PAT I E N T ’ S G U I D E TO P E R J E TA

A first-line treatment for HER2-positive (HER2+)

metastatic breast cancer

What does PERJETA treat?

PERJETA® (pertuzumab) is a prescription medicine approved for use in combination with
Herceptin® (trastuzumab) and docetaxel in people who have HER2-positive breast cancer that
has spread to different parts of the body (metastatic) and who have not received anti-HER2 therapy
or chemotherapy for metastatic breast cancer.
Important Safety Information
What are the most serious side effects of PERJETA?
PERJETA may cause heart problems, including those without symptoms (such as reduced heart
function) and those with symptoms (such as congestive heart failure).
• Your doctor may run tests to monitor your heart function before and during treatment with PERJETA
• Based on test results, your doctor may hold or discontinue treatment with PERJETA
• Contact a health care professional immediately for any of the following: new onset or worsening shortness of
breath, cough, swelling of the ankles/legs, swelling of the face, palpitations, weight gain of more than 5 pounds
in 24 hours, dizziness or loss of consciousness
Receiving PERJETA during pregnancy can result in the death of an unborn baby and birth defects.
• Birth control should be used while receiving PERJETA and for 7 months after your last dose of PERJETA.
If you are a mother who is breastfeeding, you should talk with your doctor about either stopping breastfeeding
or stopping PERJETA
• If you think you may be pregnant, you should contact your healthcare provider immediately
• If you are exposed to PERJETA during pregnancy, or become pregnant while receiving
PERJETA or within 7 months following the last dose of PERJETA in combination
with Herceptin, you are encouraged to report PERJETA exposure to Genentech
at 1-888-835-2555
Please refer to pages 12-13 for more information on these serious side effects.
Please see additional Important Safety Information throughout,
and accompanying full Prescribing Information, including most
serious side effects.
 IN THIS BROCHURE, SOME THINGS TO KNOW
LEARN ABOUT: ABOUT THIS TREATMENT

HER2-positive breast cancer 4 • PERJETA, along with Herceptin® (trastuzumab) and docetaxel, is for first-line treatment of
HER2-positive breast cancer that has spread from the first site (metastatic breast cancer)
• Understanding HER2-positive breast cancer
• Introduction to PERJETA • It is typically given every 3 weeks, along with 2 other medications

PERJETA-based treatment for your type of metastatic 6 • Your treatment will continue until your disease is no longer controlled or your side effects
breast cancer require you to stop treatment
• PERJETA-based treatment for HER2+ metastatic breast cancer • The most common side effects of this treatment are:
• How PERJETA-based treatment is given - Diarrhea - Feeling tired
• Empowering your fight against breast cancer
- Hair loss - Rash
• Common side effects with PERJETA
- Low levels of white blood cells - Damage to the nerves (numbness, tingling,
More information about treatment with PERJETA 10 with or without fever pain in hands/feet)
• How PERJETA-based treatment may help - Nausea
• How long will I be on this treatment?
• Important Safety Information My notes:
Where to find support 14
• Financial support for patients receiving PERJETA
• More information and support
• Questions you may want to ask your healthcare team
Who to call:
Glossary 18
When to call:
The information in this brochure does not replace the advice of your healthcare team. If you What are other possible serious side effects of PERJETA?
have any questions about your treatment, be sure to contact your healthcare team. Only your
doctor and healthcare team can give you medical advice about your medical condition • P ERJETA should not be used in patients who are allergic to pertuzumab
and treatment. or to any of the ingredients in PERJETA. Possible serious side effects of
PERJETA include infusion-related reactions and severe allergic reactions
(hypersensitivity reactions/anaphylaxis).
Please see additional Important Safety Information throughout, and accompanying See the following pages for many more details about
full Prescribing Information, including most serious side effects. this medication.
2 3
 ABOUT HER2+ MBC
UNDERSTANDING INTRODUCTION

AND PERJETA
HER2-POSITIVE BREAST CANCER TO PERJETA

What is HER2-positive breast cancer? A diagnosis of HER2-positive metastatic breast cancer (MBC) can be overwhelming. Your healthcare team
may have given you a lot of new information to understand. If you have received this brochure, your doctor
All cells have HER2 receptors, including healthy cells and cancer cells. In HER2-positive breast
cancer, tumor cells have more HER2 receptors than normal. Too much HER2 makes these cancer thinks PERJETA, along with Herceptin® (trastuzumab) and docetaxel, may be right for you.
cells grow and divide too fast. PERJETA is a medicine used to treat HER2-positive breast cancer. It works differently than other medicines
that treat HER2-positive breast cancer, in that PERJETA is designed to work with Herceptin, another
NONCANCEROUS CELL HER2-positive medicine.
HER2 receptor HER2 TELLS CANCER CELLS TO GROW BY SENDING SIGNALS

HER2
Signal
Noncancerous cell
• H ER2 works by sending signals that tell cells to grow and divide
• One way that HER2 can send signals is by pairing with other
RESULTS IN NORMAL CELL
HER receptors
NORMAL AMOUNTS OF HER2
GROWTH AND DIVISION
CANCER CELL

HER2-POSITIVE CANCER CELL

HER2 receptor
PERJETA AND HERCEPTIN TARGET HER2

• PERJETA and Herceptin both target HER2 but work in different ways
Herceptin PERJETA • PERJETA is thought to block one method of signaling so that
Cancer cell certain receptors are unable to pair with HER2
• Together, PERJETA and Herceptin are thought to create a stronger
blockade against HER2 signals, helping to slow down cancer
CAUSES CELLS TO GROW cell growth
TOO MUCH HER2
AND DIVIDE TOO FAST • B ecause HER2 receptors are found on normal cells as well, targeted
SIGNALS BLOCKED treatments can also affect healthy cells

HER2 receptor: A type of protein that is found on the surface of cells in everyone. This protein tells cells to grow and divide.
Too much HER2 is called “HER2 overexpression” Since normal cells also have HER2 receptors (just not as many),
Tumor: An abnormal mass or growth of tissue that occurs when cells divide too fast, in an uncontrolled way; tumors that are HER2-targeted therapies can also affect them and cause side effects,
malignant are known as cancer including serious side effects.
Please see pages 12-13 for additional safety information.
Please see additional Important Safety Information throughout, and accompanying HER2-positive: When breast cancer cells have too many HER2 receptors, they are
full Prescribing Information, including most serious side effects. called HER2-positive or “HER2+” breast cancer
4 5
 PERJETA-BASED TREATMENT FOR HOW PERJETA-BASED
HER2+ METASTATIC BREAST CANCER TREATMENT IS GIVEN

People with HER2-positive breast cancer may be eligible for PERJETA is given as an intravenous (IV) infusion

BENEFITS AND RISKS

HER2-targeted treatments

OF PERJETA
An IV infusion is when a medicine is slowly given directly into the bloodstream through a vein
One of the medicines available to people with HER2-positive metastatic breast cancer is PERJETA. or port.
It is a targeted treatment, like Herceptin® (trastuzumab), but works to fight cancer in a different way.
PERJETA is used in combination with Herceptin and docetaxel.
How often is PERJETA given?
PERJETA is typically given every 3 weeks on the same day as Herceptin and docetaxel, during the
What are the most serious side effects of PERJETA? same visit. When you are receiving treatment, PERJETA, Herceptin, and docetaxel will be given one
PERJETA may cause heart problems, including those without symptoms (such as reduced at a time. PERJETA and Herceptin will be given first (they can be given in any order). Docetaxel will
heart function) and those with symptoms (such as congestive heart failure). be given afterwards.
• Your doctor may run tests to monitor your heart function before and during treatment with PERJETA
• Based on test results, your doctor may briefly stop or discontinue treatment with PERJETA
During your first treatment
• Contact a health care professional immediately for any of the following: new onset or worsening PERJETA and Herceptin are given more slowly at your first visit. Your first dose of PERJETA will be
shortness of breath, cough, swelling of the ankles/legs, swelling of the face, palpitations, given as an infusion over 60 minutes. Herceptin will be given over 90 minutes, and then docetaxel.
weight gain of more than 5 pounds in 24 hours, dizziness or loss of consciousness After each medicine is given, your doctor or nurse will wait 30-60 minutes to check for any
infusion-related or allergic reactions.
Receiving PERJETA during pregnancy can result in the death of an unborn baby and
birth defects. During your next treatments
• Birth control should be used while receiving PERJETA and for 7 months after your last dose of PERJETA.
If you are a mother who is breastfeeding, you should talk with your doctor about either stopping
breastfeeding or stopping PERJETA 30-60 30-90
minutes minutes
• If you think you may be pregnant, you should contact your healthcare provider immediately
• If you take PERJETA during pregnancy, or become pregnant while receiving PERJETA or within
7 months following the last dose of PERJETA in combination with Herceptin, you are encouraged PERJETA HERCEPTIN
to report PERJETA exposure to Genentech at 1-888-835-2555 Infusion time may vary depending on what reactions may occur. After each medicine is given,
your doctor or nurse will wait 30-60 minutes to check for any infusion-related or allergic reactions.
They may adjust, delay, or stop treatment if a reaction occurs.
• Docetaxel will be given after you have completed your infusions of PERJETA and Herceptin.
Consult with your treatment team about infusion time for chemotherapy
Targeted treatments: Targeted cancer treatments target specific characteristics on cancer cells, and may also
affect normal cells

Port: An implanted device through which blood may be taken and drugs may be
infused without repeated needlesticks; also called “port-a-cath”
Please see additional Important Safety Information throughout, and accompanying
full Prescribing Information, including most serious side effects.
6 7
 EMPOWERING YOUR FIGHT COMMON SIDE EFFECTS
AGAINST BREAST CANCER WITH PERJETA

PERJETA is designed to work together with Herceptin, What are the most common side effects?
another HER2-targeted treatment The most common side effects of PERJETA when given with Herceptin and docetaxel for treatment
PERJETA and Herceptin® (trastuzumab) both target HER2, but they are believed to work in ways that of breast cancer that has spread to other parts of the body (metastatic) are:
help each other. The combination may increase death of cancer cells. Normal cells also have HER2
• Diarrhea
receptors (just not as many), so HER2-targeted therapies can also affect healthy cells and cause side
effects, including serious side effects. • H air loss

The role of docetaxel in your treatment plan • L ow levels of white blood cells with or without a fever
Docetaxel is a type of traditional chemotherapy. It works • Nausea
differently from HER2-targeted treatment and is an essential part
of your treatment with PERJETA and Herceptin. Your doctor will • F eeling tired
start you on all 3 medicines at first and may adjust the medicines PERJETA HERCEPTIN

& • Rash
(targeted treatment) (targeted treatment)

in your treatment plan over time.

WITH • D amage to the nerves (numbness, tingling, pain in hands/feet)
What are other possible serious side effects DOCETAXEL

of PERJETA? If your doctor changes your treatment plan, you may see a change in the side effects. Patients in
the study had fewer side effects when they stopped taking docetaxel. After stopping docetaxel,
• PERJETA should not be used in patients who are allergic all side effects in patients receiving the PERJETA-based treatment happened in less than 10% of
to pertuzumab or to any of the ingredients in PERJETA patients, except for diarrhea, a cold, rash, headache, and feeling tired.
• Infusion-related reactions: PERJETA is a medicine that is delivered into a vein through a
needle. PERJETA has been associated with infusion-related reactions, some fatal. The most White blood cell: A type of immune cell. White blood cells help the body fight infections and other diseases. When white
common infusion-related reactions when receiving PERJETA, Herceptin, and docetaxel were blood cell counts are low, people can become tired and prone to infections
feeling tired, abnormal or altered taste, allergic reactions, muscle pain, and vomiting. The most
common infusion-related reactions when receiving PERJETA alone were fever, chills, feeling
tired, headache, weakness, allergic reactions, and vomiting
• S evere allergic reactions: Some people receiving PERJETA may have severe allergic reactions,
called hypersensitivity reactions or anaphylaxis, which may happen quickly and may affect many
areas of the body. Severe allergic reactions, some fatal, have been observed in patients treated
with PERJETA

Traditional chemotherapy: A type of medicine that kills cells that grow and divide rapidly, including cancer cells and
normal cells

Please see additional Important Safety Information throughout, and accompanying

full Prescribing Information, including most serious side effects.
8 9
 HOW PERJETA-BASED HOW LONG WILL I BE ON
TREATMENT MAY HELP THIS TREATMENT?

How will my doctor and I know if PERJETA is right for me? Duration of PERJETA-based treatment
If you’ve been diagnosed with HER2-positive metastatic breast cancer and have not been previously
PERJETA + Herceptin + docetaxel dosing schedule
treated, adding PERJETA to Herceptin® (trastuzumab) and docetaxel could make your treatment stronger.
PERJETA + Herceptin + docetaxel PERJETA + Herceptin
PERJETA has only been shown to work in people with HER2-positive breast cancer. You must have a HER2
test to know if your breast cancer is HER2-positive before getting an anti-HER2 treatment, such as PERJETA. Docetaxel
MINIMUM OF
6 CYCLES
Results of a clinical study with PERJETA have shown that: PERJETA + Herceptin

TREATMENT WITH PERJETA

PERJETA helped control cancer growth If your doctor stops your docetaxel, you may still take PERJETA and Herceptin.

