%)

1 (1.1%)

(0.0%)

Urogenital

Acute kidney failure

(0.0%)

(0.0%)

1 (1.1%)

1 (1.1%)

Albuminuria

2 (1.4%)

(0.0%)

1 (1.1%)

(0.0%)

Amenorrhea

2 (1.4%)

5 (3.7%)

1 (1.1%)

(0.0%)

Breast carcinoma

6 (4.2%)

3 (2.2%)

2 (2.2%)

5 (5.3%)

page 51 / 117

Adverse Event

Term

Trastuzumab

+ AC

AC Alone

Trastuzumab

+ Paclitaxel

Paclitaxel

Alone

(N=143)

(N=135)

(N=91)

(N=95)

Breast enlargement

1 (0.7%)

1 (0.7%)

(0.0%)

1 (1.1%)

Breast neoplasm

3 (2.14%)

2 (1.5%)

1 (1.1%)

(0.0%)

Breast pain

8 (5.6%)

7 (5.2%)

2 (2.2%)

6 (6.3%)

Cystitis

1 (0.7%)

3 (2.2%)

1 (1.1%)

1 (1.1%)

Dysmenorrhea

(0.0%)

(0.0%)

(0.0%)

2 (2.1%)

Dyspareunia

1 (0.7%)

1 (0.7%)

(0.0%)

(0.0%)

Dysuria

6 (4.2%)

7 (5.2%)

3 (3.3%)

3 (3.2%)

Fibrocystic breast

2 (1.4%)

(0.0%)

(0.0%)

(0.0%)

Hematuria

3 (2.1%)

2 (1.5%)

2 (2.2%)

1 (1.1%)

Hydronephrosis

2 (1.4%)

1 (0.7%)

(0.0%)

(0.0%)

Kidney failure

1 (0.7%)

(0.0%)

(0.0%)

1 (1.1%)

Kidney function

abnormal

1 (0.7%)

(0.0%)

(0.0%)

(0.0%)

Kidney pain

1 (0.7%)

(0.0%)

(0.0%)

(0.0%)

Leukorrhea

6 (4.2%)

1 (0.7%)

(0.0%)

1 (1.1%)

Mastitis

3 (2.1%)

1 (0.7%)

2 (2.2%)

(0.0%)

Menopause

3 (2.1%)

(0.0%)

(0.0%)

(0.0%)

Menorrhagia

(0.0%)

1 (0.7%)

1 (1.1%)

2 (2.1%)

Menstrual disorder

(0.0%)

(0.0%)

(0.0%)

1 (1.1%)

Metrorrhagia

3 (2.1%)

1 (0.7%)

2 (2.2%)

(0.0%)

Nocturia

1 (0.7%)

1 (0.7%)

(0.0%)

(0.0%)

Oliguria

1 (0.7%)

(0.0%)

(0.0%)

(0.0%)

Papanicolau smear

suspicious

(0.0%)

1 (0.7%)

(0.0%)

(0.0%)

Polyuria

(0.0%)

1 (0.7%)

1 (1.1%)

(0.0%)

Urinary frequency

5 (3.5%)

8 (5.9%)

1 (1.1%)

1 (1.1%)

Urinary

incontinence

7 (4.9%)

1 (0.7%)

2 (2.2%)

1 (1.1%)

Urinary retention

2 (1.4%)

(0.0%)

(0.0%)

1 (1.1%)

Urinary tract

disorder

1 (0.7%)

1 (0.7%)

1 (1.1%)

1 (1.1%)

Urinary tract

infection

19 (13.3%)

9 (6.7%)

17 (18.7%)

13 (13.7%)

Urinary urgency

1 (0.7%)

1 (0.7%)

2 (2.2%)

(0.0%)

Urination impaired

1 (0.7%)

(0.0%)

(0.0%)

(0.0%)

Urine abnormality

2 (1.4%)

1 (0.7%)

1 (1.1%)

(0.0%)

Vaginal hemorrhage

(0.0%)

2 (1.5%)

1 (1.1%)

2 (2.1%)

Vaginal moniliasis

9 (6.3%)

2 (1.5%)

2 (2.2%)

1 (1.1%)

Vaginitis

7 (4.9%)

8 (5.9%)

5 (5.5%)

1 (1.1%)

Other Serious Adverse Events

The following other serious adverse events occurred in at least one of the 958 patients treated

with trastuzumab in the MBC clinical trials conducted prior to market approval:

Body as a Whole: abdomen enlarged, allergic reaction, anaphylactoid reaction, ascites,

carcinoma, cellulitis, chills and fever, death, dermatomyositis, hydrocephalus, necrosis,

neoplasm, pelvic pain, radiation injury, sepsis, malaise

Cardiovascular: atrial fibrillation, cardiomyopathy, cardiovascular disorder, cerebrovascular

accident, deep

thrombophlebitis, heart arrest, heart failure, hemorrhage, hypotension, pericardial

effusion, pulmonary embolus, thrombophlebitis, thrombosis, syncope, shock, supraventricular

tachycardia, vascular disorder, ventricular

arrhythmia

Digestive: colitis, dysphagia, esophageal hemorrhage, esophageal ulcer, gastritis,

gastroenteritis, gastrointestinal disorder, gastrointestinal hemorrhage, hematemesis, hepatic

coma, hepatic failure, hepatic neoplasia, hepatitis, hepatomegaly, ileus, intestinal obstruction,

liver tenderness, pancreatitis, peptic ulcer hemorrhage, pseudomembranous colitis, rectal

page 52 / 117

hemorrhage

Endocrine: hypothyroidism

Hematological: acute leukemia, coagulation disorder, lymphangitis, marrow depression, myeloid

maturation arrest, pancytopenia

Metabolic: bilirubinemia, growth retardation, hypercalcemia, hyponatremia, hypoglycemia,

hypomagnesemia, weight loss

Musculoskeletal: pathologic fracture, bone necrosis, myopathy

Nervous: ataxia, CNS neoplasia, confusion, convulsion, grand mal convulsion, manic reaction,

thinking abnormal

Respiratory: apnea, asthma, hypoxia, laryngitis, lung disorder, lung edema, pleural effusion,

pneumonia, pneumothorax, respiratory disorder

Skin: herpes zoster, skin ulceration, dry skin

Special Senses: amblyopia, deafness, retinal artery occlusion

Urogenital: breast carcinoma, breast neoplasm, cervical cancer, hematuria, hemorrhagic cystitis,

hydronephrosis, kidney failure, kidney function abnormal, pyelonephritis, vaginal hemorrhage

When using in combination with pertuzumab and docetaxel, consult Product Monographs for

pertuzumab and docetaxel for further information on these drugs.

Metastatic Gastric Cancer (MGC)

The ToGA trial (BO18255) is a randomized, open-label multicentre, phase III study of

trastuzumab in combination with a fluoropyrimidine (FP) and cisplatin versus chemotherapy

alone in patients with HER2 positive MGC. There were only 3.4% of patients in each treatment

group with locally advanced cancer. The majority of patients had metastatic disease.

The adverse drug reactions that occurred with the incidence of at least 1% in the ToGA

(BO18255) study are presented in Table 21.

Table 21 Adverse Drug Reactions With Incidence Rate ≥ 1% in ToGA (BO18255)

FP/Cisplatin

(FP)

N = 290

No. (%)

Trastuz umab /

FP/Cisplatin

(H+FP)

N = 294

No. (%)

Blood and lymphatic system

disorders

Neutropenia

165 (57)

157 (53)

Anemia

61 (21)

81 (28)

Thrombocytopenia

33 (11)

47 (16)

Febrile neutropenia

8 (3)

15 (5)

Leukopenia

11 (4)

11 (4)

Cardiac disorders

Palpitations

2 (<1)

6 (2)

Ear and labyrinth disorders

Deafness

1 (<1)

8 (3)

Eye disorders

Lacrimation increased

2 (<1)

5 (2)

Gastrointestinal disorders

Nausea

184 (63)

197 (67)

Vomiting

134 (46)

147 (50)

Diarrhea

80 (28)

109 (37)

Constipation

93 (32)

75 (26)

Stomatitis

43 (15)

72 (24)

page 53 / 117

FP/Cisplatin

(FP)

N = 290

No. (%)

Trastuz umab /

FP/Cisplatin

(H+FP)

N = 294

No. (%)

Abdominal pain

42 (14)

46 (16)

Abdominal pain upper

15 (5)

27 (9)

Dyspepsia

16 (6)

18 (6)

Hemorrhoids

3 (1)

5 (2)

Abdominal discomfort

3 (1)

3 (1)

Dry mouth

2 (<1)

4 (1)

General disorders and

administration site conditions

Fatigue

82 (28)

102 (35)

Asthenia

53 (18)

55 (19)

Pyrexia

36 (12)

54 (18)

Mucosal inflammation

18 (6)

37 (13)

Edema

25 (9)

22 (7)

Edema peripheral

12 (4)

17 (6)

Chills

23 (8)

Chest pain

4 (1)

8 (3)

Malaise

6 (2)

6 (2)

Pain

4 (1)

5 (2)

Infusion related reaction

3 (1)

Hepatobiliary disorders

Hepatic function abnormal

3 (1)

3 (1)

Infections and infestations

Nasopharyngitis

17 (6)

37 (13)

Upper respiratory tract infection

10 (3)

15 (5)

Pneumonia

2 (<1)

9 (3)

Cystitis

1 (<1)

5 (2)

Pharyngitis

2 (<1)

4 (1)

Respiratory tract infection

3 (1)

3 (1)

Infection

2 (<1)

3 (1)

Influenza

1 (<1)

4 (1)

Immune system disorders

Hypersensitivity

3 (1)

6 (2)

Injury, poisoning and

procedural

complications

Contusion

2 (<1)

3 (1)

Investigations

Weight decreased

40 (14)

69 (23)

Hemoglobin decreased

2 (<1)

7 (2)

Platelet count decreased

6 (2)

1 (<1)

Neutrophil count decreased

3 (1)

3 (1)

Metabolism and nutrition

disorders

Anorexia

133 (46)

135 (46)

Hyperkalaemia

3 (1)

Musculoskeletal and connective

tissue disorders

Back pain

15 (5)

12 (4)

Pain in extremity

7 (2)

4 (1)

Arthralgia

2 (<1)

7 (2)

Musculoskeletal pain

4 (1)

5 (2)

Myalgia

3 (1)

4 (1)

Muscular w eakness

3 (1)

2 (<1)

Muscle spasms

1 (<1)

3 (1)

page 54 / 117

FP/Cisplatin

(FP)

N = 290

No. (%)

Trastuz umab /

FP/Cisplatin

(H+FP)

N = 294

No. (%)

Musculoskeletal chest pain

3 (1)

1 (<1)

Neck pain

1 (<1)

3 (1)

Nervous system disorders

Dizziness

28 (10)

31 (11)

Peripheral sensory neuropathy

24 (8)

23 (8)

Neuropathy peripheral

21 (7)

24 (8)

Dysgeusia

14 (5)

28 ( 0)

Headache

19 (7)

14 (5)

Paraesthesia

9 (3)

9 (3)

Lethargy

8 (3)

6 (2)

Peripheral motor neuropathy

6 (2)

8 (3)

Tremor

5 (2)

3 (1)

Renal and urinary disorders

Renal impairment

39 (13)

47 (16)

Nephropathy toxic

12 (4)

18 (6)

Renal failure acute

2 (<1)

3 (1)

Renal failure

1 (<1)

3 (1)

Respiratory, thoracic and

mediastinal disorders

Cough

17 (6)

19 (6)

Dyspnea

16 (6)

9 (3)

Epistaxis

9 (3)

13 (4)

Rhinorrhea

2 (<1)

6 (2)

Psychiatric disorders

Insomnia

20 (7)

24 (8)

Depression

5 (2)

4 (1)

Anxiety

5 (2)

3 (1)

Sleep disorder

3 (1)

2 (<1)

Skin and subcutaneous tissue

disorders

Palmar-plantar

erythrodysaesthesia

syndrome

64 (22)

75 (26)

Alopecia

27 (9)

32 (11)

Rash

12 (4)

16 (5)

Nail disorder

6 (2)

13 (4)

Dry skin

4 (1)

10 (3)

Pruritus

3 (1)

8 (3)

Urticaria

3 (1)

3 (1)

Vascular disorders

Hypertension

7 (2)

11 (4)

Hypotension

6 (2)

6 (2)

Adverse Events of Special Interest

The following subsections provide additional detail regarding adverse reactions observed in

clinical trials in EBC, MBC, MGC, or post-market experience.

Cardiac (EBC and MBC)

For a description of cardiac toxicities see WARNINGS AND PRECAUTIONS.

Cardiac (Metastatic Gastric Cancer)

page 55 / 117

In the ToGA (BO18255) study, at screening, the median LVEF value was 64% (range 48%-90%)

in the FP arm and 65% (range 50%-86%) in the FP+H arm. At baseline, a LVEF value of 50% or

more (measured by ECHO or MUGA) was required at study entry.

The majority of the LVEF decreases noted in ToGA (BO18255) were asymptomatic, with the

exception of one patient in the trastuzumab-containing arm whose LVEF decrease coincided

with cardiac failure.

Table 22 Summary of LVEF Change from Baseline ToGA (BO18255)

LVEF Decrease: Lowest

Post-screening Value

FP/Cisplatin

(N = 290)

(% of patients in each treatment arm)

Trastuzumab/FP/Cisplatin

(N = 294)

(% of patients in each

treatment arm)

* LVEF decrease of ≥10%

to a value of < 50%

1.1%

4.6%

Absolute Value < 50%

1.1%

5.9%

* LVEF decrease

of ≥10% to a value

of ≥50%

11.8%

16.5%

* Only includes patients w hose method of assessment at that visit is the same as at their initial assessments (F + C, n

= 187 and H +FC, n = 237)

Table 23 Cardiac Adverse Events ToGA (BO18255)

FP/Cisplatin

(N = 290)

(% of patients in each treatment arm)

Trastuzumab/FP/Cisplatin

(N = 294)

(% of patients in each treatment arm)

Total Cardiac Events

≥Grade 3 NCI-CTC

V3.0

**1%

* 9 patients experienced 9 Events

** 4 patients experienced 5 Events

Infusion-Associated Symptoms

During the first infusion with trastuzumab, chills and/or fever are observed commonly in patients.

Other signs and/or symptoms may include nausea, vomiting, pain, rigors, headache, cough,

dizziness, rash, asthenia and hypertension. The symptoms are usually mild to moderate in

severity, and occur infrequently with subsequent infusions of trastuzumab. The symptoms can be

treated with an analgesic/antipyretic such as meperidine or acetaminophen, or an antihistamine

such as diphenhydramine (see DOSAGE AND ADMINISTRATION).

Interruption of the infusion was infrequent. Some adverse reactions to infusions of trastuzumab

including dyspnea, hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen

saturation and respiratory distress can be serious and potentially fatal (see WARNINGS AND

PRECAUTIONS).

Hematological Toxicity

In a randomized controlled clinical trial in MBC (H0648g), WHO Grade 3 or 4

hematological

toxicity was observed in 63% of patients treated with trastuzumab and an anthracycline plus

cyclophosphamide compared to an incidence of 62% in patients treated with

anthracycline/cyclophosphamide combination without trastuzumab. There was an increase in

WHO Grade 3 or 4 hematological toxicity in patients treated with the combination of trastuzumab

WHO Grade 3 Hematological

Toxicity: Hemoglobin

– 6.5-7.9 g/100 mL, 65-79 g/L, 4.0-4.9 mmol/L, Leukocytes

(1000/mm

) – 1.0-1.9, Granulocytes (1000/mm

) – 0.5-0.9, Platelets (1000/mm

) – 25-49.

WHO Grade 4 Hematological

Toxicity: Hemoglobin

– <6.5 g/100 mL, <65 g/L, <4.0 mmol/L, Leukocytes (1000/mm

) –

<1.0, Granulocytes (1000/mm

) – <0.5, Platelets (1000/mm

) – <25.

page 56 / 117

and paclitaxel compared with patients receiving paclitaxel alone (34% vs. 21%).

In a randomized, controlled trial in patients with MBC conducted in the post-market setting,

hematological toxicity was also increased in patients receiving trastuzumab and docetaxel,

compared with docetaxel alone (32% grade 3/4 neutropenia versus 22%, using NCI-CTC

criteria). The incidence of febrile neutropenia/neutropenic sepsis was also increased in patients

treated with trastuzumab plus docetaxel (23% versus 17% for patients treated with docetaxel

alone), see WARNINGS AND PRECAUTIONS.

Anemia and Leukopenia

In a randomized controlled clinical trial in MBC, an increased incidence of anemia and

leukopenia was observed in the treatment group receiving trastuzumab and chemotherapy

(26.9% and 41%), especially in the trastuzumab and AC subgroup (35.0% and 51.7%),

compared with the treatment group receiving chemotherapy alone (18.7% and 26.5%). The

majority of these cytopenic events were mild or moderate in intensity, reversible, and none

resulted in discontinuation of therapy with trastuzumab.

Hematologic toxicity is infrequent following the administration of trastuzumab as a single

agent,

with an incidence of Grade 3 toxicities for WBC, platelets, hemoglobin all < 1%. No Grade 4

toxicities were observed.

In study B-31, the incidence of grade 3 to 5 anemia was comparable between the trastuzumab +

chemotherapy and the chemotherapy alone arm (3.2% versus 3.1%). The incidence of grade 3 to

5 leukopenia was lower in patients randomized to trastuzumab + chemotherapy compared with

those randomized to chemotherapy alone (10.0% versus 10.7%).

In study N9831, the incidence of grade 3 to 5 anemia was comparable between the

trastuzumab+ chemotherapy and the chemotherapy alone arm (0.2% versus 0.0%). The

incidence of grade 3 to 5 leukopenia was higher in patients randomized to trastuzumab +

chemotherapy compared with those randomized to chemotherapy alone (8.5% versus 7.7%).

In study BCIRG-006 the incidence of grade 3 or 4 anemia according to the NCI-CTC v 2.0

classification was comparable between the AC-T arm (4.4%) and the AC-TH arm (4.9%). The

TCH arm had a higher incidence of grade 3 or 4 anemia (8.3%) as would be expected from the

known toxicity profile of carboplatin. The incidence of grade 3 or 4 leukopenia according to the

NCI-CTC v 2.0 classification (52.7% AC-T, 61.5% AC-TH, and 49.9% TCH) was similar in

patients randomized to trastuzumab + chemotherapy compared with those randomized to

chemotherapy alone.

Thrombocytopenia

In HERA study in EBC, the incidence of thrombocytopenia (0.1% vs. 0.06%) was comparable

between patients randomized to trastuzumab + chemotherapy and those randomized to

chemotherapy alone.

In study B-31 in EBC, the incidence of thrombocytopenia (2.2% in the AC→TH arm vs. 2.5% in

the AC→T arm) was lower in patients randomized to trastuzumab + chemotherapy compared

with those randomized to chemotherapy alone.

In study N9831 in EBC, the incidence of thrombocytopenia (0% in the AC→TH arm vs. 0.3% in

the AC→T arm) was lower in patients randomized to trastuzumab + chemotherapy compared

page 57 / 117

with those randomized to chemotherapy alone.

In study BCIRG-006 in EBC, the incidence of grade 3 or 4 thrombocytopenia (5.6% in the

AC→T

arm, 6.8% in the AC→TH arm) was higher in patients randomized to trastuzumab +

chemotherapy compared with those randomized to chemotherapy alone. The incidence of grade

3 or 4 thrombocytopenia in the TCH arm (9.8%) was higher as would be expected from the

known toxicity profile of carboplatin.

Neutropenia

In HERA study in EBC, the incidence of neutropenia (0.4% vs. 0.2%) was higher in patients

randomized to trastuzumab + chemotherapy compared with those randomized to chemotherapy

alone.

In study B-31 in EBC, the incidence of febrile neutropenia (3.8% in the AC→TH arm vs. 4.7% in

the AC→T arm) was lower in patients randomized to trastuzumab + chemotherapy compared

with those randomized to chemotherapy alone. The incidence of neutropenia (grade 3-5) (10.4%

in the AC→TH arm vs. 9.9% in the AC→T arm) was higher in patients randomized to

trastuzumab + chemotherapy compared with those randomized to chemotherapy alone.

In study N9831 in EBC, the incidence of febrile neutropenia (5.9% in the AC→TH arm vs. 4.3%

in the AC→T arm) was higher in patients randomized to trastuzumab + chemotherapy compared

with those randomized to chemotherapy alone. The incidence of neutropenia (grade 3-5) (29.5%

in the AC→TH arm vs. 27.3% in the AC→T arm) was higher in patients randomized to

trastuzumab + chemotherapy compared with those randomized to chemotherapy alone.

In study BCIRG-006, the incidence of febrile neutropenia according to NCI-CTC v 2.0

classification (10.9% in the AC→TH arm, 9.6% in the TCH arm, and 9.3% in the AC→T arm)

was comparable between patients randomized to trastuzumab + chemotherapy and with those

randomized to chemotherapy alone. The incidence of grade 3 or 4 neutropenia according to the

NCI-CTC v 2.0 classification (72.5% in the AC→TH arm, 67.0% in the TCH arm, and 64.6% in

the AC→T arm) was comparable between patients randomized to trastuzumab + chemotherapy

and with those randomized to chemotherapy alone.

Infection

In three studies in EBC, the incidence of infection was higher in patients randomized to

trastuzumab + chemotherapy compared with those randomized to chemotherapy alone (HERA:

29% vs. 12%; B-31: 32% AC→TH vs. 28% AC→T; N9831: 7.3% AC→TH vs. 4.7% AC→T).

In study BCIRG-006 in EBC, the overall incidence of infection (all grades) was higher with the

addition of trastuzumab to AC→T but not to TCH [44% (AC→TH), 37% (TCH), 38% (AC→T)].

The incidences of NCI-CTC Grade 3-4 infection were similar [25% (AC→TH), 21% (TCH), 23%

(AC→T)] across the three arms.

In a randomized controlled clinical trial in MBC, an increased incidence of infections, primarily

mild upper respiratory infections of minor clinical significance or catheter infections, was

observed in patients receiving trastuzumab in combination with chemotherapy.

In the ToGA (BO18255) study in MGC, infections and infestations were reported in 20 % of

patients in the FP arm vs. 32% in the FP+H arm. The major contributors to the higher incidence

of infections and infestations in the trastuzumab arm were nasopharyngitis (6% in the FP arm

page 58 / 117

13% in the FP+H arm) and upper respiratory tract infection (3% vs. 5%).