• A clinical study called CLEOPATRA studied efficacy and safety in 808 patients who were given PERJETA If your doctor delays or stops Herceptin treatment, then PERJETA should also be delayed or stopped.
with Herceptin and docetaxel or Herceptin and docetaxel alone
• Adding PERJETA to Herceptin and docetaxel increased the time people lived without their cancer
Can PERJETA and Herceptin continue if docetaxel is stopped?
growing or spreading by an average of 50%, compared with people who took Herceptin and Yes. Everyone experiences treatment differently. If your doctor stops docetaxel (eg, due to side
docetaxel alone effects), you can continue taking PERJETA and Herceptin. You can stay on PERJETA and Herceptin
until it stops working or your side effects require you to stop treatment.
• P eople taking PERJETA, along with Herceptin and docetaxel, experienced an average of 6.1 more
months of progression-free survival, which is time without their cancer progressing, compared
with people taking only Herceptin and docetaxel (18.5 months compared with 12.4 months) What should I know if I am pregnant or thinking of becoming pregnant?
Birth control should be used while receiving PERJETA and for 7 months after your last dose of
PERJETA helped people live longer PERJETA. If you are a mother who is breastfeeding, you should talk with your doctor about either
stopping breastfeeding or stopping PERJETA. If you think you may be pregnant, you should
• O n average, people who were given PERJETA, Herceptin, and docetaxel lived 15.7 months longer contact your healthcare provider immediately. If you are exposed to PERJETA during pregnancy,
than people given only Herceptin and docetaxel (56.5 months compared to 40.8 months) or become pregnant while receiving PERJETA or within 7 months following the last dose of PERJETA
in combination with Herceptin, you are encouraged to report PERJETA exposure to Genentech
PERJETA shrunk tumors at 1-888-835-2555.

• 8 0% of people taking the PERJETA combination had their tumors shrink, compared with 69% of
people taking Herceptin and docetaxel alone
• P eople who had their tumors shrink maintained this response for 62% longer on the PERJETA
combination compared with people taking only Herceptin and docetaxel (20.2 months compared
with 12.5 months)

Please see additional Important Safety Information throughout, and accompanying

full Prescribing Information, including most serious side effects.
10 11
 IMPORTANT SAFETY INFORMATION

What should I know about side effects with PERJETA? What are other possible serious side effects?
• Not all people have serious side effects; however, side effects with PERJETA therapy • PERJETA should not be used in patients who are allergic to pertuzumab or to any of the
are common. It is important to know what side effects may happen and what ingredients in PERJETA
symptoms you should watch for • Infusion-related reactions: PERJETA is a medicine that is delivered into a vein
• Your doctor may stop treatment if serious side effects happen. Be sure to contact your through a needle. PERJETA has been associated with infusion-related reactions,
healthcare team right away if you have questions or are worried about any side effects some fatal. The most common infusion-related reactions when receiving PERJETA,
Herceptin, and docetaxel were feeling tired, abnormal or altered taste, allergic
What are the most serious side effects of PERJETA? reactions, muscle pain, and vomiting. The most common infusion-related reactions
PERJETA may cause heart problems, including those without symptoms when receiving PERJETA alone were fever, chills, feeling tired, headache, weakness,
(such as reduced heart function) and those with symptoms (such as allergic reactions, and vomiting
congestive heart failure). • S evere allergic reactions: Some people receiving PERJETA may have severe
• Your doctor may run tests to monitor your heart function before and during allergic reactions, called hypersensitivity reactions or anaphylaxis, which may
treatment with PERJETA happen quickly and may affect many areas of the body. Severe allergic reactions,
some fatal, have been observed in patients treated with PERJETA
• Based on test results, your doctor may hold or discontinue treatment with PERJETA
• C ontact a health care professional immediately for any of the following: new onset What are the most common side effects?

SAFETY INFORMATION
or worsening shortness of breath, cough, swelling of the ankles/legs, swelling of the The most common side effects of PERJETA when given with Herceptin and docetaxel for
face, palpitations, weight gain of more than 5 pounds in 24 hours, dizziness or loss treatment of breast cancer that has spread to other parts of the body (metastatic) are:
of consciousness • Diarrhea
Receiving PERJETA during pregnancy can result in the death of an unborn • Hair loss
baby and birth defects. • Low levels of white blood cells with or without fever
• Birth control should be used while receiving PERJETA and for 7 months after your • Nausea
last dose of PERJETA. If you are a mother who is breastfeeding, you should talk with your • Feeling tired
doctor about either stopping breastfeeding or stopping PERJETA • Rash
• Damage to the nerves (numbness, tingling, pain in hands/feet)
• If you think you may be pregnant, you should contact your healthcare
provider immediately You are encouraged to report side effects to Genentech and the FDA. You may report side
effects to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. You may also report side
• I f you are exposed to PERJETA during pregnancy, or become pregnant while effects to Genentech at 1-888-835-2555.
receiving PERJETA or within 7 months following the last dose of PERJETA in
Talk to a healthcare professional for more information about
combination with Herceptin, you are encouraged to report PERJETA exposure
the benefits and risks of PERJETA.
to Genentech at 1-888-835-2555
Please see accompanying full Prescribing Information
for additional Important Safety Information, including
most serious side effects.
If you cannot afford your medication, visit genentech-access.com/patient
12 for financial assistance information. 13
 FINANCIAL SUPPORT FOR PATIENTS
RECEIVING PERJETA® (PERTUZUMAB)

Patient Resource Center

Genentech Access Solutions is here to help you learn how to get the Genentech medicine you need. We’re here to help.
Genentech Access Solutions can:
Genentech’s Patient Resource Center is dedicated to getting patients and caregivers to the
• Help you learn if your health insurance covers your Genentech medicine right resource for information about Genentech medicines.
• Refer you to patient assistance options if you are eligible Please call: 1-877-GENENTECH (1-877-436-3683).
Call 1-888-249-4918 or visit genentech-access.com/perjeta/patients. Remember, your doctor and healthcare team are your primary sources of information. Only they
can give you medical advice about your disease and treatment.

HERConnection is a free support program that was designed specifically for people with HER2+ breast
cancer who are taking Genentech medicines, such as PERJETA. It provides information and resources
that can help educate and empower you throughout your treatment journey.
Visit HERConnection.com to see what you’ll get and sign up.
Genentech co-pay programs may help you if you have commercial health insurance* and meet
other eligibility criteria.
We can refer you to an independent co-pay assistance foundation. This is a charitable
organization that may give financial help for medicines.
The Genentech Patient Foundation gives free Genentech medicine to people who meet income
To learn more about the Genentech Oncology Co-pay Assistance Program or to get the
guidelines and:
full list of terms and conditions, visit www.copayassistancenow.com.
• Who don’t have insurance

RESOURCES
*This might be a plan you get through your employer or one you purchased through a Health Insurance Marketplace
• Whose treatment is not covered by insurance like HealthCare.gov.

• Who are struggling with high out-of-pocket costs

To learn more and to apply for help, call 1-888-941-3331 or
visit GenentechPatientFoundation.com.

PERJETA, its logo, and the Access Solutions logo are registered trademarks of Genentech, Inc.

Please see additional Important Safety Information throughout, and accompanying

full Prescribing Information, including most serious side effects.
14 15
 MORE INFORMATION QUESTIONS YOU MAY WANT
AND SUPPORT TO ASK YOUR HEALTHCARE TEAM

Breast cancer information and support* To better understand your treatment plan, it may help to have a discussion with someone on your
healthcare team. Here are some common questions to help you get started.
American Cancer Society | www.cancer.org
1-800-227-2345
Provides information for people living with cancer, families, and friends. Is PERJETA the right treatment choice for my type of metastatic breast cancer?
Young Survival Coalition | www.youngsurvival.org
A global organization dedicated to critical issues for young women with breast cancer. 
Why is PERJETA given in combination with Herceptin® (trastuzumab) and docetaxel,
and how are they different?
Living Beyond Breast Cancer | www.lbbc.org
1-888-753-LBBC (5222)
Support and information for people who are newly diagnosed, in treatment, or living with metastatic

What do I need to do to prepare for my infusion?
breast cancer.
Metastatic Breast Cancer Network | www.mbcn.org
A national, independent, nonprofit advocacy group that is dedicated to the concerns of women 
How long do I need to take PERJETA?
and men living with metastatic breast cancer.
SHARE | www.sharecancersupport.org 
How long do I need to take docetaxel?
1-866-891-2392
A network of people with breast and other cancers who share their experiences with their disease.
Breastcancer.org | www.breastcancer.org 
What side effects should I expect?
A website dedicated to providing information about treatment options, symptoms, diagnosis,
and prevention.

How can I tell if the treatment is working?

*These organizations are an incomplete listing of cancer support organizations and are not controlled by, endorsed by,
or affiliated with Genentech, Inc. The list is meant for informational purposes only and is not intended to replace your
healthcare professional’s medical advice. Ask your doctor or oncology nurse educator any questions you may have about your
cancer or treatment plan.

Please see additional Important Safety Information throughout, and accompanying

full Prescribing Information, including most serious side effects.
16 17
 GLOSSARY

HER2 dimerization inhibitor (HDI): Port:

An anticancer medicine that works by blocking certain receptors from pairing. This aims to turn off the An implanted device through which blood may be withdrawn and drugs may be infused without
HER2 signals that tell cancer cells to grow and divide. Because normal cells also have HER2 receptors, repeated needlesticks; also called “port-a-cath”
targeted treatments can also affect healthy cells
Targeted treatments:
HER2-positive: Targeted cancer treatments target specific characteristics on cancer cells, and may also affect
When breast cancer cells have too many HER2 receptors, it is called HER2-positive or “HER2+” normal cells
breast cancer
Traditional chemotherapy:
HER2 receptor: A type of medicine that kills cells that grow and divide rapidly, including cancer cells and normal cells
A type of protein that is found on the surface of cells in everyone. This protein tells cells to grow and
divide. Too much HER2 is called “HER2 overexpression” Tumor:
An abnormal mass or growth of tissue that occurs when cells divide too rapidly, in an uncontrolled
Metastatic: way; tumors that are malignant are known as cancer
Describes when cancer has spread from the first site, such as the breast, to other parts of the body
White blood cell:
A type of immune cell. White blood cells help the body fight infections and other diseases. When
white blood cell counts are low, people can become tired and prone to infections

GLOSSARY
Please see additional Important Safety Information throughout, and accompanying
full Prescribing Information, including most serious side effects.
18 19
HOW PERJETA-BASED TREATMENT MAY HELP
• P ERJETA is an FDA-approved treatment referred to as a HER2 dimerization inhibitor (HDI)
• Adding PERJETA to Herceptin® (trastuzumab) and docetaxel increased the time people lived without their cancer
growing or spreading by an average of 50%, compared with people who took Herceptin and docetaxel alone
• People taking PERJETA along with Herceptin and docetaxel experienced an average of 6.1 more months of
progression-free survival, which is time without their cancer progressing, compared with people taking only
Herceptin and docetaxel (18.5 months compared with 12.4 months)
• On average, people who were given PERJETA, Herceptin, and docetaxel lived 15.7 months longer than people given
only Herceptin and docetaxel (56.5 months compared to 40.8 months)
• People who had their tumors shrink maintained this response for 62% longer on the PERJETA combination
compared with people taking only Herceptin and docetaxel (20.2 months compared with 12.5 months)
What does PERJETA treat?
PERJETA® (pertuzumab) is a prescription medicine approved for use in combination with Herceptin® (trastuzumab)
and docetaxel in people who have HER2-positive breast cancer that has spread to different parts of the body (metastatic)
and who have not received anti-HER2 therapy or chemotherapy for metastatic breast cancer.
What are the most serious side effects of PERJETA?
PERJETA may cause heart problems, including those without symptoms (such as reduced heart function)
and those with symptoms (such as congestive heart failure). Receiving PERJETA during pregnancy can
result in the death of an unborn baby and birth defects.
Please refer to pages 12-13 for more information on these serious side effects.
What are other possible serious side effects?
PERJETA should not be used in patients who are allergic to pertuzumab or to any of the ingredients in PERJETA.
Possible serious side effects of PERJETA include infusion-related reactions and severe allergic reactions
(hypersensitivity reactions/anaphylaxis).
What infusion-related reactions may occur with PERJETA?
PERJETA is a medicine that is delivered into a vein through a needle. PERJETA has been associated with infusion-related
reactions, some fatal. The most common infusion-related reactions when receiving PERJETA, Herceptin, and docetaxel
were feeling tired, abnormal or altered taste, allergic reactions, muscle pain, and vomiting. The most common
infusion-related reactions when receiving PERJETA alone were fever, chills, feeling tired, headache, weakness,
allergic reactions, and vomiting.
What are the most common side effects?
The most common side effects of PERJETA when given with Herceptin and docetaxel for treatment of breast cancer
that has spread to other parts of the body (metastatic) are diarrhea, hair loss, low levels of white blood cells with or
without fever, nausea, feeling tired, rash, and damage to the nerves (numbness, tingling, pain in hands/feet).

Please see additional Important Safety Information throughout, and accompanying full Prescribing Information,
including most serious side effects.

© 2022 Genentech USA, Inc. All rights reserved. M-US-00004049(v3.0) Printed in USA. 2/22
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
PERJETA safely and effectively. See full prescribing information for --------------------- DOSAGE FORMS AND STRENGTHS----------------------
PERJETA.  Injection: 420 mg/14 mL single-dose vial. (3)

PERJETA® (pertuzumab) injection, for intravenous use ------------------------------ CONTRAINDICATIONS ------------------------------

Initial U.S. Approval: 2012 PERJETA is contraindicated in patients with known hypersensitivity to
pertuzumab or to any of its excipients. (4)
WARNING: LEFT VENTRICULAR DYSFUNCTION and
EMBRYO-FETAL TOXICITY ----------------------- WARNINGS AND PRECAUTIONS -----------------------
See full prescribing information for complete boxed warning.  Infusion-Related Reactions: Monitor for signs and symptoms. If a
 Left Ventricular Dysfunction: PERJETA can result in significant infusion-associated reaction occurs, slow or interrupt the
subclinical and clinical cardiac failure manifesting as decreased infusion and administer appropriate medical therapies. (5.3)
LVEF and CHF. Evaluate cardiac function prior to and during  Hypersensitivity Reactions/Anaphylaxis: Monitor for signs and
treatment. Discontinue PERJETA treatment for a confirmed symptoms, including angioedema. If a severe hypersensitivity
clinically significant decrease in left ventricular function. (2.3, reaction/anaphylaxis occurs, discontinue the infusion immediately and
5.1, 6.1) administer appropriate medical therapies. (5.4)
 Embryo-fetal Toxicity: Exposure to PERJETA can result in ------------------------------ ADVERSE REACTIONS ------------------------------
embryo-fetal death and birth defects. Advise patients of these Metastatic Breast Cancer
risks and the need for effective contraception. (5.2, 8.1, 8.3)  The most common adverse reactions (> 30%) with PERJETA in
combination with trastuzumab and docetaxel were diarrhea, alopecia,
--------------------------- INDICATIONS AND USAGE---------------------------- neutropenia, nausea, fatigue, rash, and peripheral neuropathy. (6.1)
PERJETA is a HER2/neu receptor antagonist indicated for: Neoadjuvant Treatment of Breast Cancer
 Use in combination with trastuzumab and docetaxel for treatment of  The most common adverse reactions (> 30%) with PERJETA in
patients with HER2-positive metastatic breast cancer (MBC) who have combination with trastuzumab and docetaxel were alopecia, diarrhea,
not received prior anti-HER2 therapy or chemotherapy for metastatic nausea, and neutropenia. (6.1)
disease. (1.1)  The most common adverse reactions (>30%) with PERJETA in
 Use in combination with trastuzumab and chemotherapy as combination with trastuzumab and docetaxel when given for 3 cycles
o neoadjuvant treatment of patients with HER2-positive, locally following 3 cycles of FEC were fatigue, alopecia, diarrhea, nausea,
advanced, inflammatory, or early stage breast cancer (either greater vomiting, and neutropenia. (6.1)
than 2 cm in diameter or node positive) as part of a complete  The most common adverse reactions (>30%) with PERJETA in
treatment regimen for early breast cancer. (1.2, 2.2, 14.2) combination with docetaxel, carboplatin, and trastuzumab (TCH) were
o adjuvant treatment of patients with HER2-positive early breast cancer fatigue, alopecia, diarrhea, nausea, vomiting, neutropenia,
at high risk of recurrence (1.2, 2.2, 14.3) thrombocytopenia, and anemia. (6.1)
 The most common adverse reactions (>30%) with PERJETA in
----------------------- DOSAGE AND ADMINISTRATION -----------------------
combination with trastuzumab and paclitaxel when given for 4 cycles
 For intravenous infusion only. Do not administer as an intravenous following 4 cycles of ddAC were nausea, diarrhea, alopecia, fatigue,
push or bolus. (2.4) constipation, peripheral neuropathy, and headache. (6.1)
 HER2 testing: Perform using FDA-approved tests by laboratories with  The most common adverse reactions (>30%) with PERJETA in
demonstrated proficiency. (2.1) combination with trastuzumab and docetaxel when given for 4 cycles
 The initial PERJETA dose is 840 mg administered as a 60-minute following 4 cycles of FEC were diarrhea, nausea, alopecia, asthenia,
intravenous infusion, followed every 3 weeks thereafter by 420 mg constipation, fatigue, mucosal inflammation, vomiting, myalgia, and
administered as a 30 to 60 minute intravenous infusion. (2.2) anemia. (6.1)
 MBC: Administer PERJETA, trastuzumab or trastuzumab hyaluronidase- Adjuvant Treatment of Breast Cancer
oysk, and docetaxel every 3 weeks. (2.2)  The most common adverse reactions (>30%) with PERJETA in
 Neoadjuvant: Administer PERJETA, trastuzumab or trastuzumab combination with trastuzumab and chemotherapy were diarrhea, nausea,
hyaluronidase-oysk, and chemotherapy preoperatively every 3 weeks for alopecia, fatigue, peripheral neuropathy and vomiting. (6.1)
3 to 6 cycles. (2.2)
 Adjuvant: Administer PERJETA, trastuzumab or trastuzumab To report SUSPECTED ADVERSE REACTIONS, contact Genentech at
hyaluronidase-oysk, and chemotherapy postoperatively every 3 weeks for 1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
a total of 1 year (up to 18 cycles). (2.2)
----------------------- USE IN SPECIFIC POPULATIONS -----------------------
Females and Males of Reproductive Potential: Verify the pregnancy status of
females prior to initiation of PERJETA. (8.3)
See 17 for PATIENT COUNSELING INFORMATION.

Revised: 02/2021

Page 1 of 36
FULL PRESCRIBING INFORMATION: CONTENTS* 8.2 Lactation
WARNING: LEFT VENTRICULAR DYSFUNCTION AND EMBRYO- 8.3 Females and Males of Reproductive Potential
FETAL TOXICITY 8.4 Pediatric Use
1 INDICATIONS AND USAGE 8.5 Geriatric Use
1.1 Metastatic Breast Cancer (MBC) 8.6 Renal Impairment
1.2 Early Breast Cancer (EBC) 8.7 Hepatic Impairment
2 DOSAGE AND ADMINISTRATION 11 Description
2.1 Patient Selection 12 Clinical Pharmacology
2.2 Recommended Doses and Schedules 12.1 Mechanism of Action
2.3 Dose Modification 12.3 Pharmacokinetics
2.4 Preparation for Administration 12.6 Cardiac Electrophysiology
3 Dosage Forms and Strengths 13 NONCLINICAL TOXICOLOGY
4 Contraindications 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
5 Warnings and Precautions 14 Clinical Studies
5.1 Left Ventricular Dysfunction 14.1 Metastatic Breast Cancer
5.2 Embryo-Fetal Toxicity 14.2 Neoadjuvant Treatment of Breast Cancer
5.3 Infusion-Related Reactions 14.3 Adjuvant Treatment of Breast Cancer
5.4 Hypersensitivity Reactions/Anaphylaxis 16 HOW SUPPLIED/STORAGE AND HANDLING
6 Adverse Reactions 16.1 How Supplied
6.1 Clinical Trials Experience 17 Patient Counseling Information
6.2 Immunogenicity
6.3 Post-Marketing Experience * Sections or subsections omitted from the Full Prescribing Information are
7 Drug Interactions not listed.
8 Use in Specific Populations
8.1 Pregnancy

Page 2 of 36
FULL PRESCRIBING INFORMATION
WARNING: LEFT VENTRICULAR DYSFUNCTION and EMBRYO-FETAL
TOXICITY
 Left Ventricular Dysfunction: PERJETA can result in subclinical and clinical cardiac
failure manifesting as decreased LVEF and CHF. Evaluate cardiac function prior to
and during treatment. Discontinue PERJETA treatment for a confirmed clinically
significant decrease in left ventricular function [see Dosage and Administration (2.3),
Warnings and Precautions (5.1) and Adverse Reactions (6.1)].
 Embryo-fetal Toxicity: Exposure to PERJETA can result in embryo-fetal death and
birth defects. Advise patients of these risks and the need for effective contraception [see
Warnings and Precautions (5.2) and Use in Specific Populations (8.1) (8.3)].
1 INDICATIONS AND USAGE
1.1 Metastatic Breast Cancer (MBC)
PERJETA is indicated for use in combination with trastuzumab and docetaxel for the treatment
of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2
therapy or chemotherapy for metastatic disease [see Dosage and Administration (2.2) and
Clinical Studies (14.1)].
1.2 Early Breast Cancer (EBC)
PERJETA is indicated for use in combination with trastuzumab and chemotherapy for
 the neoadjuvant treatment of patients with HER2-positive, locally advanced,
inflammatory, or early stage breast cancer (either greater than 2 cm in diameter or node
positive) as part of a complete treatment regimen for early breast cancer [see Dosage and
Administration (2.2) and Clinical Studies (14.2)].
 the adjuvant treatment of patients with HER2-positive early breast cancer at high risk of
recurrence [see Dosage and Administration (2.2) and Clinical Studies (14.3)].
2 DOSAGE AND ADMINISTRATION
2.1 Patient Selection
Select patients based on HER2 protein overexpression or HER2 gene amplification in tumor
specimens [see Indications and Usage (1) and Clinical Studies (14)]. Assessment of HER2
protein overexpression and HER2 gene amplification should be performed using FDA-approved
tests specific for breast cancer by laboratories with demonstrated proficiency. Information on the
FDA-approved tests for the detection of HER2 protein overexpression and HER2 gene
amplification is available at: http://www.fda.gov/CompanionDiagnostics.
Improper assay performance, including use of suboptimally fixed tissue, failure to utilize
specified reagents, deviation from specific assay instructions, and failure to include appropriate
controls for assay validation, can lead to unreliable results.

2.2 Recommended Doses and Schedules

The initial dose of PERJETA is 840 mg administered as a 60-minute intravenous infusion,
followed every 3 weeks by a dose of 420 mg administered as an intravenous infusion over
30 to 60 minutes.
When administered with PERJETA, the recommended initial dose of trastuzumab is 8 mg/kg
administered as a 90-minute intravenous infusion, followed every 3 weeks by a dose of 6 mg/kg
administered as an intravenous infusion over 30 to 90 minutes.

Page 3 of 36
When administered with PERJETA, the recommended initial dose of trastuzumab hyaluronidase-
oysk is 600 mg/10,000 units (600 mg trastuzumab and 10,000 units hyaluronidase) administered
subcutaneously over approximately 2 to 5 minutes once every three weeks irrespective of the
patient’s body weight.
PERJETA, trastuzumab or trastuzumab hyaluronidase-oysk, and taxane should be administered
sequentially. PERJETA and trastuzumab or trastuzumab hyaluronidase-oysk can be given in any
order. Taxane should be administered after PERJETA and trastuzumab or trastuzumab
hyaluronidase-oysk. An observation period of 30 to 60 minutes is recommended after each
PERJETA infusion and before commencement of any subsequent administration of trastuzumab
or trastuzumab hyaluronidase-oysk, or taxane [see Warnings and Precautions (5.3)].
In patients receiving an anthracycline-based regimen, PERJETA and trastuzumab or
trastuzumab hyaluronidase-oysk should be administered following completion of the
anthracycline.
Metastatic Breast Cancer (MBC)
When administered with PERJETA, the recommended initial dose of docetaxel is 75 mg/m 2
administered as an intravenous infusion. The dose may be escalated to 100 mg/m 2 administered
every 3 weeks if the initial dose is well tolerated.
Neoadjuvant Treatment of Breast Cancer
PERJETA should be administered every 3 weeks for 3 to 6 cycles as part of one of the following
treatment regimens for early breast cancer [see Clinical Studies (14.2)]:
 Four preoperative cycles of PERJETA in combination with trastuzumab or trastuzumab
hyaluronidase-oysk and docetaxel followed by 3 postoperative cycles of fluorouracil,
epirubicin, and cyclophosphamide (FEC) as given in NeoSphere
 Three or four preoperative cycles of FEC alone followed by 3 or 4 preoperative cycles of
PERJETA in combination with docetaxel and trastuzumab or trastuzumab
hyaluronidase-oysk as given in TRYPHAENA and BERENICE, respectively
 Six preoperative cycles of PERJETA in combination with docetaxel, carboplatin, and
trastuzumab (TCH) or trastuzumab hyaluronidase-oysk (escalation of docetaxel above 75
mg/m2 is not recommended) as given in TRYPHAENA
 Four preoperative cycles of dose-dense doxorubicin and cyclophosphamide (ddAC) alone
followed by 4 preoperative cycles of PERJETA in combination with paclitaxel and
trastuzumab or trastuzumab hyaluronidase-oysk as given in BERENICE
Following surgery, patients should continue to receive PERJETA and trastuzumab or
trastuzumab hyaluronidase-oysk to complete 1 year of treatment (up to 18 cycles).
Adjuvant Treatment of Breast Cancer
PERJETA should be administered in combination with trastuzumab or trastuzumab
hyaluronidase-oysk every 3 weeks for a total of 1 year (up to 18 cycles) or until disease
recurrence or unmanageable toxicity, whichever occurs first, as part of a complete regimen for
early breast cancer, including standard anthracycline- and/or taxane-based chemotherapy as
given in APHINITY. PERJETA and trastuzumab or trastuzumab hyaluronidase-oysk should
start on Day 1 of the first taxane-containing cycle [see Clinical Studies (14.3)].

2.3 Dose Modification

For recommendations on delayed or missed doses, please refer to Table 1.
Page 4 of 36
 Table 1 Recommendations regarding delayed or missed doses
Time PERJETA Trastuzumab Trastuzumab
between two (intravenous) hyaluronidase-oysk
sequential
doses
< 6 weeks Administer PERJETA Administer Administer
420 mg intravenously trastuzumab 6 mg/kg trastuzumab
as soon as possible. Do intravenously as soon hyaluronidase-oysk
not wait until the next as possible. Do not wait 600 mg/10,000 units
planned dose. until the next planned subcutaneously as
dose. soon as possible.
≥ 6 weeks Readminister Readminister Do not wait until the
PERJETA loading dose trastuzumab loading next planned dose.
of 840 mg dose of 8 mg/kg
intravenously as a 60 intravenously over
minute infusion, approximately
followed by a 90 minutes, followed
maintenance dose of by a maintenance dose
420 mg administered of 6 mg/kg
intravenously over a administered intraveno
period of 30 to 60 usly over a period of 30
minutes every 3 weeks or 90 minutes every 3
thereafter. weeks thereafter.

PERJETA should be discontinued if trastuzumab or trastuzumab hyaluronidase-oysk treatment is

discontinued.
Dose reductions are not recommended for PERJETA.
For chemotherapy dose modifications, see relevant prescribing information.

Left Ventricular Ejection Fraction (LVEF):

Assess left ventricular ejection fraction (LVEF) prior to initiation of PERJETA and at regular
intervals during treatment as indicated in Table 2. The recommendations on dose modifications
in the event of LVEF dysfunction are also indicated in Table 2 [see Warnings and Precautions
(5.1)].
Table 2 Dose Modifications for Left Ventricular Dysfunction
Pre- Monitor Withhold PERJETA Resume PERJETA and
treatment LVEF every: and trastuzumab or trastuzumab or
LVEF: trastuzumab trastuzumab
hyaluronidase-oysk hyaluronidase-oysk
for at least 3 weeks for after 3 weeks if LVEF
an LVEF decrease to: has recovered to:
Metastatic ≥ 50% ~12 weeks Either Either
Page 5 of 36
 Breast <40% 40%-45% >45% 40%-45%
Cancer with a fall of with a fall of
≥10%-points <10%-points
below pre- below pre-
treatment treatment
value value
Early ≥ 55%* ~12 weeks <50% with a fall of Either
Breast (once during ≥10%-points below pre-
Cancer neoadjuvant treatment value ≥50% <10% points
therapy) below pre-
treatment
value
*For patients receiving anthracycline-based chemotherapy, a LVEF of ≥ 50% is required after
completion of anthracyclines, before starting PERJETA and trastuzumab or trastuzumab
hyaluronidase-oysk.
Infusion-Related Reactions
The infusion rate of PERJETA may be slowed or interrupted if the patient develops an
infusion-related reaction [see Warnings and Precautions (5.3)].
Hypersensitivity Reactions/Anaphylaxis
The infusion should be discontinued immediately if the patient experiences a serious
hypersensitivity reaction [see Warnings and Precautions (5.4)].