Hypersensitivity Reactions Including Anaphylaxis and Pulmonary Events

In HERA study, there were 4 cases of interstitial pneumonitis in trastuzumab-treated patients

compared to none in the control arm.

The incidence of allergic reactions (chemotherapy alone versus trastuzumab + chemotherapy:

3.7% versus 3.4% in study B-31 and 1.2% versus 0.3% in study N9831) was comparable

between the two treatment arms in both studies.

The incidence of pulmonary events in the original analysis for adjuvant studies (16.1% versus

7.8% in study B-31 and 4.1% versus 1.4% in study N9831) was higher in patients randomized to

trastuzumab + chemotherapy versus chemotherapy alone. The most common pulmonary event

was dyspnea. The majority of these events were mild to moderate in intensity. Fatal pulmonary

events were reported in 4 patients in the trastuzumab + chemotherapy arm. Only 1 of these

patients actually received trastuzumab. The cause of death in these 4 patients was cardio-

respiratory arrest, bronchopneumonia, respiratory insufficiency, and pneumonia accompanied by

neutropenic fever. Pneumonitis/lung infiltrates were reported in 20 patients who participated in

either adjuvant clinical trial. Twelve of these 20 patients had received trastuzumab +

chemotherapy. The etiology of pneumonitis/lung infiltrates was possible

hypersensitivity/inflammation reaction (n= 4), pneumonia (n=5), radiation therapy toxicity (n=1)

ad unknown etiology (n= 2).

In the most recent safety update for the NSABP B-31 and NCCTG N9831 Joint Analysis report

(median follow-up of 8.1 years for the AC→TH group and 8.5 years for the AC→T group), the

incidences of pulmonary adverse events reported in study B-31 were 17.5% in the AC→T + H

group and 8.5% in the AC→T group. Likewise, the incidences of pulmonary adverse events

reported in study N9831 were 4.0% in the AC→T + H group and 1.7% in the AC→T group.

These results confirm the results from the original analysis, which showed a higher rate of

pulmonary events in the trastuzumab patients. Dyspnea remained the most common pulmonary

adverse event reported in both studies. Dyspnea can be a result of cardiac left ventricular

dysfunction.

Pneumonitis/pulmonary infiltrates were reported in 26 patients in both studies (7 in study B-31,

18 in study N9831) and17 of these patients were in the AC→T + H group. All 7 patients in study

B-31 were in the AC→T + H group, and 10 of the patients in study N9831 were in the AC→T +

group. There were 8 patients with this adverse event in study N9831 in the AC→T group

In study BCIRG-006, the incidence of allergic reactions according to the NCI-CTC v 2.0

classification was 9.4%, 12.3% and 14.9% in AC→T, AC→TH and TCH arms, respectively.

Among women receiving trastuzumab for treatment of MBC in a randomized controlled clinical

trial, the incidence of pulmonary toxicity was also increased in patients randomized to

trastuzumab + chemotherapy compared with those randomized to chemotherapy alone (e.g.

dyspnea 36.3% vs. 25.2%, lung disorder 8.1% vs. 4.8%, lung edema 0.4% vs. 0%, pleural

effusion 6.4% vs. 3.9%).

In the post-market setting, severe hypersensitivity reactions (including anaphylaxis), infusion

reactions, and pulmonary adverse events have been reported. These events include

page 59 / 117

anaphylaxis, angioedema, bronchospasm, hypotension, hypoxia, dyspnea, lung infiltrates, pleural

effusions, non-cardiogenic pulmonary edema, and acute respiratory distress syndrome (see

WARNINGS AND PRECAUTIONS).

Thrombosis/Embolism

In study BCIRG-006, the incidence of all grades thrombosis/embolism according to the NCI-

CTC v 2.0 classification was higher in patients receiving trastuzumab in combination with

docetaxel and carboplatin (TCH) (3.2%) compared to the AC→TH group (2.0%) and AC→T

group (1.7%). The incidence of thrombosis/embolism, grade 3 (deep vein thrombosis, requiring

anticoagulant) and grade 4 (embolic event including pulmonary embolism) combined, was higher

in patients receiving trastuzumab in combination with docetaxel and carboplatin (TCH) (2.7%)

compared to the AC→TH group (1.8%) and AC→T group (1.5%).

In study B-31, thrombosis/embolism (all grades) was reported in 3.8% of patients randomized to

trastuzumab + chemotherapy versus 2.7% of patients randomized to the chemotherapy alone

arm. In study N9831, thrombosis/embolism (all grades) was reported in 1.9% of patients

randomized to trastuzumab + chemotherapy versus 2.9% of patients randomized to

chemotherapy alone.

The incidence of thrombotic adverse events was also higher in patients receiving trastuzumab

and chemotherapy compared to chemotherapy alone in a randomized clinical trial in MBC setting

(2.1% vs. 0%).

Diarrhea

Among women receiving adjuvant therapy for breast cancer, the incidence of NCI-CTC (v 2.0)

Grade 3-5 diarrhea (2.5% vs. 2.6% [B-31]) and of NCI-CTC Grade 3-5 diarrhea (3.4% vs. 0.7%

[N9831]), and of Grade 1-4 diarrhea (7% vs. 1% [HERA]) were commonly higher in patients

receiving trastuzumab as compared to controls. In BCIRG-006 study, the incidence of Grade

diarrhea was higher [5.6% AC-TH, 5.4% TCH vs. 3.1% AC-T] and of Grade 1-4 was higher

[51% AC-TH, 63% TCH vs. 43% AC-T] among women receiving trastuzumab.

Of patients treated with trastuzumab as a single agent for the treatment of MBC, 25%

experienced diarrhea. An increased incidence of diarrhea, primarily mild to moderate in severity,

was observed in patients receiving trastuzumab in combination with chemotherapy.

In the ToGA (BO18255) study in MGC, 109 patients (37%) participating in the trastuzumab-

containing treatment arm versus 80 patients (28%) in the comparator arm experienced any grade

diarrhea. Using NCI-CTCAE v3.0 severity criteria, the percentage of patients experiencing grade

≥ 3 diarrhea was 4% in the FP arm vs. 9% in the FP+H arm.

Hepatic and Renal Toxicity

In a randomized controlled clinical trial in MBC, WHO Grade 3 or 4

hepatic toxicity was

observed in 6% of patients treated with trastuzumab and an anthracycline plus

cyclophosphamide compared with an incidence of 8% in patients treated with

anthracycline/cyclophosphamide combination without trastuzumab. Hepatic toxicity was less

WHO Grade 3 Hepatic Toxicity: Bilirubin – 5.1-10 x N, Transaminases (ASAT/ALAT) – 5.1-10 x N, Alkaline

Phosphatase – 5.1-10 x N, w here N is the upper limit of normal of population under study.

WHO Grade 4 Hepatic Toxicity: Bilirubin – >10 x N, Transaminases (ASAT/ALAT) – >10 x N, Alkaline Phosphatase –

>10 x N, w here N is the upper limit of normal of population under study.

page 60 / 117

frequently observed among patients receiving trastuzumab and paclitaxel than among patients

receiving paclitaxel (7% vs. 15%).

WHO Grade 3 or 4 hepatic toxicity was observed in 12% of patients following administration of

trastuzumab as a single agent. This toxicity was associated with progression of disease in the

liver in 60% of these patients.

The toxicity grading scale used for HERA, NSABP B-31, NCCTG N9831, and BCIRG-006

studies in the adjuvant treatment of EBC was the NCI-CTC v 2.0. The definitions for grade 3

and 4 elevations of serum creatinine were: grade 3 (> 3.0 to 6.0 X ULN) and grade 4 (> 6.0 X

ULN).

The frequencies of grade 3-4 elevated serum creatinine reported in each study are shown, by

treatment arm in

Table 24.

Table 24 Frequencies of Grade 3-4 Elevated Serum Creatinine in Studies of the Adjuvant

Treatment of Early Breast Cancer

Study

Treatment Arm

Grade 3-4 Serum Creatinine Elevation

Regimen

N

N

%

HERA

observation only

1708

1-year Trastuzumab

1678

NSABP B-31

AC→T

AC→TH

1030

NCCTG N9831

AC→T

AC→TH

BCIRG-006

AC→T

1041

AC→TH

1077

1056

A higher incidence of renal impairment (13% in the FP arm vs. 16% in the FP+H arm) and toxic

nephropathy (4% in the FP arm vs. 6% in the FP+H arm) was reported in the ToGA (BO18255)

trial in MGC using NCI-CTCAE (v 3.0) criteria. Grade ≥3 renal toxicity was higher in patients

receiving trastuzumab than those in the chemotherapy alone arm (3% and 2% respectively).

NCI-CTCAE (v 3.0) grade ≥3 adverse events in the Hepatobiliary Disorders SOC:

Hyperbilirubinaemia was reported in 1% of patients receiving trastuzumab compared to <1% in

patients in the chemotherapy alone arm.

Blood and Lymphatic System Disorders

In the ToGA (BO18255) study in MGC, the total percentages of patients who experienced an AE

of ≥ grade 3 NCI-CTC AE v3.0 categorised under the SOC of Blood and Lymphatic System

Disorders were 38% in the FP arm and 40% in the FP + H arm.

Table 25 Blood and Lymphatic System Disorders SOC: The Most Frequently Reported

AEs of Grade ≥ 3 With Incidence Rate ≥ 1%

FP/Cisplatin

(N = 290)

(% of patients in each treatment

arm)

Trastuzumab/FP/Cisplatin (N = 294)

(% of patients in each treatment arm)

Neutropenia

Anaemia

Febrile Neutropenia

Thrombocytopenia

page 61 / 117

FP/Cisplatin

(N = 290)

(% of patients in each treatment

arm)

Trastuzumab/FP/Cisplatin (N = 294)

(% of patients in each treatment arm)

Leukopenia

<1%

9.2

Less Common Clinical Trial Adverse Reactions

Early Breast Cancer (EBC)

Listing of Adverse Events with Incidence Rate of < 1% in Study B-31

(Final analysis after median follow-up of 8.1 years in the AC - T+H group)

Allergy/immunology: allergy-other, autoimmune reaction

Auditory/hearing: hearing-other, inner ear/hearing, middle ear/hearing

Blood/bone marrow: hematologic-other, hemolysis, transfusion: platelets, transfusion: pRBC

(packed red blood cells)

Cardiovascular (arrhythmia): arrythmia-other, nodal/junctional arrythmia/dysrhythmia,

palpitations, sinus tachycardia, supraventricular arrhythmias*, vasovagal episode, ventricular

arrhythmia,

Cardiovascular (general): cardiac troponin I (cTnI), cardiac-ischemia/infarction*, circulatory or

cardiac-other, hypotension, pericardial effusion/pericarditis, peripheral arterial ischemia, phlebitis

(superficial), visceral arterial ischemia (non-myocardial),

Coagulation: coagulation-other, prothrombin time (PT)

Constitutional symptoms: constitutional symptoms-other, rigors/chills*, weight loss

Dermatology/skin: bruising (in absence of thrombocytopenia), dermatitis, dry skin, erythema

multiforme, flushing, hand-foot skin reaction, injection site reaction, pigmentation changes,

urticaria (hives, welts, wheals), wound non-infectious

Endocrine: endocrine-other, feminization of male, hypothyroidism, syndrome of inappropriate

anti-diuretic hormone (SIADH)