2.4 Preparation for Administration

Administer as an intravenous infusion only. Do not administer as an intravenous push or bolus.
Do not mix PERJETA with other drugs.
Preparation
Prepare the solution for infusion, using aseptic technique, as follows:
 Parenteral drug products should be inspected visually for particulates and discoloration
prior to administration.
 Withdraw the appropriate volume of PERJETA solution from the vial(s) using a sterile
needle and syringe.
 Dilute into a 250 mL 0.9% sodium chloride PVC or non-PVC polyolefin infusion bag.
 Mix diluted solution by gentle inversion. Do not shake.
 Administer immediately once prepared.
 If the diluted infusion solution is not used immediately, it can be stored at 2 oC to 8oC for
up to 24 hours.
 Dilute with 0.9% Sodium Chloride injection only. Do not use dextrose (5%) solution.
3 DOSAGE FORMS AND STRENGTHS
Injection: 420 mg/14 mL (30 mg/mL) in a single-dose vial

Page 6 of 36
4 CONTRAINDICATIONS
PERJETA is contraindicated in patients with known hypersensitivity to pertuzumab or to any of
its excipients.
5 WARNINGS AND PRECAUTIONS
5.1 Left Ventricular Dysfunction
Decreases in LVEF have been reported with drugs that block HER2 activity, including
PERJETA. Assess LVEF prior to initiation of PERJETA and at regular intervals during
treatment to ensure that LVEF is within normal limits. If the LVEF declines and has not
improved, or has declined further at the subsequent assessment, discontinuation of PERJETA
and trastuzumab should be strongly considered [Dosage and Administration (2.3)].
In CLEOPATRA, for patients with MBC, PERJETA in combination with trastuzumab and
docetaxel was not associated with increases in the incidence of symptomatic left ventricular
systolic dysfunction (LVSD) or decreases in LVEF compared with placebo in combination with
trastuzumab and docetaxel [see Clinical Studies (14.1)]. Left ventricular dysfunction occurred in
4% of patients in the PERJETA-treated group and 8% of patients in the placebo-treated group.
Symptomatic left ventricular systolic dysfunction (congestive heart failure) occurred in 1% of
patients in the PERJETA-treated group and 2% of patients in the placebo-treated group [see
Adverse Reactions (6.1)]. Patients who have received prior anthracyclines or prior radiotherapy
to the chest area may be at higher risk of decreased LVEF.
In patients receiving neoadjuvant treatment in NeoSphere, the incidence of LVSD was higher in
the PERJETA-treated groups compared to the trastuzumab- and docetaxel-treated group. An
increased incidence of LVEF declines was observed in patients treated with PERJETA in
combination with trastuzumab and docetaxel. In the overall treatment period, LVEF decline
 10% and a drop to less than 50% occurred in 2% of patients treated with neoadjuvant
trastuzumab and docetaxel as compared to 8% of patients treated with neoadjuvant PERJETA in
combination with trastuzumab and docetaxel. Left ventricular dysfunction occurred in 0.9% of
patients treated with neoadjuvant trastuzumab and docetaxel as compared to 3% of patients
treated with neoadjuvant PERJETA in combination with trastuzumab and docetaxel.
Symptomatic LVSD occurred in 0.9% of patients treated with neoadjuvant PERJETA in
combination with trastuzumab and no patients in the other 3 arms. LVEF recovered to  50% in
all patients.
In patients receiving neoadjuvant PERJETA in TRYPHAENA, in the overall treatment period,
LVEF decline  10% and a drop to less than 50% occurred in 7% of patients treated with
PERJETA plus trastuzumab and FEC followed by PERJETA plus trastuzumab and docetaxel,
16% of patients treated with PERJETA plus trastuzumab and docetaxel following FEC, and 11%
of patients treated with PERJETA in combination with TCH. Left ventricular dysfunction
occurred in 6% of patients treated with PERJETA plus trastuzumab and FEC followed by
PERJETA plus trastuzumab and docetaxel, 4% of patients treated with PERJETA plus
trastuzumab and docetaxel following FEC, and 3% of patients treated with PERJETA in
combination with TCH. Symptomatic LVSD occurred in 4% of patients treated with PERJETA
plus trastuzumab and docetaxel following FEC, 1% of patients treated with PERJETA in
combination with TCH, and none of the patients treated with PERJETA plus trastuzumab and
FEC followed by PERJETA plus trastuzumab and docetaxel. LVEF recovered to  50% in all
but one patient.
In patients receiving neoadjuvant PERJETA in BERENICE, in the neoadjuvant period, LVEF
decline ≥ 10% and a drop to less than 50% as measured by ECHO/MUGA assessment occurred
Page 7 of 36
in 7% of patients treated with PERJETA plus trastuzumab and paclitaxel following ddAC, and
2% of patients treated with PERJETA plus trastuzumab and docetaxel following FEC. Ejection
fraction decreased (asymptomatic LVD) occurred in 7% of patients treated with PERJETA plus
trastuzumab and paclitaxel following ddAC and 4% of the patients treated with PERJETA plus
trastuzumab and docetaxel following FEC in the neoadjuvant period. Symptomatic LVSD
(NYHA Class III/IV Congestive Heart Failure) occurred in 2% of patients treated with
PERJETA plus trastuzumab and paclitaxel following ddAC and none of the patients treated with
PERJETA plus trastuzumab and docetaxel following FEC in the neoadjuvant period.
In patients receiving adjuvant PERJETA in APHINITY, the incidence of symptomatic heart
failure (NYHA Class III/IV) with a LVEF decline ≥ 10% and a drop to less than 50% was <1%
(0.6% of PERJETA-treated patients vs. 0.2% of placebo-treated patients). Of the patients who
experienced symptomatic heart failure, 47% of PERJETA-treated patients and 67% of placebo-
treated patients had recovered (defined as 2 consecutive LVEF measurements above 50%) at the
data cutoff. The majority of the events (86%) were reported in anthracycline-treated patients.
Asymptomatic or mildly symptomatic (NYHA Class II) declines in LVEF ≥ 10% and a drop to
less than 50% were reported in 3% of PERJETA-treated patients and 3% of placebo-treated
patients, of whom 80% of PERJETA-treated patients and 81% of placebo-treated patients
recovered at the data cutoff.
PERJETA has not been studied in patients with a pretreatment LVEF value of  50%, a prior
history of CHF, decreases in LVEF to  50% during prior trastuzumab therapy, or conditions
that could impair left ventricular function such as uncontrolled hypertension, recent myocardial
infarction, serious cardiac arrhythmia requiring treatment or a cumulative prior anthracycline
exposure to  360 mg/m2 of doxorubicin or its equivalent.

5.2 Embryo-Fetal Toxicity

Based on its mechanism of action and findings in animal studies, PERJETA can cause fetal harm
when administered to a pregnant woman. PERJETA is a HER2/neu receptor antagonist. Cases
of oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia,
skeletal abnormalities, and neonatal death have been reported with use of another HER2/neu
receptor antagonist (trastuzumab) during pregnancy. In an animal reproduction study,
administration of pertuzumab to pregnant cynomolgus monkeys during the period of
organogenesis resulted in oligohydramnios, delayed fetal kidney development, and embryo-fetal
death at exposures 2.5 to 20 times the exposure in humans at the recommended dose, based on
Cmax.
Verify the pregnancy status of females of reproductive potential prior to the initiation of
PERJETA. Advise pregnant women and females of reproductive potential that exposure to
PERJETA in combination with trastuzumab during pregnancy or within 7 months prior to
conception can result in fetal harm, including embryo-fetal death or birth defects. Advise
females of reproductive potential to use effective contraception during treatment and for 7
months following the last dose of PERJETA in combination with trastuzumab [see Use in
Specific Populations (8.1, 8.3)].

5.3 Infusion-Related Reactions

PERJETA has been associated with infusion reactions, including fatal events. [see Adverse
Reactions (6.1)]. An infusion reaction was defined in CLEOPATRA as any event described as
hypersensitivity, anaphylactic reaction, acute infusion reaction, or cytokine release syndrome
occurring during an infusion or on the same day as the infusion. The initial dose of PERJETA
Page 8 of 36
was given the day before trastuzumab and docetaxel to allow for the examination of PERJETA-
associated reactions. On the first day, when only PERJETA was administered, the overall
frequency of infusion reactions was 13% in the PERJETA-treated group and 10% in the placebo-
treated group. Less than 1% were Grade 3 or 4. The most common infusion reactions ( 1.0%)
were pyrexia, chills, fatigue, headache, asthenia, hypersensitivity, and vomiting.
During the second cycle when all drugs were administered on the same day, the most common
infusion reactions in the PERJETA-treated group ( 1.0%) were fatigue, dysgeusia,
hypersensitivity, myalgia, and vomiting.
In NeoSphere, TRYPHAENA, and APHINITY, PERJETA was administered on the same day as
the other study treatment drugs. For APHINITY, infusion-related reactions occurred in 21% of
patients on the first day of PERJETA administration (in combination with trastuzumab and
chemotherapy) and in 18% of patients in the placebo arm. The incidence of Grade 3-4 National
Cancer Institute - Common Terminology Criteria for Adverse Events (NCI - CTCAE v4.0)
reactions was 1% for the PERJETA arm and 0.7% for the placebo arm.
Observe patients closely for 60 minutes after the first infusion and for 30 minutes after
subsequent infusions of PERJETA. If a significant infusion-related reaction occurs, slow or
interrupt the infusion, and administer appropriate medical therapies. Monitor patients carefully
until complete resolution of signs and symptoms. Consider permanent discontinuation in
patients with severe infusion reactions [see Dosage and Administration (2.2)].
5.4 Hypersensitivity Reactions/Anaphylaxis
In CLEOPATRA, the overall frequency of hypersensitivity/anaphylaxis reactions was 11% in the
PERJETA-treated group and 9% in the placebo-treated group. The incidence of Grade 3 – 4
hypersensitivity/anaphylaxis reactions was 2% in the PERJETA-treated group and 3% in the
placebo-treated group according to NCI - CTCAE v3.0. Overall, 4 patients in the PERJETA-
treated group and 2 patients in the placebo-treated group experienced anaphylaxis.
In NeoSphere, TRYPHAENA, BERENICE, and APHINITY, hypersensitivity/anaphylaxis
events were consistent with those observed in CLEOPATRA. In NeoSphere, two patients in the
PERJETA- and docetaxel-treated group experienced anaphylaxis. In APHINITY, the overall
frequency of hypersensitivity/anaphylaxis was 5% in the PERJETA treated group vs. 4% in the
placebo-treated group. The incidence was highest in the PERJETA plus TCH treated group (8%)
of which 1% were NCI-CTCAE (v4.0) Grade 3 – 4.
Patients should be observed closely for hypersensitivity reactions. Severe hypersensitivity,
including anaphylaxis and fatal events, have been observed in patients treated with PERJETA
[see Clinical Trials Experience (6.1)]. Angioedema has been described in post-marketing
reports. Medications to treat such reactions, as well as emergency equipment, should be available
for immediate use. PERJETA is contraindicated in patients with known hypersensitivity to
pertuzumab or to any of its excipients [see Contraindications (4)].
6 ADVERSE REACTIONS
The following adverse reactions are discussed in greater detail in other sections of the label:
 Left Ventricular Dysfunction [see Warnings and Precautions (5.1)]
 Embryo-Fetal Toxicity [see Warnings and Precautions (5.2)]
 Infusion-Related Reactions [see Warnings and Precautions (5.3)]
 Hypersensitivity Reactions/Anaphylaxis [see Warnings and Precautions (5.4)]
Page 9 of 36
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates
observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials
of another drug and may not reflect the rates observed in clinical practice.
Metastatic Breast Cancer (MBC)
The adverse reactions described in Table 3 were identified in 804 patients with HER2-positive
metastatic breast cancer treated in CLEOPATRA. Patients were randomized to receive either
PERJETA in combination with trastuzumab and docetaxel or placebo in combination with
trastuzumab and docetaxel. The median duration of study treatment was 18.1 months for
patients in the PERJETA-treated group and 11.8 months for patients in the placebo-treated
group. No dose adjustment was permitted for PERJETA or trastuzumab. Adverse reactions
resulting in permanent discontinuation of all study therapy were 6% in the PERJETA-treated
group and 5% for patients in the placebo-treated group. The most common adverse reactions
(>1%) that led to discontinuation of all study therapy was left ventricular dysfunction (1% for
patients in the PERJETA-treated group and 2% for patients in the placebo-treated group). The
most common adverse reactions that led to discontinuation of docetaxel alone were edema,
fatigue, edema peripheral, neuropathy peripheral, neutropenia, nail disorder and pleural effusion.
Table 3 reports the adverse reactions that occurred in at least 10% of patients in the PERJETA-
treated group. The safety profile of PERJETA remained unchanged with an additional 2.75
years of follow-up (median total follow-up of 50 months) in CLEOPATRA.
The most common adverse reactions ( 30%) seen with PERJETA in combination with
trastuzumab and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and
peripheral neuropathy. The most common NCI - CTCAE v3.0 Grade 3 – 4 adverse reactions
( 2%) were neutropenia, febrile neutropenia, leukopenia, diarrhea, peripheral neuropathy,
anemia, asthenia, and fatigue. An increased incidence of febrile neutropenia was observed for
Asian patients in both treatment arms compared with patients of other races and from other
geographic regions. Among Asian patients, the incidence of febrile neutropenia was higher in
the pertuzumab-treated group (26%) compared with the placebo-treated group (12%).