Gastrointestinal: colitis, duodenal ulcer, dysphagia, dysphagia-esophageal, flatulence, gastric

ulcer, gastritis,

mouth dryness, mucositis due to radiation, pancreatitis, proctitis, salivary gland

changes, sense of smell

Hemorrhage: CNS hemorrhage/bleeding, epistaxis, hematuria*, hemorrhage/bleeding without

thrombocytopenia, melena/GI bleeding, petechiae/purpura, rectal bleeding/hematochezia,

Hepatic: alkaline phosphatase*, bilirubin*, GGT (gamma-glutamyl transpeptidase), hepatic

enlargement, hepatic-other, hypoalbuminemia

Infection/febrile neutropenia: catheter-related infection

Lymphatics: lymphatics-other

Metabolic/laboratory: amylase, CPK (creatinine phosphokinase), hypocalcemia, hypokalemia,

hypercholesterolemia, hyperkalemia, hypertriglyceridemia, hypomagnesemia, hyponatremia,

hypophosphatemia, lipase, metabolic-other

Musculoskeletal: arthritis, muscle weakness, osteonecrosis

Neurology: arachnoiditis/meningismus/radiculitis, CNS cerebrovascular ischemia*, confusion,

cognitive disturbance/learning problems, delusions, depressed level of consciousness,

extrapyramidal/involuntary movement/, restlessness, leukoencephalopathy, memory loss,

neurologic-other, neuropathy-cranial, personality/behavioral, seizure(s), speech impairment,

tremor, vertigo

Not coded: raw term unknown

Ocular/visual: cataract, glaucoma, conjunctivitis, ocular-other, vision-double vision (diplopia),

vision-flashing lights/floaters, vision-photophobia

Pain: dysmenorrhea, dyspareunia, earache (otalgia), pain due to radiation, pelvic pain, pleuritic

pain, rectal or perirectal pain (proctalgia), tumour pain

page 62 / 117

Pulmonary: acute respiratory distress syndrome (ARDS), hypoxia, pleural effusion (non-

malignant), pneumonitis/pulmonary infiltrates, pneumothorax, pulmonary fibrosis, voice

changes/stridor/larynx

Radiation morbidity: radiation-other

Renal/genitourinary: bladder spasms, creatinine, incontinence, proteinuria, renal failure,

renal/genitourinary-other, ureteral obstruction

Sexual/reproductive function: libido, sexual/reproductive function-other

*AE term is itemized on the AE CRF.

Listing of Adverse Events with Incidence Rate of < 1% in Study N9831 (Final analysis

after median follow-up of 8.1 years in the AC - T+H group)

Auditory/hearing: inner ear/hearing

Blood/bone marrow: bone marrow cellularity, hemoglobin (HGB)*, platelets*, transfusion:

platelets, transfusion: pRBCS (packed red blood cells)

Cardiovascular (arrhythmia): arrythmia-other, sinus bradycardia, sinus tachycardia,

supraventricular arrhythmias, vasovagal episode, ventricular arrhythmia

Cardiovascular (general): circulatory or cardiac-other, hypotension, pericardial

effusion/pericarditis, phlebitis (superficial), visceral arterial ischemia (non-myocardial)

Constitutional symptoms: fever (in the absence of neutropenia), rigors/chills, weight gain,

weight loss

Dermatology/skin: dermatitis, erythema multiforme, hand-foot skin reaction, injection site

reaction, photosensitivity, radiation dermatitis, rash/desquamation, skin other, wound-infectious

Endocrine: endocrine-other, hypothyroidism, syndrome of inappropriate anti-diuretic hormone

(SIADH)

Gastrointestinal: anorexia, colitis, constipation, dehydration, diarrhea with prior colostomy*,

dyspepsia, GI-other, ileus, stomatitis/pharyngitis*

Hemorrhage: CNS hemorrhage/bleeding, hemorrhage/bleeding with thrombocytopenia

Hepatic: SGOT (AST) (serum glutamic oxaloacetic transaminase), SGPT (ALT) serum glutamic

pyruvic

transaminase

Lymphatics: lymphatics*

Metabolic/laboratory: hypoglycemia, hypokalemia, hyponatremia

Musculoskeletal: arthritis

Neurology: ataxia (incoordination), CNS cerebrovascular ischemia, confusion,

dizziness/lightheadedness, hallucinations, insomnia, memory loss, mood alteration-

anxiety/agitation, mood alteration-depression, speech impairment, syncope (fainting)

Ocular/visual: conjunctivitis

Pain: abdominal pain or cramping, bone pain, dyspareunia, headache, neuropathic pain, pain-

other, pleuritic pain

Pulmonary: acute respiratory distress syndrome (ARDS), apnea, cough, FEV

, hypoxia, pleural

effusion (non-malignant), pulmonary fibrosis, pulmonary-other

Renal/genitourinary: dysuria (painful urination), fistula or genitourinary fistula, renal failure,

renal/genitourinary-other, urinary frequency/urgency

Sexual/reproductive function: irregular menses (change from baseline)

*AE term is itemized on the AE CRF.

Listing of Adverse Events with Incidence Rate of < 1% in in Study BCIRG-006 (5 Year

Follow Up) According to NCI-CTC Classification v 2.0

page 63 / 117

Allergy/immunology: vasculitis

Auditory/hearing: external auditory canal

Blood/bone marrow: leukocytes (total WBC), platelets, transfusion: platelets, transfusion:

pRBCS (packed red blood cells)

Cardiovascular (general): CNS cerebrovascular ischemia, hypertension, hypotension, phlebitis

(superficial), thrombosis/embolism, cardiac- ischemia/infarction, edema, myocarditis

Cardiovascular (arrhythmia): sinus tachycardia, vasovagal episode, conduction abnormality/

atrioventricular heart

block, sinus bradycardia, ventricular arrhythmia

(PVCs/bigeminy/trigeminy/ventricular tachycardia)

Dermatology/skin: photosensitivity, radiation recall reaction (reaction following chemotherapy in

the absence of additional radiation therapy that occurs in a previous radiation port), urticaria

(hives, welts, wheals).

Gastrointestinal: colitis, duodenal ulcer (requires radiographic or endoscopic documentation),

dysphagia-esophageal related to radiation, gastric ulcer (requires radiographic or endoscopic

documentation), dyspepsia/heartburn

Hemorrhage: hematemesis, hematuria (in the absence of vaginal bleeding), hemoptysis,

hemorrhage/bleeding without grade 3 or 4 thrombocytopenia, melena/GI bleeding,

petechiae/purpura (hemorrhage/bleeding into skin or mucosa)

Hepatic: alkaline phosphatase, bilirubin, GGT (gamma - glutamyl transpeptidase), hepatic pain,

hypoalbuminemia, SGOT (AST) (serum glutamic oxaloacetic transaminase), SGPT (ALT) (serum

glutamic pyruvic transaminase)

Endocrine: cushingoid appearance (e.g., moon face with or without buffalo hump, centripetal

obesity, cutaneous striae), hypothyroidism

Metabolic/laboratory: hypercalcemia, hypercholesterolemia, hyperkalemia, hypernatremia,

hypertriglyceridemia, hyperuricemia, hypocalcemia, hypoglycemia, hyponatremia

Musculoskeletal: arthritis, myositis (inflammation/damage of muscle)

Neurology: arachnoiditis/meningismus/radiculitis, ataxia (incoordination), depressed level of

consciousness, extrapyramidal/involuntary movement/ restlessness, hallucinations, mood

alteration- euphoria, neuropathy-cranial, personality/behavioral, seizure(s), speech impairment

(e.g., dysphasia or aphasia)

Ocular/visual: cataract, glaucoma, middle ear/hearing, vision- double vision (diplopia), vision-

flashing lights/floaters, vision- night blindness (nyctalopia), vision-photophobia

Pain: dysmenorrhea, dyspareunia, pain due to radiation, pelvic pain, pleuritic pain, pain due to

radiation, rectal or perirectal pain (proctalgia), chest pain (non-cardiac and non-pleuritic)

Pulmonary: apnea, FEV

, hiccoughs (hiccups, singultus), pleural effusion (non-malignant),

pulmonary fibrosis, pneumonitis/pulmonary infiltrates, pneumothorax, dyspnea (shortness of

breath)

Renal/genitourinary: bladder spasms, creatinine, proteinuria, renal failure, urinary retention,

urine color change (not related to other dietary or physiologic cause e.g., bilirubin, concentrated

urine, hematuria)

Listing of Adverse Events with Incidence Rate of < 1% in in Study BCIRG-006 (5 Year

Follow Up) According to COSTART Classification

Body as a whole: abdomen enlarged, abdominal pain, abscess, aggravation reaction, allergic

reaction, ascites, asthenia, body odor, cellulitis, chest pain substernal, chills, collagen disorder,

granuloma, halitosis, headache, hernia, hormone level altered, hydrocephalus, hypothermia,

immune system disorder, infection, infection fungal, infection parasitic, injection site edema,

injection site hemorrhage, injection site inflammation, injection site reaction, lab test abnormal,

page 64 / 117

malaise, mucous membrane disorder, neck rigidity, necrosis, neoplasm, pelvic pain, peritonitis,

photosensitivity reaction, radiation injury, rheumatoid arthritis, scleroderma, viral infection

Cardiac adverse events (body as a whole): chest pain substernal, face edema, pain, angina

pectoris

Cardiovascular system: aortic stenosis, aphthous stomatitis, arrhythmia, arteriosclerosis,

bigeminy, bradycardia, bundle branch block, cardiomyopathy, cardiospasm, cardiovascular

disorder, carotid occlusion, cerebrovascular accident, cheilitis, congestive heart failure, coronary

artery disorder, coronary occlusion, dyspnea, electrocardiogram

abnormal, endocarditis,

extrasystoles, heart arrest, heart failure, heart malformation, hyperkinesia, hyperlipemia,

hypokinesia, hypotension, hypertonia, left heart failure, myocardial ischemia, pallor, palpitation,

pericarditis, peripheral vascular disorder, spider angioma, supraventricular extrasystoles,

supraventricular tachycardia, syncope, T inverted, tachycardia, thrombophlebitis, varicose vein,

vascular anomaly, vascular disorder, venous pressure increased, ventricular extrasystoles,

peripheral edema

Digestive system: cholecystitis, cholelithiasis, cirrhosis of liver, colitis, constipation, diarrhea,

dysphagia, eructation, esophageal hemorrhage, fecal incontinence, gamma glutamyl

transpeptidase increased, gastritis,

gastroenteritis, gastrointestinal disorder, gastrointestinal

hemorrhage, gingivitis, glossitis, hepatitis, hepatomegaly, increased appetite, jaundice, liver

function tests abnormal, liver necrosis, liver tenderness, melena, mouth ulceration, nausea, oral

moniliasis, perforated stomach ulcer, periodontal abscess, proctitis, rectal hemorrhage,

sialadentitis, stomach atony, stomatitis, tongue discoloration, tongue disorder, tongue edema,

tooth disorder, tooth malformation, vomiting

Endocrine system: diabetes mellitus, endocrine disorder, goiter, hyperthyroidism, thyroid

disorder

Hemic and lymphatic system: aplastic anemia, ecchymosis, hemolysis, hypochromic anemia,

leukopenia, lymphadenopathy, macrocytic anemia, myeloproliferative disorder, pancytopenia,

petechia, purpura, thrombocytopenia

Metabolic and nutritional disorders: acidosis, albuminuria, bun increased, electrolyte

abnormality, enzymatic abnormality, generalized edema, healing abnormal, hypercalcemia,