Page 10 of 36
 Table 3 Summary of Adverse Reactions Occurring in  10%
of Patients on the PERJETA Treatment Arm in CLEOPATRA
Body System/ PERJETA Placebo
Adverse Reactions + trastuzumab + trastuzumab
+ docetaxel + docetaxel
n=407 n=397
Frequency Frequency
rate % rate %
All Grades All Grades
Grades 3–4 Grades 3–4
% % % %
General disorders and administration site
conditions
Fatigue 37 2 37 3
Mucosal inflammation 28 1 20 1
Asthenia 26 2 30 2
Edema peripheral 23 0.5 30 0.8
Pyrexia 19 1 18 0.5
Skin and subcutaneous tissue disorders
Alopecia 61 0 60 0.3
Rash 34 0.7 24 0.8
Nail disorder 23 1 23 0.3
Pruritus 14 0 10 0
Dry skin 11 0 4 0
Gastrointestinal disorders
Diarrhea 67 8 46 5
Nausea 42 1 42 0.5
Vomiting 24 1 24 2
Stomatitis 19 0.5 15 0.3
Constipation 15 0 25 1
Blood and lymphatic system disorders
Neutropenia 53 49 50 46
Anemia 23 2 19 4
Leukopenia 18 12 20 15
Febrile neutropenia* 14 13 8 7
Nervous system disorders
Neuropathy peripheral 32 3 34 2
Headache 21 1 17 0.5

Page 11 of 36
Dysgeusia 18 0 16 0
Dizziness 13 0.5 12 0
Musculoskeletal and connective tissue disorders
Myalgia 23 1 24 0.8
Arthralgia 15 0.2 16 0.8
Infections and infestations
Upper respiratory tract infection 17 0.7 13 0
Nasopharyngitis 12 0 13 0.3
Respiratory, thoracic, and mediastinal disorders
Dyspnea 14 1 16 2
Metabolism and nutrition disorders
Decreased appetite 29 2 26 2
Eye disorders
Lacrimation increased 14 0 14 0
Psychiatric disorders
Insomnia 13 0 13 0
* In this table this denotes an adverse reaction that has been reported in association with a fatal
outcome
The following clinically relevant adverse reactions were reported in  10% of patients in
the PERJETA-treated group in CLEOPATRA:
Infections and infestations: Paronychia (7% in the PERJETA-treated group vs. 4% in the
placebo-treated group)
Adverse Reactions Reported in Patients Receiving PERJETA and Trastuzumab After
Discontinuation of Docetaxel
In CLEOPATRA, adverse reactions were reported less frequently after discontinuation of
docetaxel treatment. All adverse reactions in the PERJETA and trastuzumab treatment group
occurred in  10% of patients with the exception of diarrhea (19%), upper respiratory tract
infection (13%), rash (12%), headache (11%), and fatigue (11%).
Neoadjuvant Treatment of Breast Cancer (NeoSphere)
In NeoSphere, the most common adverse reactions seen with PERJETA in combination with
trastuzumab and docetaxel administered for 4 cycles were similar to those seen in the PERJETA-
treated group in CLEOPATRA. The most common adverse reactions (> 30%) were alopecia,
neutropenia, diarrhea, and nausea. The most common NCI – CTCAE v3.0 Grade 3 – 4 adverse
reactions (> 2%) were neutropenia, febrile neutropenia, leukopenia, and diarrhea. In this group,
one patient permanently discontinued neoadjuvant treatment due to an adverse event. Table 4
reports the adverse reactions that occurred in patients who received neoadjuvant treatment with
PERJETA for breast cancer in NeoSphere.

Page 12 of 36
 Table 4 Summary of Adverse Reactions Occurring in ≥ 10%
in the Neoadjuvant Setting for Patients Receiving PERJETA in NeoSphere
PERJETA
Trastuzumab + trastuzumab PERJETA PERJETA
+ docetaxel + docetaxel + trastuzumab + docetaxel
n=107 n=107 n=108 n=108
Body System/ Frequency rate Frequency rate Frequency rate Frequency rate
Adverse Reactions % % % %
All Grades All Grades All Grades All Grades
Grades 3–4 Grades 3–4 Grades 3–4 Grades 3–4
% % % % % % % %
General disorders
and administration
site conditions
Fatigue 27 0 26 0.9 12 0 26 1
Mucosal
inflammation 21 0 26 2 3 0 26 0
Asthenia 18 0 21 2 3 0 16 2
Pyrexia 10 0 17 0 8 0 9 0
Edema peripheral 10 0 3 0 0.9 0 5 0
Skin and
subcutaneous
tissue disorders
Alopecia 66 0 65 0 3 0 67 0
Rash 21 2 26 0.9 11 0 29 1
Gastrointestinal
disorders
Diarrhea 34 4 46 6 28 0 54 4
Nausea 36 0 39 0 14 0 36 1
Stomatitis 7 0 18 0 5 0 10 0
Vomiting 12 0 13 0 5 0 16 2
Blood and
lymphatic system
disorders
Neutropenia 64 59 50 45 0.9 0.9 65 57
Leukopenia 21 11 9 5 0 0 14 9
Nervous system
disorders
Dysgeusia 10 0 15 0 5 0 7 0
Headache 11 0 11 0 14 0 13 0
Peripheral Sensory
Neuropathy 12 0.9 8 0.9 2 0 11 0
Musculoskeletal
and connective
tissue disorders
Myalgia 22 0 22 0 9 0 21 0
Arthralgia 8 0 10 0 5 0 10 0
Metabolism and
nutrition disorders
Decreased appetite 7 0 14 0 2 0 15 0

Page 13 of 36
Psychiatric
disorders
Insomnia 11 0 8 0 4 0 9 0

The following adverse reactions were reported in < 10% of patients receiving neoadjuvant
treatment and occurred more frequently in PERJETA-treated groups in NeoSphere:
(Ptz=pertuzumab; H=trastuzumab; D=docetaxel)
Blood and lymphatic system disorders: Anemia (7% in the H+D arm, 3% in the Ptz+H+D
arm, 5% in the Ptz+H arm and 9% in the Ptz+D arm), Febrile neutropenia (7% in the H+D arm,
8% in the Ptz+H+D arm, 0% in the Ptz+H arm and 7% in the Ptz+D arm)
Nervous system disorders: Dizziness (4% in the H+D arm, 3% in the Ptz+H+D arm, 6% in the
Ptz+H arm and 3% in the Ptz+D arm)
Infections and infestations: Upper respiratory tract infection (3% in the H+D arm, 5% in the
Ptz+H+D arm, 2% in the Ptz+H arm and 7% in the Ptz+D arm)
Eye disorders: Lacrimation increased (2% in the H+D arm, 4% in the Ptz+H+D arm, 0.9% in
the Ptz+H arm, and 4% in the Ptz+D arm)
Neoadjuvant Treatment of Breast Cancer (TRYPHAENA)
In TRYPHAENA, when PERJETA was administered in combination with trastuzumab and
docetaxel for 3 cycles following 3 cycles of FEC, the most common adverse reactions (> 30%)
were diarrhea, nausea, alopecia, neutropenia, vomiting, and fatigue. The most common NCI-
CTCAE (version 3) Grade 3 – 4 adverse reactions (> 2%) were neutropenia, leukopenia, febrile
neutropenia, diarrhea, left ventricular dysfunction, anemia, dyspnea, nausea, and vomiting.
Similarly, when PERJETA was administered in combination with docetaxel, carboplatin, and
trastuzumab (TCH) for 6 cycles, the most common adverse reactions (> 30%) were diarrhea,
alopecia, neutropenia, nausea, fatigue, vomiting, anemia, and thrombocytopenia. The most
common NCI-CTCAE (version 3) Grade 3 – 4 adverse reactions (> 2%) were neutropenia,
febrile neutropenia, anemia, leukopenia, diarrhea, thrombocytopenia, vomiting, fatigue, ALT
increased, hypokalemia, and hypersensitivity.
Adverse reactions resulting in permanent discontinuation of any component of neoadjuvant
treatment occurred in 7% of patients receiving PERJETA in combination with trastuzumab and
docetaxel following FEC, and 8% for patients receiving PERJETA in combination with TCH.
The most common adverse reactions (>2%) resulting in permanent discontinuation of PERJETA
were left ventricular dysfunction, drug hypersensitivity, and neutropenia. Table 5 reports the
adverse reactions that occurred in patients who received neoadjuvant treatment with PERJETA
for breast cancer in TRYPHAENA.

Page 14 of 36
 Table 5 Summary of Adverse Reactions Occurring in  10% of Patients Receiving
Neoadjuvant Treatment with PERJETA in TRYPHAENA

PERJETA PERJETA PERJETA

+ trastuzumab + trastuzumab + TCH
+ FEC followed by + docetaxel following
PERJETA FEC
+ trastuzumab
+ docetaxel

n=72 n=75 n=76

Body
System/Adverse Frequency rate Frequency rate Frequency rate
Reactions % % %
All Grades All Grades All Grades
Grades 3–4 Grades 3–4 Grades 3–4
% % % % % %
General disorders
and
administration site
conditions
Fatigue 36 0 36 0 42 4
Mucosal 24 0 20 0 17 1
inflammation
Pyrexia 17 0 9 0 16 0
Asthenia 10 0 15 1 13 1
Edema peripheral 11 0 4 0 9 0
Skin and
subcutaneous
tissue disorders
Alopecia 49 0 52 0 55 0
Rash 19 0 11 0 21 1
Palmar-Plantar 7 0 11 0 8 0
Erythrodysaesthesia
Syndrome
Dry skin 6 0 9 0 11 0
Gastrointestinal
disorders
Diarrhea 61 4 61 5 72 12
Nausea 53 0 53 3 45 0
Vomiting 40 0 36 3 39 5
Dyspepsia 25 1 8 0 22 0
Constipation 18 0 23 0 16 0
Stomatitis 14 0 17 0 12 0
Blood and
lymphatic system
disorders
Neutropenia 51 47 47 43 49 46

Page 15 of 36
Leukopenia 22 19 16 12 17 12
Anemia 19 1 9 4 38 17
Febrile neutropenia 18 18 9 9 17 17
Thrombocytopenia 7 0 1 0 30 12
Immune system
disorders
Hypersensitivity 10 3 1 0 12 3
Nervous system
disorders
Headache 22 0 15 0 17 0
Dysgeusia 11 0 13 0 21 0
Dizziness 8 0 8 1 16 0
Neuropathy 6 0 1 0 11 0
peripheral
Musculoskeletal
and connective
tissue disorders
Myalgia 17 0 11 1 11 0
Arthralgia 11 0 12 0 7 0
Respiratory,
thoracic, and
mediastinal
disorders
Dyspnea 13 0 8 3 11 1
Epistaxis 11 0 11 0 16 1
Cough 10 0 5 0 12 0
Oropharyngeal pain 8 0 7 0 12 0
Metabolism and
nutrition
disorders
Decreased appetite 21 0 11 0 21 0
Eye disorders
Lacrimation 13 0 5 0 8 0
increased
Psychiatric
disorders
Insomnia 11 0 13 0 21 0
Investigations
ALT increased 7 0 3 0 11 4
FEC=5-fluorouracil, epirubicin, cyclophosphamide, TCH=docetaxel, carboplatin, trastuzumab
The following selected adverse reactions were reported in < 10% of patients receiving
neoadjuvant treatment in TRYPHAENA: (Ptz=pertuzumab; H=trastuzumab;
D=docetaxel; FEC= fluorouracil, epirubicin, and cyclophosphamide; TCH=docetaxel,
carboplatin, and trastuzumab)
Skin and subcutaneous tissue disorders: Nail disorder (10% in the Ptz+H+FEC/Ptz+H+D
arm, 7% in the FEC/Ptz+H+D arm, and 9% in the Ptz+TCH arm), Paronychia (0% in the
Ptz+H+FEC/Ptz+H+D arm, and 1% in both the FEC/Ptz+H+D and Ptz+TCH arms), Pruritus
Page 16 of 36
(3% in the Ptz+H+FEC/Ptz+H+D arm, 4% in the FEC/Ptz+H+D arm, and 4% in the Ptz+TCH
arm)
Infections and infestations: Upper respiratory tract infection (8.3% in the
Ptz+H+FEC/Ptz+H+D arm, 4.0% in the FEC/Ptz+H+D arm, and 2.6% in the Ptz+TCH arm),
Nasopharyngitis (6.9% in the Ptz+H+FEC/Ptz+H+D arm, 6.7% in the FEC/Ptz+H+D arm, and
7.9% in the Ptz+TCH arm)
Neoadjuvant Treatment of Breast Cancer (BERENICE)
In BERENICE, when PERJETA was administered in combination with trastuzumab and
paclitaxel for 4 cycles following 4 cycles of ddAC, the most common adverse reactions (> 30%)
were nausea, diarrhea, alopecia, fatigue, constipation, peripheral neuropathy and headache. The
most common Grade 3 – 4 adverse reactions (> 2%) were neutropenia, febrile neutropenia,
neutrophil count decreased, white blood cell count decreased, anemia, diarrhea, peripheral
neuropathy, alanine aminotransferase increased and nausea.
When PERJETA was administered in combination with trastuzumab and docetaxel for 4 cycles
following 4 cycles of FEC, the most common adverse reactions (> 30%) were diarrhea, nausea,
alopecia, asthenia, constipation, fatigue, mucosal inflammation, vomiting, myalgia, and anemia.
The most common Grade 3 – 4 adverse reactions (> 2%) were febrile neutropenia, diarrhea,
neutropenia, neutrophil count decreased, stomatitis, fatigue, vomiting, mucosal inflammation,
neutropenic sepsis and anemia.
Adverse reactions resulting in permanent discontinuation of any component of neoadjuvant
treatment were 14% for patients receiving PERJETA in combination with trastuzumab and
paclitaxel following ddAC and 8% for patients receiving PERJETA in combination with
trastuzumab and docetaxel following FEC. The most common adverse reactions (>1%) resulting
in permanent discontinuation of any component of neoadjuvant treatment were neuropathy
peripheral, ejection fraction decreased, diarrhea, neutropenia and infusion related reaction. Table
6 reports the adverse reactions that occurred in patients who received neoadjuvant treatment with
PERJETA for breast cancer in BERENICE.
Table 6 Summary of Adverse Reactions Occurring in  10% of Patients Receiving
Neoadjuvant Treatment with PERJETA in BERENICE