hypercholesteremia, hyperlipemia, hypoglycemia, hypophosphatemia, hypoproteinemia,

hypovelemia, lactic dehydrogenase increased, liver fatty deposit, respiratory alkalosis, thirst,

uremia, weight loss

Musculoskeletal system: arthritis, arthrosis, bone disorder, bone pain, bursitis, generalized

spasm, myalgia,

myasthenia, myositis, osteomyelitis, tendinous contracture, tenosynovitis

Nervous system: abnormal dreams, abnormal gait, agitation, amnesia, anxiety, ataxia, CNS

stimulation, coma, delirium, depression, dizziness, dry mouth, dysautonomia, emotional liability,

facial paralysis, grand mal convulsion, hyperesthesia, hyperkinesia, hypesthesia, hypokinesia,

ileus, incoordination, increased salivation, myelitis, myoclonus, nervousness, neuralgia,

nystagmus, paresthesia, peripheral neuritis, reflexes decreased, somnolence, thinking abnormal,

tremor, trismus, vasodilatation, apnea

Respiratory system: asthma, atelectasis, bronchitis, cough increased, dyspnea, hemoptysis,

hiccup, hyperventilation, hypoxia, laryngismus, laryngitis, larynx edema, lung disorder, lung

edema, lung fibrosis, pleural disorder, pneumonia, pneumothorax, respiratory disorder, sputum

increased, application site reaction

Skin and appendages: dry skin, eczema, erythema multiforme, exfoliative dermatitis, fungal

dermatitis, furunculosis, hair disorder, herpes zoster, hirsutism, ichthyosis, maculopapular rash,

psoriasis, pustular rash, skin benign neoplasm, skin carcinoma, skin discoloration, skin

granuloma, skin hypertrophy, skin nodule, skin ulcer, sweating, vesiculobullous rash

Special senses: abnormality of accommodation, blepharitis, blindness, conjunctival edema,

corneal lesion, deafness, ear disorder, extraocular palsy, eye disorder, eye hemorrhage,

page 65 / 117

glaucoma, keratitis, lacrimation disorder, mydriasis, ophthalmitis, otitis media, parosmia, ptosis,

pupillary disorder, refraction disorder, retinal vascular disorder, taste loss, taste perversion,

tinnitus, vestibular disorder, vitreous disorder

Urogenital system: amenorrhea, breast carcinoma, breast enlargement, breast neoplasm,

cervix disorder, cervix

neoplasm, cystitis, dysmenorrhea, dyspareunia, dysuria, endometrial

disorder, endometrial hyperplasia, female lactation, genital edema, kidney function abnormal,

kidney pain, mastitis, menopause, menorrhagia, menstrual

disorder, metrorrhagia, nocturia,

oliguria, ovarian disorder, polyuria, ruptured uterus, toxic nephropathy, unintended pregnancy,

urethritis, urinary frequency, urinary incontinence, urinary tract disorder, urinary tract infection,

urine abnormality, uterine disorder, uterine fibroids enlarged, uterine hemorrhage, uterine

neoplasm, vaginal hemorrhage, vaginal moniliasis, vaginitis, vulvovaginal disorder, vulvovaginitis

Metastatic Gastric Cancer (MGC)

Listing of Adverse Drug Reactions With Incidence Rate < 1% in ToGA (BO18255)

Cardiac disorders: arrhythmia, atrial fibrillation, atrial flutter, bradycardia, cardiac failure, left

ventricular dyfunction

Eye disorders: dry eye

Gastrointestinal disorders: abdominal pain lower, haemorrhoidal haemorrhage, lip swelling

General disorders and administration site conditions: influenza like illness, mucous

membrane disorder

Hepatobiliary disorders: hepatic failure, hepatitis toxic, hepatotoxicity, jaundice

Infections and infestations: bronchitis, cellulitis, herpes zoster, lower respiratory tract infection,

lung infection, neutropenic sepsis, paronychia, rhinitis, sepsis, sinusitis, urinary tract infection

Investigations: alanine aminotransferase increased, aspartate aminotransferase increased,

blood alkaline phosphatase increased, blood alkaline phosphatase increased, blood lactate

dehydrogenase increased, blood potassium increased, blood pressure decreased, ejection

fraction decreased, gamma-glutamyltransferase

increased, transaminases increased, white

blood cell count decreased

Metabolism and nutrition disorders: decreased appetite, fluid retention

Musculoskeletal and connective tissue disorders: arthritis, joint swelling

Nervous system disorders: neurotoxicity, paresis, somnolence, toxic neuropathy

Renal and urinary disorders: renal disorder

Respiratory, thoracic and mediastinal disorders: acute respiratory distress syndrome,

hypoxia, pharyngeal edema, pleural effusion, pneumonitis

Skin and subcutaneous tissue disorders: acne, dermatitis, erythema, hyperhidrosis, rash

macular, rash papular, rash pruritic

9.3

Post-Market Adverse Drug Reactions

Table 26 Adverse Reactions Reported in the Post-Market Setting

System organ class

Adverse reaction

Infections and infestations

Cystitis

Neutropenic sepsis

Blood and lymphatic system disorders

Hypoprothrombinemia

Immune thrombocytopenia

Immune system disorders

Anaphylactoid reaction

Anaphylactic reaction

Anaphylactic shock

Metabolism and nutrition disorders

Tumour lysis syndrome

page 66 / 117

System organ class

Adverse reaction

Eye disorders

Madarosis

Cardiac disorders

Cardiogenic shock

Tachycardia

Pericardial effusion

Respiratory, thoracic and mediastinal disorders

Bronchospasm

Oxygen saturation decreased

Respiratory failure

Interstitial lung disease

Lung infiltration

Acute respiratory distress syndrome

Respiratory distress

Pulmonary fibrosis

Hypoxia

Laryngeal oedema

Hepatobiliary disorders

Hepatocellular injury

Renal and urinary disorders

Glomerulonephropathy

Renal failure

Pregnancy, puerperium and perinatal conditions

Pulmonary hypoplasia

Renal hypoplasia

Oligohydramnios

Adverse Events

Table 27 below indicates adverse events that have been reported in patients who have received

trastuzumab.

Table 27 Adverse Events

System organ class

Adverse Event

Infections and infestations

Meningitis

Bronchitis

Blood and lymphatic system disorders

Leukaemia

Nervous system disorders

Cerebrovascular disorder

Lethargy

Coma

Ear and labyrinth disorders

Vertigo

Respiratory, Thoracic and Mediastinal system disorders

Hiccups

Dyspnea exertional

Gastrointestinal disorders

Gastritis

Pancreatitis

Musculoskeletal and connective tissue disorders

Musculoskeletal pain

Renal and urinary disorders

Dysuria

Reproductive system and breast disorders

Breast pain

General disorders and administration site conditions

Chest discomfort

10

DRUG INTERACTIONS

10.1

Overview

There have been no formal drug interaction studies performed with trastuzumab in humans.

Strong evidence for clinically significant interactions with concomitant medications used in

clinical studies has not been observed.

page 67 / 117

10.2

Drug-Drug Interactions

Administration of paclitaxel in combination with trastuzumab resulted in a two-fold decrease in

clearance of trastuzumab in a non-human primate study. In one clinical study, an apparent 1.5-

fold increase in serum levels of trastuzumab was seen when trastuzumab was administered

with paclitaxel. However this observation could not be confirmed using a population

pharmacokinetic approach (see DETAILED PHARMACOLOGY: Clinical Pharmacokinetics).

A population pharmacokinetic method using data from phase I, phase II and pivotal phase III

studies, was used to estimate the steady state pharmacokinetics in patients administered

trastuzumab at a loading dose of 4 mg/kg followed by a 2 mg/kg maintenance dose

administered weekly. The administration of concomitant chemotherapy (either anthracycline/

cyclophosphamide or paclitaxel) did not appear to influence the pharmacokinetics of

trastuzumab.

Experience from phase III clinical trials suggests that there is a potential drug interaction

between trastuzumab and anthracycline chemotherapy. However, the clinical pharmacokinetic

profile of doxorubicin or epirubicin in the presence of trastuzumab has not been described to

date, and the exact nature of this potential interaction has yet to be described.

When using in combination with pertuzumab and docetaxel, consult Product Monographs for

pertuzumab and docetaxel for further information on these drugs.

11

ACTION AND CLINICAL PHARMACOLOGY

11.1

Mechanism of Action

Trastuzumab is a recombinant DNA-derived humanized monoclonal antibody that selectively

targets the extracellular domain of the human epidermal growth factor receptor 2 protein

(HER2). The antibody is an IgG

isotype that contains human framework regions with

complementarity-determining regions of a murine anti-p185 HER2 antibody that binds to human

HER2.

The HER2 (or c-erbB2) proto-oncogene or c-erbB2 encodes for a single transmembrane

spanning, receptor-like protein of 185 kDa, which is structurally related to the epidermal growth

factor receptor. HER2 protein overexpression is observed in 25%-30% of primary breast

cancers. Studies of HER2-positivity rates in gastric cancer (GC) using immunohistochemistry

(IHC) and fluorescence in situ hybridization (FISH) or chromogenic in situ hybridization (CISH)

have shown that there is a broad variation of HER2-positivity ranging from 6.8% to 34.0% for

IHC and 7.1% to 42.6% for FISH A consequence of HER2 gene amplification is an increase in

HER2 protein expression on the surface of these tumour cells, which results in a constitutively-

activated HER2 protein. Studies indicate that patients whose tumours overexpress HER2 have

a shortened disease-free survival compared to patients whose tumours do not overexpress

HER2. HER2 protein overexpression can be determined using an immunohistochemistry-based

assessment of fixed tumour blocks, ELISA techniques on tissue or serum samples or

Fluorescence In Situ Hybridisation (FISH) technology. N.B., to date, only data derived from

immunohistochemistry staining is relevant to treatment with trastuzumab (see WARNINGS AND

PRECAUTIONS: Selection of Patients).

page 68 / 117

Trastuzumab has been shown, in both in vitro assays and in animals, to inhibit the proliferation

of human tumour cells that overexpress HER2.

Trastuzumab is a mediator of antibody-dependent cell-mediated cytotoxicity (ADCC). In vitro,

ADCC

mediated by trastuzumab has been shown

to be preferentially exerted on

HER2

overexpressing cancer cells compared with cancer cells that do not overexpress HER2.

11.2

Pharmacokinetics

The pharmacokinetics of trastuzumab have been studied in breast cancer patients with

metastatic disease. In phase I studies, short duration intravenous infusions of 10, 50, 100, 250

and 500 mg once weekly in patients demonstrated dose-dependent pharmacokinetics at doses

below 100 mg. Mean half-lives increased and clearance decreased with increasing dose level.

The half-life of trastuzumab averaged 1.7 and 12 days at the 10 and 500 mg dose levels,

respectively.

Early Breast Cancer (EBC)/Metastatic Breast Cancer (MBC)

A population pharmacokinetic method, using data from phase I, phase II and pivotal phase III

studies, was used to estimate the steady state pharmacokinetics in patients administered

trastuzumab at a loading dose of 4 mg/kg followed by a weekly maintenance dose of 2 mg/kg. In

this assessment, the typical clearance of trastuzumab was 0.225 L/day and the typical volume of

distribution was 2.95 L, with a corresponding terminal half-life of 28.5 days (95% confidence

interval, 25.5 - 32.8 days). The inter-patient variability in clearance and volume of distribution

was 43% and 29% (co-efficient of variation), respectively. These values are lower than those

estimated from the base model. Steady state weekly AUC of 578 mgday/L, peak concentrations

of 110 mg/L and trough concentrations of 66 mg/L should be reached by 143 days, or

approximately 20 weeks. It should be noted that these values represent free and dimer

complexes of trastuzumab as the assay utilized was unable to detect the trimer complex.

Trastuzumab

may persist in the circulation for approximately 24 weeks (range: 22-28 weeks,

based on a 6-fold

terminal elimination half-life value) (see WARNINGS AND PRECAUTIONS:

Cardiovascular, Cardiotoxicity).

EBC patients administered an initial loading dose of 8 mg/kg followed by a three weekly

maintenance dose of 6 mg/kg achieved steady state (see Table 28 below). These concentrations

were comparable to those reported previously in patients with MBC.

Table 28 Summary of Trastuzumab Pharmacokinetic Parameters for Patients Enrolled into

the Trastuzumab 1-year Treatment Group (sampled PK Population)

PK Parameter

Cycle 18

(trastuzumab 1-year arm)

Mean ± SD (n)

C

max

(µg/mL)

225 ± 30 (30)

Concentration – Day 21* (µg/mL)

68.9 ± 14 (28)

Concentration – Day 42 (µg/mL)

30.7 ± 14 (28)

AUC

0-21d

(dayµg/mL)

2260 ± 340 (28)

AUC

0-42d

(dayµg/mL)

3270 ± 560 (28)

Half-life (day)

18.8 ± 7.2 (29)

* Day 21 concentration w as calculated by linear interpolation from concentrations observed in patients on Days 14

and 28

page 69 / 117

Detectable concentrations of the circulating extracellular domain of the HER2 receptor (shed

antigen) are found in the serum of some patients with HER2-overexpressing tumours. Patients

with higher baseline shed antigen levels were more likely to have lower serum trough

concentrations of trastuzumab, however, with weekly dosing, most patients with elevated shed

antigen levels achieved target serum concentrations by week 6. Levels of shed antigen were

only determined at baseline in the clinical trials. As a result, the available data are too limited to

adequately characterize the interrelationship of HER2 overexpression and serum shed antigen

concentrations.

Data suggest that the disposition of trastuzumab is not altered based on age or serum

creatinine (up to 2.0 mg/dL or 176.8 μmol/L). No formal interaction studies have been

performed.

Metastatic Gastric Cancer (MGC)

A population pharmacokinetic method, using data from the Phase III study ToGA (BO18255),

was used to estimate the steady state pharmacokinetics in patients with MGC administered

trastuzumab 3-weekly at a loading dose of 8 mg/kg followed by a 3-weekly maintenance dose of

6 mg/kg. In this assessment, the typical clearance of trastuzumab was 0.378 L/day and the

typical volume of distribution was 3.91 L, with a corresponding equilibrium half-life of 12.2 days.

The median predicted steady-state AUC values (over a period of 3 weeks at steady state) is

equal to 1030 mgday/L, the median steady-state C

is equal to 128 mg/L and the median

steady-state C

values is equal to 23 mg/L. Steady state concentrations should be reached by

49 days, (four equilibrium half lives) or approximately 7 weeks.

Trastuzumab clearance in MGC patients is higher than that in MBC patients, leading to lower

AUC, C

and C

at steady-state.

The estimated equilibrium half-life of trastuzumab was 12.2 days in the ToGA (BO18255) trial

and 26.3 days for studies BO15935 and WO16229 (in MBC). The lower value in the ToGA

(BO18255) trial was due to the increase in clearance in the MGC patients.

Special Populations and Conditions

Detailed pharmacokinetic studies in the elderly and those with renal or hepatic impairment have

not been carried out.

12

STORAGE, STABILITY AND DISPOSAL

Vials of HERZUMA

(trastuzumab) are stable at 2°C - 8°C prior to reconstitution. Discard any

vial that is past the expiry date indicated on the label. A vial of HERZUMA

reconstituted with

BWFI, containing 1.1% benzyl alcohol, as supplied, is stable for 28 days after reconstitution

when stored refrigerated at 2°C -8°C. Discard any remaining reconstituted solution after 28

days. If unpreserved SWFI (not supplied) is used, the reconstituted solution of HERZUMA

should be used immediately and any unused portion must be discarded. Do not freeze

HERZUMA

that has been reconstituted.

The solution of HERZUMA

for infusion diluted in polyvinylchloride, polyethylene or

polypropylene bags containing 0.9% Sodium Chloride Injection, USP, is physicochemically

stable for up to 24 hours at temperatures up to 30°C prior to use. However, since diluted

HERZUMA

contains no preservative, the reconstituted and diluted solution should be stored

page 70 / 117

refrigerated (2°C -8°C). From a microbiological point of view, the infusion solution of

HERZUMA

should be used immediately.

Disposal of unused/expired medicines

The release of pharmaceuticals in the environment should be minimized. Medicines should not

be disposed of via wastewater and disposal through household waste should be avoided. Use

established “collection systems”, if available in your location. Local requirements should be

followed for the disposal process of unused/expired medicines.

13

SPECIAL HANDLING INSTRUCTIONS

Disposal of syringes/sharps

The following procedures should be strictly adhered to regarding the use and disposal of

syringes and other medicinal sharps:

Needles and syringes should never be reused.

Place all used needles and syringes into a sharps container (puncture-proof disposable

container).

Dispose of the full container or waste material according to local requirements.

page 71 / 117

PART II: SCIENTIFIC INFORMATION

14

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Trastuzumab

Chemical name: Trastuzumab

Molecular formula and molecular mass: HC - C

2192

3387

LC - C

1032

1603

145,165 g/mol

Structural formula: Each heavy chain consists of 449 amino acids (without the C-terminal lysine

residue) with 11 cysteine residues and each light chain consists of 214 amino acids with 5 cysteine

residues.

Figure 1 Amino Acid Sequence of HERZUMA

®

(Trastuzumab)

Heavy Chain

1 EVQLVESGGG LVQPGGSLRL SCAASGFNIK DTYIHWVRQA PGKGLEWVAR

51 IYPTNGYTRY ADSVKGRFTI SADTSKNTAY LQMNSLRAED TAVYYCSRWG

101 GDGFYAMDYW GQGTLVTVSS ASTKGPSVFP LAPSSKSTSG GTAALGCLVK

151 DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSVVT VPSSSLGTQT

201 YICNVNHKPS NTKVDKKVEP KSCDKTHTCP PCPAPELLGG PSVFLFPPKP

251 KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN

1

301 STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ

351 VYTLPPSREE MTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV

401 LDSDGSFFLY SKLTVDKSRW QQGNVFSCSV MHEALHNHYT QKSLSLSPGK

2

Light Chain

1 DIQMTQSPSS LSASVGDRVT ITCRASQDVN TAVAWYQQKP GKAPKLLIYS

51 ASFLYSGVPS RFSGSRSGTD FTLTISSLQP EDFATYYCQQ HYTTPPTFGQ

101 GTKVEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV

151 DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG

201 LSSPVTKSFN RGEC

Physicochemical properties: HERZUMA

is a humanized IgG1 monoclonal antibody produced by

mammalian (Chinese hamster ovary) cell suspension culture and purified by affinity and ion

exchange chromatography including specific viral inactivation and removal procedures.

Product Characteristics

HERZUMA

is a recombinant humanized monoclonal immunoglobulin G1 antibody that has

previously been demonstrated to bind to the extracellular domain (ECD) of the HER2 protein with

high affinity, preventing activation of its intracellular tyrosine kinase.

page 72 / 117

15

COMPARATIVE CLINICAL TRIALS

15.1

Comparative Trial Design and Study Demographics

Clinical studies conducted to support similarity between HERZUMA

and the reference biologic

drug, HERCEPTIN

, included:

Study CT-P6 1.5, a randomized, double-blind, parallel-group, single-dose study to compare the

PK, safety and immunogenicity of HERZUMA

and HERCEPTIN

in healthy volunteers

Study CT-P6 3.2, a randomized, double-blind, parallel-group, active-controlled study to

compare the efficacy and safety of HERZUMA

and HERCEPTIN

as neoadjuvant and

adjuvant treatment in patients with HER2-positive early breast cancer.

An overview of the study design(s) and demographic characteristics of patients enrolled in each

clinical study are presented in Table 29.

Table 29 Summary of trial design and patient demographics

Study #

Trial design

Dosage, route of

administration and

duration

Study subjects

(n)

Mean age

(Range)

(years)

Sex

(n)

CT-P6 1.5

Randomized,

controlled, 2-arm,

parallel-group, double-

blind, single-dose

study in healthy male

subjects

HERZUMA

HERCEPTIN

6 mg/kg, IV infusion for 90

minutes (± 5 minutes)

Randomized :

70 healthy

subjects

HERZUMA

: 35

HERCEPTIN

HERZUMA

36.2 (20 -

HERCEPTIN

: 34.1 (18 -

Male:

page 73 / 117

Study #

Trial design

Dosage, route of

administration and

duration

Study subjects

(n)

Mean age

(Range)

(years)

Sex

(n)

CT-P6 3.2

Randomized,

controlled, 2-arm,

parallel-group, double-

blind, multicentre,

international study in

patients w ith HER2-

Positive EBC

Neoadjuvant Period

HERZUMA

HERCEPTIN

Loading dose of 8 mg/kg

on Day 1 of Cycle 1, and

then 6 mg/kg repeated

every 3 w eeks on Day 1 of

Cycles 2-8

90-minute IV infusion

(± 5 minutes)

Docetaxel:

Immediately

after the dose

of study drug (Day 1 of

each cycle), 3-w eekly for

12 w eeks (Cycles 1-4)

75 mg/m

as a 1-hour IV

infusion

FEC:

Immediately

after the dose

of study drug (Day 1 of

each cycle), 3-w eekly for

12 w eeks (Cycles 5-8)

Fluorouracil 500 mg/m

a 3- to 5-minute IV bolus

or as an infusion for 30

minutes (± 5 minutes);

Epirubicin 75 mg/m

as a

3- to 5-minute IV bolus or

as an infusion for 30

minutes (± 5 minutes);

Cyclophosphamide

500 mg/m

as an IV bolus

for 3 to 5 minutes

Adjuvant Period

HERZUMA

HERCEPTIN

6 mg/kg, 3-w eekly for up

to 1 year from the first day

of study drug

administration in the

Neoadjuvant Period,

excluding surgery (or up to

10 cycles after surgery)

90-minute IV infusion

(± 5 minutes)

Randomized:

562 EBC

patients

HERZUMA

HERCEPTIN

HERZUMA

52.1

(24 - 79)

HERCEPTIN

: 52.0

(22 - 74)

Female

: 562

The treatment of EBC patients with trastuzumab in the neoadjuvant setting is a model for

assessing comparative clinical safety and efficacy; however, it is not an authorized indication in

Canada.

page 74 / 117

15.2

Comparative Study Results

15.2.1 Comparative Bioavailability Studies

15.2.1.1

Pharmacokinetics

Comparability criteria were met for the PK parameters C

and AUC

as the point estimate for the

ratio of the geometric means for HERZUMA

and HERCEPTIN

for C

and the 90% CI for the

ratio of the geometric means for AUC

were within the acceptance margins of 80.0% to 125.0%

(see Table 30).