PERJETA PERJETA
+ trastuzumab + trastuzumab
+ paclitaxel following + docetaxel following
ddAC FEC

n=199 n=198

Frequency rate Frequency rate

Body System/Adverse Reactions % %
All Grades All Grades
Grades 3–4 Grades 3–4
% % % %
General disorders and administration site
conditions
Fatigue 58 1 38 5
Asthenia 19 2 41 0

Page 17 of 36
Mucosal inflammation 22 1 37 4
Pyrexia 15 0 18 0
Edema peripheral 9 0 12 1
Skin and subcutaneous tissue disorders
Alopecia 62 0 59 0
Rash 14 0 11 0
Dry skin 14 0 10 0
Nail discoloration 15 0 2 0
Palmar-Plantar Erythrodysaesthesia 6 0 10 0.5
Syndrome
Gastrointestinal disorders
Nausea 71 3 69 2
Diarrhea 67 3 69 10
Constipation 35 0.5 38 0.5
Vomiting 23 1 35 4
Stomatitis 25 0 27 5
Dyspepsia 19 0 16 0
Abdominal pain upper 6 0 13 0
Abdominal pain 5 0 10 0
Gastroesophageal reflux disease 12 0 2 0
Blood and lymphatic system disorders
Anemia 27 3 30 3
Neutropenia 22 12 16 9
Febrile neutropenia 7 7 17 17
Nervous system disorders
Headache 30 0.5 14 0.5
Dysgeusia 20 0 19 0.5
Neuropathy peripheral 42 3 26 0.5
Paresthesia 15 0 9 0
Dizziness 12 0 8 0
Musculoskeletal and connective tissue
disorders
Myalgia 20 0 33 1
Arthralgia 20 0 21 1
Back pain 10 0 9 0
Pain in extremity 10 0 8 0
Bone pain 12 0.5 5 0
Infections and infestations
Urinary tract infection 11 1 2 0
Respiratory, thoracic, and mediastinal
disorders
Epistaxis 25 0 19 0
Dyspnea 15 0.5 15 0.5
Cough 20 0.5 9 0
Oropharyngeal pain 10 0 8 0.5
Metabolism and nutrition disorders
Decreased appetite 20 0 23 0
Page 18 of 36
Eye disorders
Lacrimation increased 9 0 18 0
Psychiatric disorders
Insomnia 19 0 13 0
Vascular disorders
Hot flush 19 0 13 0
Investigations
White blood cell count decreased 11 4 3 2
Injury, poisoning and procedural
complications
Infusion related reaction 16 1 13 1
ddAC = dose-dense doxorubicin, cyclophosphamide, FEC=5-fluorouracil, epirubicin,
cyclophosphamide
The following selected adverse reactions were reported in < 10% of patients receiving
neoadjuvant treatment in BERENICE: (Ptz=pertuzumab; H=trastuzumab; P=paclitaxel;
ddAC=dose-dense doxorubicin and cyclophosphamide; D=docetaxel; FEC= fluorouracil,
epirubicin, and cyclophosphamide)
Skin and Subcutaneous tissue disorders: Pruritus (9% in the ddAC/Ptz+H+P arm, and 8% in
the FEC/Ptz+H+D arm), Nail disorder (7% in the ddAC/Ptz+H+P arm, and 10% in the
FEC/Ptz+H+D arm)
Infections and infestations: Upper respiratory tract infection (7% in the ddAC/Ptz+H+P arm,
and 2% in the FEC/Ptz+H+D arm), nasopharyngitis (7% in the ddAC/Ptz+H+P arm, and 9% in
the FEC/Ptz+H+D arm), paronychia (0.5% in the ddAC/Ptz+H+P arm, and 1% in the
FEC/Ptz+H+D arm)
Adjuvant Treatment of Breast Cancer (APHINITY)
The adverse reactions described in Table 7 were identified in 4769 patients with HER2-positive
early breast cancer treated in APHINITY. Patients were randomized to receive either PERJETA
in combination with trastuzumab and chemotherapy or placebo in combination with trastuzumab
and chemotherapy.
Adverse reactions resulting in permanent discontinuation of any study therapy were 13% for
patients in the PERJETA-treated group and 12% for patients in the placebo-treated group.
Adverse reactions resulting in permanent discontinuation of PERJETA or placebo was 7% and
6%, respectively. The most common adverse reactions (>0.5%) resulting in permanent
discontinuation of any study treatment were ejection fraction decreased, neuropathy peripheral,
diarrhea, and cardiac failure. Table 7 reports the adverse reactions that occurred in at least 10%
of patients in the PERJETA-treated group.
When PERJETA was administered in combination with trastuzumab and chemotherapy, the most
common adverse reactions (> 30%) were diarrhea, nausea, alopecia, fatigue, peripheral
neuropathy, and vomiting. The most common Grade 3 – 4 adverse reactions (> 2%) were
neutropenia, febrile neutropenia, diarrhea, neutrophil count decreased, anemia, white blood cell
count decreased, leukopenia, fatigue, nausea, and stomatitis.
The incidence of diarrhea, all Grades, was higher when chemotherapy was administered with
targeted therapy (61% in the PERJETA-treated group vs. 34% in the placebo-treated group), and
was higher when administered with non-anthracycline based therapy (85% in the PERJETA-
treated group vs. 62% in the placebo-treated group) than with anthracycline based therapy (67%
Page 19 of 36
in the PERJETA-treated group vs. 41% in the placebo-treated group). The incidence of diarrhea
during the period that targeted therapy was administered without chemotherapy was 18% in the
PERJETA-treated group vs. 9% in the placebo-treated group. The median duration of all Grades
diarrhea was 8 days for the PERJETA-treated group vs. 6 days for the placebo-treated group.
The median duration of Grade ≥3 diarrhea was 20 days for the PERJETA-treated group vs. 8
days for the placebo-treated group. More patients required hospitalization for diarrhea as a
serious adverse event in the PERJETA-treated group (2.4%) than in the placebo-treated group
(0.7%).
Table 7 Summary of Adverse Reactions Occurring in  10% of Patients Receiving
Adjuvant Treatment with PERJETA in APHINITY
PERJETA Placebo
+ trastuzumab + trastuzumab
+ chemotherapy + chemotherapy
Body System/ n=2364 n=2405
Adverse Reactions Frequency rate % Frequency rate %
All Grades All Grades
Grades 3–4 Grades 3–4
% % % %
General disorders and administration site conditions
Fatigue 49 4 44 3
Mucosal inflammation 23 2 19 0.7
Asthenia 21 1 21 2
Pyrexia 20 0.6 20 0.7
Edema peripheral 17 0 20 0.2
Skin and subcutaneous tissue disorders
Alopecia 67 <0.1 67 <0.1
Rash 26 0.4 20 0.2
Pruritus 14 0.1 9 <0.1
Dry skin 13 0.1 11 <0.1
Nail disorder 12 0.2 12 0.1
Gastrointestinal disorders
Diarrhea 71 10 45 4
Nausea 69 2 65 2
Vomiting 32 2 30 2
Constipation 29 0.5 32 0.3
Stomatitis 28 2 24 1
Dyspepsia 14 0 14 0
Abdominal pain 12 0.5 11 0.6
Abdominal pain upper 10 0.3 9 0.2
Blood and lymphatic system disorders
Anemia 28 7 23 5
Neutropenia 25 16 23 16
Febrile neutropenia* 12 12 11 11
Nervous system disorders
Page 20 of 36
Dysgeusia 26 0.1 22 <0.1
Neuropathy peripheral 33 1 32 1
Headache 22 0.3 23 0.4
Paresthesia 12 0.5 10 0.2
Dizziness 11 0 11 0.2
Musculoskeletal and connective tissue disorders
Arthralgia 29 0.9 33 1
Myalgia 26 0.9 30 1
Pain in extremity 10 0.2 10 0.2
Infections and infestations
Nasopharyngitis 13 <0.1 12 0.1
Respiratory, thoracic, and mediastinal disorders
Epistaxis 18 <0.1 14 0
Cough 16 <0.1 15 <0.1
Dyspnea 12 0.4 12 0.5
Metabolism and nutrition disorders
Decreased appetite 24 0.8 20 0.4
Vascular disorders
Hot flush 20 0.2 21 0.4
Eye disorders
Lacrimation increased 13 0 13 <0.1
Psychiatric disorders
Insomnia 17 0.3 17 <0.1
Investigations
Neutrophil count decreased 14 10 14 10
Injury, poisoning and procedural complications
Radiation skin injury 13 0.3 11 0.3
* In this table this denotes an adverse reaction that has been reported in association with a fatal
outcome
For the adverse reactions that were reported in ≥10% of patients with at least 5%
difference between the PERJETA-treated group and the placebo-treated group in
APHINITY, the breakdown per chemotherapy regimen is provided: (Ptz=pertuzumab;
H=trastuzumab; AC=anthracyclines; TCH=docetaxel, carboplatin, and trastuzumab)
Gastrointestinal disorders: Diarrhea (67% in the Ptz+H+AC chemo arm, 85% in the Ptz+TCH
arm, 41% in the Pla+H+AC chemo arm, 62% in the Pla+TCH arm)
Skin and subcutaneous disorders: Rash (26% in the Ptz+H+AC chemo arm, 25% in the
Ptz+TCH arm, 21% in the Pla+H+AC chemo arm, 19% in the Pla+TCH arm), Pruritus (14% in
the Ptz+H+AC chemo arm, 15% in the Ptz+TCH arm, 9% in the Pla+H+AC chemo arm, 9% in
the Pla+TCH arm)
The following clinically relevant adverse reactions were reported in  10% of patients in
the PERJETA-treated group in APHINITY:

Page 21 of 36
Blood and lymphatic system disorders: Leukopenia (9% in the PERJETA-treated group vs.
9% in the placebo-treated group)
Infections and infestations: Upper respiratory tract infection (8% in the PERJETA-treated
group vs. 7% in the placebo-treated group), paronychia (4% in the PERJETA-treated group vs.
2% in the placebo-treated group)
Adverse Reactions Reported in Patients Receiving PERJETA and Trastuzumab After
Discontinuation of Chemotherapy
In the APHINITY study, during the targeted treatment alone phase, all adverse reactions in the
PERJETA treatment group occurred in  10% of patients with the exception of diarrhea (18%),
arthralgia (15%), radiation skin injury (12%), and hot flush (12%).
6.2 Immunogenicity
As with all therapeutic proteins, there is the potential for immunogenicity. The detection of
antibody formation is highly dependent on the sensitivity and specificity of the assay.
Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in
an assay may be influenced by several factors including assay methodology, sample handling,
timing of sample collection, concomitant medications, and underlying disease. For these reasons,
comparison of the incidence of antibodies to pertuzumab in the studies described below with the
incidence of antibodies in other studies or to other products may be misleading.
Patients in CLEOPATRA were tested at multiple time-points for antibodies to PERJETA. 3%
(13/389) of patients in the PERJETA-treated group and 7% (25/372) of patients in the placebo-
treated group tested positive for anti-PERJETA antibodies. Of these 38 patients, none
experienced anaphylactic/hypersensitivity reactions that were clearly related to the anti-drug
antibodies (ADA). The presence of pertuzumab in patient serum at the levels expected at the
time of ADA sampling can interfere with the ability of this assay to detect anti-pertuzumab
antibodies. In addition, the assay may be detecting antibodies to trastuzumab. As a result, data
may not accurately reflect the true incidence of anti-pertuzumab antibody development.
In the neoadjuvant period of BERENICE, 0.3% (1/383) of patients treated with PERJETA tested
positive for anti-PERJETA antibodies. This patient did not experience any
anaphylactic/hypersensitivity reactions.
6.3 Post-Marketing Experience
The following adverse reactions have been identified during post-approval use of PERJETA.
Because these reactions are reported voluntarily from a population of uncertain size, it is not
always possible to reliably estimate their frequency or establish a causal relationship to drug
exposure.
 Tumor lysis syndrome (TLS): Cases of possible TLS have been reported in patients
treated with PERJETA. Patients with significant tumor burden (e.g., bulky metastases)
may be at a higher risk. Patients could present with hyperuricemia, hyperphosphatemia,
and acute renal failure which may represent possible TLS. Providers should consider
additional monitoring and/or treatment as clinically indicated.
7 DRUG INTERACTIONS
No drug-drug interactions were observed between pertuzumab and trastuzumab, or between
pertuzumab and docetaxel, paclitaxel, or carboplatin.

Page 22 of 36
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Pharmacovigilance Program
There is a pregnancy pharmacovigilance program for PERJETA. If PERJETA is administered
during pregnancy, or if a patient becomes pregnant while receiving PERJETA or within 7
months following the last dose of PERJETA in combination with trastuzumab, health care
providers and patients should immediately report PERJETA exposure to Genentech at 1-888-
835-2555.
Risk Summary
Based on its mechanism of action and findings in animal studies, PERJETA can cause fetal
harm when administered to a pregnant woman. There are no available data on the use of
PERJETA in pregnant women. However, in post-marketing reports, use of another HER2/neu
receptor antagonist (trastuzumab) during pregnancy resulted in cases of oligohydramnios and
oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and
neonatal death. In an animal reproduction study, administration of pertuzumab to pregnant
cynomolgus monkeys during the period of organogenesis resulted in oligohydramnios, delayed
fetal kidney development, and embryo-fetal deaths at clinically relevant exposures that were
2.5 to 20-fold greater than exposures in humans receiving the recommended dose, based on C max
[see Data]. Apprise the patient of the potential risks to a fetus. There are clinical
considerations if PERJETA in combination with trastuzumab is used during pregnancy or within
7 months prior to conception [see Clinical Considerations].
The estimated background risk of major birth defects and miscarriage for the indicated
population is unknown. In the U.S. general population, the estimated background risk of major
birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%,
respectively.
Clinical Considerations
Fetal/Neonatal Adverse Reactions
Monitor women who received PERJETA in combination with trastuzumab during pregnancy or
within 7 months prior to conception for oligohydramnios. If oligohydramnios occurs, perform
fetal testing that is appropriate for gestational age and consistent with community standards of
care.
Data
Animal Data
Pregnant cynomolgus monkeys were treated on Gestational Day (GD)19 with loading doses of
30 to 150 mg/kg pertuzumab, followed by bi-weekly doses of 10 to 100 mg/kg. These dose
levels resulted in clinically relevant exposures of 2.5 to 20-fold greater than exposures in humans
receiving the recommended dose, based on Cmax. Intravenous administration of pertuzumab
from GD19 through GD50 (period of organogenesis) was embryotoxic, with dose-dependent
increases in embryo-fetal death between GD25 to GD70. The incidences of embryo-fetal loss
were 33, 50, and 85% for dams treated with bi-weekly pertuzumab doses of 10, 30, and
100 mg/kg, respectively (2.5 to 20-fold greater than the recommended human dose, based on
Cmax). At Caesarean section on GD100, oligohydramnios, decreased relative lung and kidney
weights, and microscopic evidence of renal hypoplasia consistent with delayed renal

Page 23 of 36
development were identified in all pertuzumab dose groups. Pertuzumab exposure was reported
in offspring from all treated groups, at levels of 29% to 40% of maternal serum levels at GD100.

8.2 Lactation
Risk Summary
There is no information regarding the presence of pertuzumab in human milk, the effects on the
breastfed infant or the effects on milk production. Published data suggest that human IgG is
present in human milk but does not enter the neonatal and infant circulation in substantial
amounts. Consider the developmental and health benefits of breast feeding along with the
mother’s clinical need for PERJETA treatment and any potential adverse effects on the breastfed
child from PERJETA or from the underlying maternal condition. This consideration should also
take into account the elimination half-life of pertuzumab and the trastuzumab wash out period of
7 months.
8.3 Females and Males of Reproductive Potential
Pregnancy Testing
Verify the pregnancy status of females of reproductive potential prior to the initiation of
PERJETA.
Contraception
Females
Based on the mechanism of action and animal data, PERJETA can cause embryo-fetal harm
when administered during pregnancy. Advise females of reproductive potential to use effective
contraception during treatment and for 7 months following the last dose of PERJETA in
combination with trastuzumab [see Use in Specific Populations (8.1)].

8.4 Pediatric Use

The safety and effectiveness of PERJETA have not been established in pediatric patients.

8.5 Geriatric Use

In studies in the indicated populations, CLEOPATRA, NeoSphere, TRYPHAENA, BERENICE,
and APHINITY, 464 patients who received PERJETA were  65 years of age and 47 were  75
years of age. The most common ( 10%) Grade 3-4 adverse reactions in both age groups were
neutropenia (22%  65 years, 23%  75 years), febrile neutropenia (12%  65 years, 13%  75
years), diarrhea (15%  65 years, 17%  75 years) and anemia (15%  75 years).
The incidence of the following all grade adverse events was at least 5% higher in patients
aged  65 years of age, compared to patients aged < 65 years of age: decreased appetite (13%
higher), anemia (7% higher), weight decreased (7% higher), asthenia (7% higher), dysgeusia (7%
higher), neuropathy peripheral and hypomagnesemia (both 5% higher).
No overall differences in efficacy of PERJETA were observed in patients aged  65 and <65
years of age. There are too few patients aged  75 years to draw conclusions on efficacy in this
age group.
Based on a population pharmacokinetic analysis, no significant difference was observed in the
pharmacokinetics of pertuzumab between patients < 65 years (n=306) and patients  65 years
(n=175).

Page 24 of 36
8.6 Renal Impairment
Dose adjustments of PERJETA are not needed in patients with mild (creatinine clearance [CLcr]
60 to 90 mL/min) or moderate (CLcr 30 to 60 mL/min) renal impairment. No dose adjustment
can be recommended for patients with severe renal impairment (CLcr less than 30 mL/min)
because of the limited pharmacokinetic data available [see Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

No clinical studies have been conducted to evaluate the effect of hepatic impairment on the
pharmacokinetics of pertuzumab.
11 DESCRIPTION
Pertuzumab is a recombinant humanized monoclonal antibody that targets the extracellular
dimerization domain (Subdomain II) of the human epidermal growth factor receptor 2 protein
(HER2). Pertuzumab is produced by recombinant DNA technology in a mammalian cell
(Chinese Hamster Ovary) culture. Pertuzumab has an approximate molecular weight of
148 kDa.
PERJETA injection is a sterile, clear to slightly opalescent, colorless to pale brown liquid for
intravenous infusion. Each single-dose vial contains 420 mg of pertuzumab at a concentration of
30 mg/mL in 20 mM L-histidine acetate (pH 6.0), 120 mM sucrose and 0.02% polysorbate 20.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Pertuzumab targets the extracellular dimerization domain (Subdomain II) of the human
epidermal growth factor receptor 2 protein (HER2) and, thereby, blocks ligand-dependent
heterodimerization of HER2 with other HER family members, including EGFR, HER3, and
HER4. As a result, pertuzumab inhibits ligand-initiated intracellular signaling through two
major signal pathways, mitogen-activated protein (MAP) kinase, and phosphoinositide 3-kinase
(PI3K). Inhibition of these signaling pathways can result in cell growth arrest and apoptosis,
respectively. In addition, pertuzumab mediates antibody-dependent cell-mediated cytotoxicity
(ADCC).
While pertuzumab alone inhibited the proliferation of human tumor cells, the combination of
pertuzumab and trastuzumab augmented anti-tumor activity in HER2-overexpressing xenograft
models.

12.3 Pharmacokinetics
Pertuzumab demonstrated linear pharmacokinetics at a dose range of 2 – 25 mg/kg. Based on a
population PK analysis that included 481 patients, the median clearance (CL) of pertuzumab was
0.24 L/day and the median half-life was 18 days. With an initial dose of 840 mg followed by a
maintenance dose of 420 mg every three weeks thereafter, the steady-state concentration of
pertuzumab was reached after the first maintenance dose.
The population PK analysis suggested no PK differences based on age, gender, ethnicity
(Japanese vs. non-Japanese), or disease status (neoadjuvant or adjuvant vs. metastatic setting).
Baseline serum albumin level and lean body weight as covariates only exerted a minor influence
on PK parameters. Therefore, no dose adjustments based on body weight or baseline albumin
level are needed.
No dedicated renal impairment trial for PERJETA has been conducted. Based on the results of
the population pharmacokinetic analysis, pertuzumab exposure in patients with mild (CLcr

Page 25 of 36
60 to 90 mL/min, n=200) and moderate renal impairment (CLcr 30 to 60 mL/min, n=71) were
similar to those in patients with normal renal function (CLcr greater than 90 mL/min, n=200).
No relationship between CLcr and pertuzumab exposure was observed over the range of
observed CLcr (27 to 244 mL/min).

12.6 Cardiac Electrophysiology

The effect of pertuzumab with an initial dose of 840 mg followed by a maintenance dose of
420 mg every three weeks on QTc interval was evaluated in a subgroup of 20 patients with
HER2-positive breast cancer in CLEOPATRA. No large changes in the mean QT interval (i.e.,
greater than 20 ms) from placebo based on Fridericia correction method were detected in the
trial. A small increase in the mean QTc interval (i.e., less than 10 ms) cannot be excluded
because of the limitations of the trial design.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term studies in animals have not been performed to evaluate the carcinogenic potential of
pertuzumab.
Studies have not been performed to evaluate the mutagenic potential of pertuzumab.
No specific fertility studies in animals have been performed to evaluate the effect of pertuzumab.
No adverse effects on male and female reproductive organs were observed in repeat-dose
toxicity studies of up to six months duration in cynomolgus monkeys.
14 CLINICAL STUDIES
14.1 Metastatic Breast Cancer
CLEOPATRA (NCT00567190) was a multicenter, double-blind, placebo-controlled trial of
808 patients with HER2-positive metastatic breast cancer. HER2 overexpression was defined as
a score of 3+ IHC or FISH amplification ratio of 2.0 or greater as determined by a central
laboratory. Patients were randomly allocated 1:1 to receive placebo plus trastuzumab and
docetaxel or PERJETA plus trastuzumab and docetaxel. Randomization was stratified by prior
treatment (prior or no prior adjuvant/neoadjuvant anti-HER2 therapy or chemotherapy) and
geographic region (Europe, North America, South America, and Asia). Patients with prior
adjuvant or neoadjuvant therapy were required to have a disease-free interval of greater than
12 months before trial enrollment.
PERJETA was given intravenously at an initial dose of 840 mg, followed by 420 mg every
3 weeks thereafter. Trastuzumab was given intravenously at an initial dose of 8 mg/kg, followed
by 6 mg/kg every 3 weeks thereafter. Patients were treated with PERJETA and trastuzumab
until progression of disease, withdrawal of consent, or unacceptable toxicity. Docetaxel was
given as an initial dose of 75 mg/m2 by intravenous infusion every 3 weeks for at least 6 cycles.
The docetaxel dose could be escalated to 100 mg/m 2 at the investigator’s discretion if the initial
dose was well tolerated. At the time of the primary analysis, the mean number of cycles of study
treatment administered was 16.2 in the placebo-treated group and 19.9 in the PERJETA-treated
group.
The primary endpoint of CLEOPATRA was progression-free survival (PFS) as assessed by an
independent review facility (IRF). PFS was defined as the time from the date of randomization
to the date of disease progression or death (from any cause) if the death occurred within
18 weeks of the last tumor assessment. Additional endpoints included overall survival (OS),
PFS (investigator-assessed), objective response rate (ORR), and duration of response.
Page 26 of 36
Patient demographic and baseline characteristics were balanced between the treatment arms.
The median age was 54 (range 22 to 89 years), 59% were White, 32% were Asian, and 4% were
Black. All were women with the exception of 2 patients. Seventeen percent of patients were
enrolled in North America, 14% in South America, 38% in Europe, and 31% in Asia. Tumor
prognostic characteristics, including hormone receptor status (positive 48%, negative 50%),
presence of visceral disease (78%) and non-visceral disease only (22%) were similar in the study
arms. Approximately half of the patients received prior adjuvant or neoadjuvant anti-HER2
therapy or chemotherapy (placebo 47%, PERJETA 46%). Among patients with hormone
receptor positive tumors, 45% received prior adjuvant hormonal therapy and 11% received
hormonal therapy for metastatic disease. Eleven percent of patients received prior adjuvant or
neoadjuvant trastuzumab.
CLEOPATRA demonstrated a statistically significant improvement in IRF-assessed PFS in the
PERJETA-treated group compared with the placebo-treated group [hazard ratio (HR)=0.62 (95%
CI: 0.51, 0.75), p  0.0001] and an increase in median PFS of 6.1 months (median PFS of
18.5 months in the PERJETA-treated group vs. 12.4 months in the placebo-treated group) (see
Figure 1). The results for investigator-assessed PFS were comparable to those observed for IRF-
assessed PFS.
Consistent results were observed across several patient subgroups including age (< 65 or
 65 years), race, geographic region, prior adjuvant/neoadjuvant anti-HER2 therapy or
chemotherapy (yes or no), and prior adjuvant/neoadjuvant trastuzumab (yes or no). In the
subgroup of patients with hormone receptor-negative disease (n=408), the hazard ratio was 0.55
(95% CI: 0.42, 0.72). In the subgroup of patients with hormone receptor-positive disease
(n=388), the hazard ratio was 0.72 (95% CI: 0.55, 0.95). In the subgroup of patients with disease
limited to non-visceral metastasis (n=178), the hazard ratio was 0.96 (95% CI: 0.61, 1.52).
At the time of the final PFS analysis, 165 patients had died, and more deaths had occurred in the
placebo-treated group (23.6%) compared with the PERJETA-treated group (17.2%); OS was not
mature and interim OS analysis results did not meet the pre-specified stopping boundary for
statistical significance. The final analysis of OS (Table 8, Figure 2) was performed when 389
patients had died (221 in the placebo-treated group and 168 in the PERJETA-treated group). A
statistically significant OS improvement in favor of the PERJETA-treated group was
demonstrated [HR=0.68 (95% CI; 0.56, 0.84), p=0.0002] with an increase in median OS of 15.7
months (median OS of 56.5 months in the PERJETA-treated group vs. 40.8 months in the
placebo-treated group). OS results in patient subgroups were consistent with those observed for
IRF-assessed PFS with the exception of the subgroup of patients with disease limited to non-
visceral metastasis [HR=1.11 (95% CI: 0.66, 1.85)].