Table 30 Analysis of PK Parameters (from measured data) in Study CT-P6 1.5

Trastuzumab

(1 x 6 mg/kg)

From measured data

Geometric Mean

Arithmetic Mean (CV %)

Parameter

HERZUMA

®

HERCEPTIN

®

Roche (US)

Ratio (%) of

Geometric LS Means

90% CI of

Ratio (%)

(h·µg /mL)

18183.7

18942.0 (19.3)

18312.5

19121.2 (18.8)

99.3

92.9 - 106.2

(h·µg /mL)

19523.1

20307.5 (18.7)

19709.4

20519.9 (17.6)

99.1

93.0 - 105.5

(µg/mL)

128.0

133.0 (17.9)

132.5

137.3 (15.5)

96.6

90.9 - 102.6

2.2 (43.3)

2.6 (63.7)

189.3 (19.0)

183.7 (20.4)

Note: Number of subjects in each treatment group is 35.

and T

are expressed as the arithmetic mean (CV %) only.

: Area under the serum concentration-time curve from time 0 to infinity; AUC

: Area under the serum

concentration-time curve from time 0 to the last measurable concentration; CI: Confidence interval; C

: Observed

maximum

serum concentration; LS: Least squares; PK: Pharmacokinetics; T

: Terminal half-life; T

: Time to

maximum

serum concentration.

15.2.2

Comparative Safety and Efficacy

15.2.2.1

Efficacy

Early Breast Cancer

Study CT-P6 3.2

The comparative efficacy and safety study CT-P6 3.2 was designed to rule out any clinically

meaningful differences between HERZUMA

and HERCEPTIN

, both given in combination with

docetaxel (Cycles 1 through 4) followed by 5-fluorouracil, epirubicin, and cyclophosphamide (FEC)

(Cycles 5 through 8), in terms of efficacy as determined by pathological complete response (pCR),

in patients with HER2-positive operable early breast cancer. The study included female patients 18

years of age or older with histologically confirmed and newly diagnosed breast cancer. Patients

had HER2-positive status confirmed locally, defined as 3+ score by immunohistochemistry (IHC).

When the IHC result was equivocal (defined as 2+ score), the patient had a positive fluorescence

in situ hybridization (FISH) or a chromogenic in situ hybridization (CISH) result.

page 75 / 117

Demographic and baseline disease characteristics were similar between the HERZUMA

arm and

the HERCEPTIN

arm with respect to age, race, height, weight, hormone receptor status and

stage of disease. Overall, at screening 58.4% of study patients were hormone receptor positive

(estrogen and/or progesterone), and the most frequently reported stage was Stage IIb (I: 10.0%,

IIa: 29.2%, IIb: 36.7%, IIIa: 23.1%).

The primary efficacy endpoint was the proportion of patients achieving pCR, defined as the

absence of invasive tumour cells in the breast and in axillary lymph nodes, regardless of the ductal

carcinoma in situ (DCIS). The pCR was determined at the time of surgery, using hematoxylin and

eosin evaluation of the resected specimen.

Comparability between HERZUMA

and HERCEPTIN

was demonstrated since the two-sided

95% confidence interval of the risk ratio for pCR after the Neoadjuvant Period was entirely

contained within the pre-defined equivalence interval of [0.74 to 1.35].

Table 31 Pathological Complete Response (pCR) Rate after the Neoadjuvant Period in Study

CT-P6 3.2 (ITT set)

ITT set

HERZUMA

(n=278)

HERCEPTIN

®

(n=284)

Primary endpoint: pCR

Response rate (%)

(95% CI)

120 (43.17%)

(37.26 – 49.21)

134 (47.18%)

(41.26 – 53.17)

Risk ratio estimate

(95% CI)

for risk ratio estimate

0.9149

(0.7622 – 1.0981)

Abbreviations: CI, Confidence interval; ITT, intent-to-treat; pCR, pathological complete response

Asymptotic CI.

15.2.2.2

Safety

The types, frequency and severity of adverse events were comparable between the biosimilar and

the reference biologic drug.

15.2.2.3

Immunogenicity

In Study CT-P6 1.5, no subject tested positive for ADAs at any time point. In Study CT-P6 3.2, no

patients tested positive for ADAs at any post-baseline time points during the Neoadjuvant and

Adjuvant Periods.

16

COMPARATIVE NON-CLINICAL PHARMACOLOGY AND TOXICOLOGY

16.1

Comparative Non-Clinical Pharmacodynamics

In vitro Studies

The active substance of HERZUMA

, trastuzumab, is a humanized monoclonal antibody that has

been designed to bind to the ECD of the HER2 protein with high affinity. It was reported that

trastuzumab exerts its action by several mechanisms including: prevention of receptor dimerization

and activation, inhibition of signaling pathways, and downregulation of HER2 receptors. However,

although trastuzumab has been shown to activate the complement cascade, no CDC activity against

tumour cell lines occurred, probably due to the presence of regulatory proteins such as CD46, CD55

and CD59 on breast cancer cell lines.

page 76 / 117

In vitro similarity assays such as in vitro bioactivity (anti-proliferation activity), HER2 binding affinity,

cell-based HER2 binding affinity, FcRn binding affinity, FcγRI/RIIa/RIIb/RIIIa(F/V type)/RIIIb binding

affinity, ADCC activity (peripheral blood mononuclear cell [PBMC] and reporter assay) and C1q

binding affinity have been performed to demonstrate similarity in the mode of action between

HERZUMA

and HERCEPTIN

and it was concluded to be highly similar.

16.2

Comparative Toxicology

A repeat-dose toxicity study with intravenous administration of HERZUMA

and HERCEPTIN

once

weekly for 4 weeks has been performed in both sexes cynomolgus monkeys (n=3/sex per group) at

2 doses of 14 and 42 mg/kg (Study ZIP0014). HERZUMA

and HERCEPTIN

were well tolerated

and no test article-related changes was identified in mortality, body weights, electrocardiography

(ECG),

haematology, blood

chemistry,

urinalysis,

organ weight,

macroscopic

findings

histopathological finding. Overall, the toxicological responses and the toxicokinetic profiles of

treatment with HERZUMA

or HERCEPTIN

in cynomolgus monkeys were similar.

17

CLINICAL TRIALS – REFERENCE BIOLOGIC DRUG

Early Breast Cancer (EBC)

In the adjuvant treatment setting, trastuzumab was investigated in 4 large multicentre,

randomized, trials:

The HERA study was designed to compare one year of three-weekly trastuzumab

treatment versus observation in patients with HER2 positive EBC following surgery,

established chemotherapy and radiotherapy (if applicable).

The NSAPB B31 and NCCTG N9831 studies that comprise the Joint Analysis were

designed to investigate the clinical utility of combining trastuzumab treatment with

paclitaxel following AC chemotherapy in HER2 positive EBC following surgery.

Additionally, the NCCTG N9831 study investigated adding trastuzumab sequentially

after AC-paclitaxel chemotherapy in patients with HER2 positive EBC following

surgery.

The BCIRG-006 study was designed to investigate combining trastuzumab treatment

with docetaxel either following AC chemotherapy, or in combination with docetaxel and

carboplatin in patients with HER2 positive EBC following surgery.

The comparative efficacy and safety between different chemotherapy regimens (i.e. concurrent

versus sequential, anthracycline containing versus non-anthracycline containing) was not

studied.

page 77 / 117

Eligible patients in the four studies included women with operable, non-metastatic adenocarcinoma of the breast whose tumours

overexpressed HER2 and who had either node-positive or high-risk node-negative disease. Definitions used in each protocol are

shown in Table 32.

Table 32 Eligible Populations in EBC Studies, by TNM Categories

a

STUDY

AJCC TNM Version

T

N

M

Comment

HERA

Staging Manual 5

edition (1997)

≥T1c, T2, T3, pT4

N0, N1, N2, N3

Prior (neo)adjuvant

chemotherapy required.

Prior radiotherapy

required for nodal

(axillary, internal

mammary) or pT4

disease.

NSABP B-31

Staging Manual 5

edition (1997)

updated May 2003 to:

Staging Manual 6

edition (2002)

clinical T1, T2, T3

updated May 2003

T1, T2, T3

(clinical and pathologic)

cN0, cN1

updated May 2003

cN0, cN1 and pN1,

pN2a, pN3a

No prior chemotherapy or

radiotherapy permitted.

Whole breast irradiation

required during study;

partial breast or internal

mammary radiation

prohibited.

NCCTG N9831

Staging Manual 5

edition (1997)

T1, T2, T3

pN1, pN2

(minimum

1/6 nodes)

No prior chemotherapy or

radiotherapy permitted.

Breast + regional

lymphatic irradiation

during study, per

radiotherapist.

T1c (ER-/PR- only), T2,

pN0 (minimum sentinel

node

or 1/6 nodes)

BCIRG-006

Staging Manual 5

edition (1997) [not

specified in

protocol]

T1, T2, T3

pN1, pN2

(minimum

1/6 nodes)

No prior chemotherapy or

radiotherapy permitted.

Breast + regional

lymphatic irradiation

during study, per

radiotherapist.

≥T2, or ER-/PR-,

nuclear Grade 2-3, or

age <35 yrs

pN0 (minimum sentinel

node

or 1/6 nodes)

Required for all studies: (1) invasive adenocarcinoma on histologic examination; (2) complete excision of primary tumour w ith tumour-free margins on histologic

examination of specimens from definitive surgery; and (3) HER2 positive tumour

page 78 / 117

HERA

In the adjuvant setting, trastuzumab was investigated in HERA, a multicentre, randomized, trial

designed to compare one and two years of three-weekly trastuzumab treatment versus observation

in patients with HER2 positive EBC following surgery, established chemotherapy and radiotherapy

(if applicable). In addition, a comparison of two years trastuzumab treatment versus one year

trastuzumab treatment was performed, with the objective to assess the superiority of two years of

trastuzumab treatment relative to one year of trastuzumab treatment. Breast tumour specimens

were required to show HER2 overexpression (3+ by IHC) or gene amplification (by FISH) as

determined at a central laboratory.

Patients assigned to receive trastuzumab were given an initial loading dose of 8 mg/kg, followed by

6 mg/kg every three weeks for either one or two years. One year of trastuzumab treatment was

defined as 12 calendar months of treatment from day 1 of first administration and 18 infusions

maximum. Two years of trastuzumab treatment were defined as 24 calendar months of treatment

from day 1 of first administration and 35 infusions maximum.

The efficacy results from the HERA trial are summarized in Table 33. Please see ADVERSE

REACTIONS and WARNINGS AND PRECAUTIONS: Cardiovascular/Cardiotoxicity/Early Breast

Cancer for a summary of the HERA safety information.

Table 33 Efficacy Results from the HERA Trial: Results at 12 months* and 8 years** of

median follow-up

Median follow -up

12 months

Median follow -up

8 years

Parameter

Observation

N=1693

trastuzumab

1 Year

N=1693

Observation

N=1697***

trastuzumab

1 Year

N=1702***

Disease-free

survival (DFS)

- No. patients with

event

219 (12.9%)

127 (7.5%)

570 (33.6%)

471 (27.7%)

- No. patients

without event

1474 (87.1%)

1566 (92.5%)

1127 (66.4%)

1231 (72.3%)

P-value versus

Observation

<0.0001

Hazard Ratio

versus Observation

0.54

0.76

Adjusted (99.9%)

Confidence

Interval****

(0.38, 0.78)

Recurrence-free

survival

- No. patients with

event

208 (12.3%)

113 (6.7%)

506 (29.8%)

399 (23.4%)

- No. patients

without event

1485 (87.7%)

1580 (93.3%)

1191 (70.2%)

1303 (76.6%)

Hazard Ratio

versus Observation

0.51

0.73

Distant disease-

free survival

- No. patients with

event

184 (10.9%)

99 (5.8%)

488 (28.8%)

399 (23.4%)

- No. patients

without event

1508 (89.1%)

1594 (94.6%)

1209 (71.2%)

1303 (76.6%)

Hazard Ratio

versus Observation

0.50

0.76

page 79 / 117

Median follow -up

12 months

Median follow -up

8 years

Parameter

Observation

N=1693

trastuzumab

1 Year

N=1693

Observation

N=1697***

trastuzumab

1 Year

N=1702***

Overall survival

(death)

- No. patients with

event

40 (2.4%)

31 (1.8%)

350 (20.6%)

278 (16.3%)

- No. patients

without event

1653 (97.6%)

1662 (98.2%)

1347 (79.4%)

1424 (83.7%)

Hazard Ratio

versus Observation

0.75

0.76

*Co-primary endpoint of DFS of 1 year vs observation met the pre-defined statistical boundary of 0.0010.

**Final analysis (including crossover of 52% of patients from the observation arm to trastuzumab).

***There is a discrepancy in the overall sample size due to a small number of patients w ho w ere randomized after the

cut-off date for the 12-month median follow -up analysis.

**** Adjusted (both for the interim analysis and the 2 comparisons of each trastuzumab arm (1 year and 2 years) vs.

observation) confidence interval presented, to reflect the stopping boundary of p≤ 0.0010 of the comparison

trastuzumab 1year vs. observation. The interval represents the 99.9% confidence interval.

The efficacy results from the interim efficacy analysis crossed the protocol pre-specified statistical

boundary of 0.0010 for the comparison of 1-year of trastuzumab vs. observation. After a median

follow-up of 12 months, the hazard ratio (HR) for disease free survival (DFS) was 0.54 (adjusted

99.9% CI: 0.38, 0.78) which translates into an absolute benefit, in terms of a 2-year disease-free

survival rate, of 7.6 percentage points (85.8% vs. 78.2%) in favour of the trastuzumab arm. Please

see Figure 2.

A final analysis was performed after a median follow-up of 8 years, which showed that 1 year

trastuzumab treatment is associated with a 24% risk reduction compared to observation only (HR =

0.76, unadjusted 95% CI: 0.67, 0.86). This translates into an absolute benefit in terms of an 8 year

disease free survival rate of 6.4% in favour of 1 year trastuzumab treatment.

In this final analysis, superiority of 2 years trastuzumab treatment over 1 year trastuzumab

treatment could not be demonstrated (DFS HR in the intent to treat (ITT) population of 2 years vs 1

year = 0.99 (unadjusted 95% CI: 0.87, 1.13), p-value = 0.90 and OS HR = 0.98 (unadjusted 95%

CI: 0.83, 1.15); p-value = 0.78). The rate of secondary cardiac endpoints was increased in the 2-

year treatment arm (8.1% vs 4.6% in the 1-year treatment arm). More patients experienced at least

one grade 3 or 4 adverse event in the 2-year treatment arm (20.4%) compared with the 1-year

treatment arm (16.3%).

page 80 / 117

Figure 2 Kaplan-Meier curve of Disease Free survival (After a Median Follow-up of 12

Months)

* Adjusted (both for the interim analysis and the 2 comparisons of each trastuzumab arm (1 year and 2 years) vs.

observation) confidence interval presented, to reflect the stopping boundary of p≤ 0.0010 of the comparison trastuzumab

1year vs. observation. The interval represents the 99.9% confidence interval.

The benefit in disease-free survival was seen in all subgroups analysed (Please see Figure 3).

Events

2-yr DFS

HR

adjusted (99.9%) CI*

p-value

Trastuzumab 1 year

85.8

0.54

0.38, 0.78

<0.0001

Observation

78.2

page 81 / 117

Figure 3 Risk Ratios and 95% Confidence Intervals for Disease-Free Survival by Subgroup

(After a Median Follow-up of 12 Months)

Note: 95%-CIs are not adjusted for multiple testing.

Twenty one (1.2%) patients in the trastuzumab arm and 16 (0.9) patients in the observation had

CNS metastases as first site of relapse.

Figure 4 Kaplan-Meier Curve of Recurrence-Free Survival (After a Median Follow-up of 12

Months)

Note: 95%-CI is not adjusted for multiple testing.

page 82 / 117

Figure 5 Kaplan-Meier Curve of Distant-Disease-Free Survival (After a Median Follow-up of

12 Months)

Note: 95%-CI is not adjusted for multiple testing.

Joint Analysis: NSABP B-31 and NCCTG N9831

Two cooperative group trials, NSABP B-31 and NCCTG N9831, evaluated the efficacy of

incorporating trastuzumab into standard adjuvant systemic therapy in women with early stage,

HER2 positive breast cancer. Breast tumour specimens were required to show HER2

overexpression (3+ by IHC) or gene amplification (by FISH). HER2 testing was verified by a

central

laboratory prior to randomization (N9831) or was required to be performed at a reference

laboratory (B-31). Patients were randomized to receive doxorubicin and cyclophosphamide

followed by paclitaxel (AC→T) or doxorubicin and cyclophosphamide followed by paclitaxel

plus

trastuzumab (AC→T + H). In both trials patients received four cycles (3 weeks per cycle) of

doxorubicin, at 60 mg/m

IV push, concurrently with IV cyclophosphamide at 600 mg/m

over 20–

30 minutes. Paclitaxel was administered weekly (80mg/m

) or every 3 weeks (175mg/m

) for a total

of 12 weeks in NSABP B-31; paclitaxel was administered weekly (80mg/m

) for 12

weeks in

NCCTG N9831. Trastuzumab was administered at a loading dose of 4 mg/kg load

followed by 2

mg/kg IV weekly. Trastuzumab commenced with paclitaxel and continued for a total of 52 weeks in

both trials. Disease-free survival was the pre-specified primary endpoint of the combined efficacy

analysis of these studies.

A total of 3752 patients were evaluable for analysis of efficacy at the time of the definitive disease-

free survival analysis. Median follow-up from the time of randomization was 1.8 years for the

chemotherapy alone arm and 2.0 years for the trastuzumab + chemotherapy arm for both

studies

combined. Efficacy results are presented in Table 34 and Figure 6. For the primary endpoint,

disease-free survival, addition of trastuzumab to chemotherapy reduced the risk of a first event by

52%. Please see ADVERSE REACTIONS and WARNINGS AND PRECAUTIONS:

Cardiovascular/Cardiotoxicity/Early Breast Cancer for a summary of the Joint Analysis safety

information.

page 83 / 117

Table 34 Joint Analysis: NSABP B-31 and NCCTG N9831 Efficacy Results at the Time of the

Definitive Disease-Free Survival Analysis* (ITT population)

AC→T

a

n=1880

AC→T+trastuzumab

a

n=1872

No. with Event

No. with Event

Hazard Ratio

b

(95% CI)

p-value

c

Disease-free

survival (DFS)

0.48

(0.39 - 0.59)

< 0.0001

Overall survival

(OS)

0.67

CI = confidence interval.

Disease-free survival w as defined as the time from randomization to recurrence, contralateral breast cancer or other

second primary cancer, or death, w hichever occurred first. Overall survival w as defined as the time from

randomization to death.

* at median duration of follow up of 1.8 years for the patients in the AC→T arm and 2.0 years for patients in the

AC→TH arm

NSABP B-31 and NCCTG

N9831 regimens: doxorubicin and cyclophosphamide follow ed by paclitaxel (AC→T) or

paclitaxel plus trastuxumab (AC→TH).

Hazard ratio estimated by Cox regression stratified by clinical trial, intended paclitaxel schedule, number of

positive nodes, and hormone receptor status.

stratified log-rank test.

NS=non-significant.

Figure 6 Duration of Disease-Free Survival in Patients from the Joint Analysis: NSABP B-31

and NCCTG N9831

There were insufficient numbers of patients within each of the following subgroups to determine if

the treatment effect was different from that of the overall patient population: Black, Hispanic,

Asian/Pacific Islander patients, node-negative high-risk patients, and patients > 65 years of age.

page 84 / 117

The pre-planned final analysis of overall survival (OS) from the joint analysis of studies NSABP B-

31 and NCCTG N9831 was performed when 707 deaths had occurred (median follow-up 8.3 years

in the AC→T+H group). Treatment with AC→T+H resulted in a statistically significant improvement

in OS compared with AC→T (stratified HR=0.64; 95.1% CI [0.55, 0.74]; log-rank p-value < 0.0001);

formal boundary for statistical significance p-value=0.0245). At 8 years, the survival rate was

estimated to be 86.9% in the AC→T+H arm and 79.4% in the AC→T arm, an absolute benefit of

7.4% (refer to Figure 7).

The final OS results from the joint analysis of studies NSABP B-31 and NCCTG N9831 are

summarized in Table 35.

Table 35 Final Overall Survival Analysis from the Joint Analysis: NSABP B-31 and NCCTG

N9831

AC→T

a

n=2032

AC→T+trastuzumab

a

n=2031

No. with Event

No. with Event

Hazard Ratio

(95.1% CI)

p-value

Overall Survival

418 (20.6%)

289 (14.2%)

0.64

(0.55–0.74)

< 0.0001

NSABP B-31 and NCCTG

N9831 regimens: doxorubicin and cyclophosphamide follow ed by paclitaxel (AC→T) or

paclitaxel plus trastuzumab (AC→TH).

Figure 7 Duration of Overall Survival in Patients from the Joint Analysis: NSABP B- 31 and

NCCTG N9831

page 85 / 117

Disease-Free Survival (DFS) analysis was also performed at the final analysis of OS from the joint

analysis of studies NSABP B-31 and NCCTG N9831. The updated DFS analysis results showed a

similar DFS benefit compared to the definitive primary DFS analysis.

BCIRG-006

In the BCIRG-006 study, patients were randomized (1:1:1) to receive doxorubicin and

cyclophosphamide followed by docetaxel (ACT), doxorubicin and cyclophosphamide followed by

docetaxel plus trastuzumab (AC→TH), or docetaxel and carboplatin plus trastuzumab (TCH).

Trastuzumab was administered weekly (initial dose of 4 mg/kg followed by weekly dose of 2 mg/kg)

concurrently with either T or TC, and then every 3 weeks (6 mg/kg) as monotherapy for a total of 52

weeks.

In the ACT arm, doxorubicin 60 mg/m

IV was administered in combination with

cyclophosphamide 600 mg/m

IV on an every 3 week basis for 4 cycles followed by docetaxel 100

mg/m

as 1 hour IV infusion on an every 3 week basis for 4 cycles.

In the ACTH arm, every 3 weeks for four cycles, patients in the AC→TH arm received 60 mg/m

doxorubicin as a 5- to 15-minute intravenous (IV) bolus injection followed by 600 mg/m

cyclophosphamide as a 5- to 60-minute IV bolus injection. Three weeks after the last

treatment with

AC (i.e., on Day 1 of Cycle 5), a 4-mg/kg trastuzumab loading dose was administered as a 90-

minute IV infusion. Beginning on Day 8 of Cycle 5, 2 mg/kg trastuzumab was administered as a 30-

minute IV infusion every week. Docetaxel 100 mg/m