Page 27 of 36
 Table 8 Summary of Efficacy from CLEOPATRA

PERJETA Placebo
+ trastuzumab + trastuzumab
+ docetaxel + docetaxel HR
Parameter n=402 n=406 (95% CI) p-value
Progression-Free Survival
(independent review)

No. of patients with an event 191 (47.5%) 242 (59.6%) 0.62

Median months 18.5 12.4 (0.51, 0.75)  0.0001
Overall Survival*
(final analysis)

No. of patients who died 168 (41.8%) 221 (54.4%) 0.68

Median months 56.5 40.8 (0.56, 0.84) 0.0002
Objective Response Rate
(ORR, independent review)
No. of patients analyzed 343 336
Objective response (CR + PR) 275 (80.2%) 233 (69.3%)
Complete response (CR) 19 (5.5%) 14 (4.2%)
Partial Response (PR) 256 (74.6%) 219 (65.2%)
Median Duration of Response 20.2 12.5
(months)
Difference in ORR 10.8%
95% CI (4.2%, 17.5%) 0.0011
* Final analysis of overall survival, cutoff date Feb 2014
CI=Confidence Interval

Page 28 of 36
Figure 1 Kaplan-Meier Curve of IRF-Assessed Progression-Free Survival for
CLEOPATRA

Figure 2 Kaplan-Meier Curve of Overall Survival for CLEOPATRA (Final Analysis)

Page 29 of 36
14.2 Neoadjuvant Treatment of Breast Cancer
NeoSphere
NeoSphere (NCT00545688) was a multicenter, randomized trial conducted in 417 patients with
operable, locally advanced, or inflammatory HER2-positive breast cancer (T2-4d) who were
scheduled for neoadjuvant therapy. HER2 overexpression was defined as a score of 3+ IHC or
FISH amplification ratio of 2.0 or greater as determined by a central laboratory. Patients were
randomly allocated to receive 1 of 4 neoadjuvant regimens prior to surgery as follows:
trastuzumab plus docetaxel, PERJETA plus trastuzumab and docetaxel, PERJETA plus
trastuzumab, or PERJETA plus docetaxel. Randomization was stratified by breast cancer type
(operable, locally advanced, or inflammatory) and estrogen receptor (ER) or progesterone
receptor (PgR) positivity.
PERJETA was given intravenously at an initial dose of 840 mg, followed by 420 mg every
3 weeks for 4 cycles. Trastuzumab was given intravenously at an initial dose of 8 mg/kg,
followed by 6 mg/kg every 3 weeks for 4 cycles. Docetaxel was given as an initial dose of
75 mg/m2 by intravenous infusion every 3 weeks for 4 cycles. The docetaxel dose could be
escalated to 100 mg/m2 at the investigator’s discretion if the initial dose was well tolerated.
Following surgery all patients received 3 cycles of 5-fluorouracil (600 mg/m 2), epirubicin
(90 mg/m2), and cyclophosphamide (600 mg/m2) (FEC) given intravenously every 3 weeks and
trastuzumab administered intravenously every 3 weeks to complete 1 year of therapy. After
surgery, patients in the PERJETA plus trastuzumab arm received docetaxel every 3 weeks for
4 cycles prior to FEC.
The primary endpoint of the study was pathological complete response (pCR) rate in the breast
(ypT0/is). The FDA-preferred definition of pCR is the absence of invasive cancer in the breast
and lymph nodes (ypT0/is ypN0).
Demographics were well balanced (median age was 49 – 50 years old, the majority were
Caucasian (71%) and all were female. Overall, 7% of patients had inflammatory cancer, 32%
had locally advanced cancer, and 61% had operable cancer. Approximately half the patients in
each treatment group had hormone receptor-positive disease (defined as ER-positive and/or PgR-
positive).
The efficacy results are summarized in Table 9. Statistically significant improvements in pCR
rates by both the study and FDA-preferred definitions were observed in patients receiving
PERJETA plus trastuzumab and docetaxel compared to patients receiving trastuzumab plus
docetaxel. The pCR rates and magnitude of improvement with PERJETA were lower in the
subgroup of patients with hormone receptor-positive tumors compared to patients with hormone
receptor-negative tumors.
Table 9 Summary of Efficacy from NeoSphere
Endpoint/Study Population H+T Ptz+H+T Ptz+H Ptz+T
Overall ITT N=107 N=107 N=107 N=96
pCR1, n 23 42 12 17
(%) (21.5%) (39.3%) (11.2%) (17.7%)
[95% CI]2 [14.1, 30.5] [30.0, 49.2] [5.9, 18.8] [10.7, 26.8]
0.0018
p-value (with Simes 0.0063 0.0223
(vs.
correction for CMH test)3 (vs. H+T) (vs. H+T)
Ptz+H+T)
Page 30 of 36
Hormone receptor-positive
N=50 N=50 N=514 N=46
subgroup
pCR1, n 6 11 1 4
(%) (12.0%) (22.0%) (2.0%) (8.7%)
[95% CI]2 [4.5, 24.3] [11.5, 36.0] [0.1, 10.5] [2.4, 20.8]
Hormone receptor-negative
N=57 N=57 N=554 N=50
subgroup
pCR1, n 17 31 11 13
(%) (29.8%) (54.4%) (20.0%) (26.0%)
[95% CI] 2 [18.4, 43.4] [40.7, 67.6] [10.4, 33.0] [14.6, 40.3]
T=docetaxel, Ptz=PERJETA, H=trastuzumab
CI=Confidence Interval
1
ypT0/is ypN0 (absence of invasive cancer in the breast and lymph nodes)
2
95% CI for one sample binomial using Pearson-Clopper method.
3
p-value from Cochran-Mantel-Haenszel (CMH) test, with Simes multiplicity adjustment
4 One patient had unknown hormone receptor status. The patient did not achieve a pCR.

TRYPHAENA
An additional neoadjuvant study (TRYPHAENA, NCT00976989) was conducted in 225 patients
with HER2-positive locally advanced, operable, or inflammatory (T2-4d) breast cancer designed
primarily to assess cardiac safety in which all arms included PERJETA. HER2 overexpression
was defined as a score of 3+ IHC or FISH amplification ratio of 2.0 or greater as determined by a
central laboratory.
Patients were randomly allocated to receive 1 of 3 neoadjuvant regimens prior to surgery as
follows: 3 cycles of FEC followed by 3 cycles of docetaxel all in combination with PERJETA
and trastuzumab, 3 cycles of FEC alone followed by 3 cycles of docetaxel and trastuzumab in
combination with PERJETA, or 6 cycles of docetaxel, carboplatin, and trastuzumab (TCH) in
combination with PERJETA. Randomization was stratified by breast cancer type (operable,
locally advanced, or inflammatory) and ER and/or PgR positivity.
PERJETA was given by intravenous infusion at an initial dose of 840 mg, followed by 420 mg
every 3 weeks. Trastuzumab was given by intravenous infusion at an initial dose of 8 mg/kg,
followed by 6 mg/kg every 3 weeks. 5-Fluorouracil (500 mg/m 2), epirubicin (100 mg/m2), and
cyclophosphamide (600 mg/m2) were given intravenously every 3 weeks for 3 cycles. In the
PERJETA plus trastuzumab, docetaxel, and FEC arms, docetaxel was given as an initial dose of
75 mg/m2 by intravenous infusion every 3 weeks for 3 cycles with the option to escalate to 100
mg/m2 at the investigator’s discretion if the initial dose was well tolerated. However, in the
PERJETA plus TCH arm, docetaxel was given intravenously at 75 mg/m 2 (no escalation was
permitted) and carboplatin (AUC 6) was given intravenously every 3 weeks for 6 cycles.
Following surgery all patients received trastuzumab to complete 1 year of therapy, which was
administered intravenously every 3 weeks.
Demographics were well balanced (median age was 49-50 years old, the majority were
Caucasian [76%]) and all were female. Overall 6% of patients had inflammatory cancer, 25%
had locally advanced cancer and 69% had operable cancer, with approximately half the patients
in each treatment group having ER-positive and/or PgR-positive disease.

Page 31 of 36
The pCR (ypT0/is ypN0) rates were 56.2% (95% CI: 44.1%, 67.8%), 54.7% (95% CI: 42.7%,
66.2%), and 63.6% (95% CI: 51.9%, 74.3%) for patients treated with PERJETA plus
trastuzumab and FEC followed by PERJETA plus trastuzumab and docetaxel, PERJETA plus
trastuzumab and docetaxel following FEC, or PERJETA plus TCH, respectively. The pCR rates
were lower in the subgroups of patients with hormone receptor-positive tumors: 41.0% (95% CI:
25.6%, 57.9%), 45.7% (95% CI: 28.8%, 63.4%), and 47.5% (95% CI: 31.5%, 63.9%) than with
hormone receptor-negative tumors: 73.5% (95% CI: 55.6%, 87.1%), 62.5% (95% CI: 45.8%,
77.3%), and 81.1% (95% CI: 64.8%, 92.0%), respectively.
BERENICE
A two-arm non-randomized study (BERENICE, NCT02132949) was conducted in 401 patients
with HER2-positive locally advanced, inflammatory, or early-stage HER2-positive breast cancer.
HER2 overexpression was defined as a score of 3+ IHC or ISH amplification ratio of 2.0 or
greater as determined by a central laboratory.
Patients received 1 of 2 neoadjuvant regimens prior to surgery as follows: 4 cycles of dose dense
doxorubicin and cyclophosphamide (ddAC) followed by 4 cycles of PERJETA in combination
with trastuzumab and weekly paclitaxel for 12 weeks or 4 cycles of 5-fluorouracil, epirubicin
and cyclophosphamide (FEC) followed by 4 cycles of PERJETA in combination with
trastuzumab and docetaxel. The choice of neoadjuvant treatment regimen was made by the
Investigator on a site-specific basis. Dosing for the regimens was as follows:
 PERJETA was given by intravenous infusion at an initial dose of 840 mg, followed by
420 mg every 3 weeks. Trastuzumab was given by intravenous infusion at an initial dose
of 8 mg/kg, followed by 6 mg/kg every 3 weeks.
 In the ddAC cohort, (doxorubicin 60 mg/m 2 and cyclophosphamide 600 mg/m2) were
given intravenously every 2 weeks (ddAC) for 4 cycles with G-CSF (granulocyte colony
stimulating factor) support at investigator discretion, followed by paclitaxel 80 mg/m 2
given intravenously weekly for 12 weeks, with PERJETA and trastuzumab every 3 weeks
from the start of paclitaxel for 4 cycles.
 In the FEC cohort, 5-Fluorouracil (5-FU) (500 mg/m2), epirubicin (100 mg/m2), and
cyclophosphamide (600 mg/m2) were given intravenously every 3 weeks for 4 cycles,
followed by docetaxel given as an initial dose of 75 mg/m 2 by intravenous infusion every
3 weeks for 4 cycles with PERJETA and trastuzumab, and with the option to escalate to
100 mg/m2 at the investigator’s discretion if the initial dose was well tolerated.
Following surgery, all patients received PERJETA and trastuzumab administered intravenously
every 3 weeks to complete 1 year of therapy.
The median age of the overall study population was 49 years old (range 21-78), 12% of patients
were 65 or older, 83% were Caucasian, and all but one patient was female. Overall 3% of
patients had inflammatory cancer, 23% had locally advanced cancer (Stage 3A or greater), 5%
were not classified per TNM staging, with approximately two thirds of the patients in each
treatment group having ER-positive and/or PgR-positive disease. All patients had an ECOG
performance status of 0 or 1.
The pCR (ypT0/is ypN0) rates were 61.8% (95% CI: 54.7, 68.6) and 60.7% (95% CI: 53.6, 67.5)
for patients treated with ddAC followed by PERJETA plus trastuzumab and paclitaxel, or FEC
followed by PERJETA plus trastuzumab and docetaxel, respectively. The pCR rates were lower
in the subgroups of patients with hormone receptor-positive tumors: 51.6% (95% CI: 42.6,

Page 32 of 36
60.5%) and 57.3% (95% CI: 48.1, 66.1%) than with hormone receptor-negative tumors: 81.5%
(95% CI: 70.0, 90.1%) and 68.0% (95% CI: 56.2, 78.3%), respectively.

14.3 Adjuvant Treatment of Breast Cancer

APHINITY (NCT01358877) was a multicenter, randomized, double-blind, placebo-controlled
study conducted in 4804 patients with HER2-positive early breast cancer who had their primary
tumor excised prior to randomization. Patients were then randomized to receive PERJETA or
placebo, in combination with adjuvant trastuzumab and chemotherapy. Randomization was
stratified by the following factors: region, nodal status, protocol version, central hormone
receptor status, and adjuvant chemotherapy regimen.
Investigators selected one of the following anthracycline-based or non-anthracycline-based
chemotherapy regimens for individual patients:
 3 or 4 cycles of FEC (5-FU 500-600 mg/m2, epirubicin 90-120 mg/m2, cyclophosphamide
500-600 mg/m2) or FAC (5-FU 500-600 mg/m2, doxorubicin 50 mg/m2,
cyclophosphamide 500-600 mg/m2), followed by 3 or 4 cycles of docetaxel (75 mg/m 2
which could be escalated to 100 mg/m 2 every 3 weeks) or 12 cycles of weekly paclitaxel
(80 mg/m2).
 4 cycles of AC (doxorubicin 60 mg/m2 and cyclophosphamide 500-600 mg/m2) or EC
(epirubicin 90-120 mg/m2 and cyclophosphamide 500-600 mg/m2) either every 3 weeks
or every 2 weeks with GCSF support, followed by docetaxel (100 mg/m 2 for 3 cycles or
75 mg/m2 for first cycle and 100 mg/m2 for subsequent three cycles, or 75 mg/m2 for four
cycles) or 12 cycles of weekly paclitaxel (80 mg/m2).
 6 cycles of docetaxel (75 mg/m2) in combination with carboplatin (AUC 6)
PERJETA and trastuzumab were administered intravenously every 3 weeks starting on Day 1 of
the first taxane-containing cycle, for a total of 52 weeks (up to 18 cycles) or until recurrence,
withdrawal of consent, or unmanageable toxicity.
After completion of chemotherapy, patients received radiotherapy and/or hormone therapy as per
investigator’s discretion.
The major efficacy outcome of the study was invasive disease-free survival (IDFS), defined as
the time from randomization to first occurrence of ipsilateral local or regional invasive breast
cancer recurrence, distant recurrence, contralateral invasive breast cancer, or death from any
cause. Additional efficacy endpoints were IDFS including second primary non-breast cancer,
disease-free survival (DFS), and overall survival (OS).
Demographics were generally balanced between the two treatment arms. The median age was 51
years (range 18-86), 13% of patients were 65 or older, and over 99% of patients were female.
Sixty-three percent of patients had node-positive disease, 64% had hormone receptor-positive
disease, and 71% were Caucasian. All patients had an ECOG performance status of 0 or 1.
Seventy-eight percent received an anthracycline containing regimen.
PERJETA-treated patients and placebo-treated patients both received a median number of 18
cycles of anti-HER2 therapy. After a median follow-up of 45.4 months, a statistically significant
improvement in IDFS was demonstrated in patients randomized to receive PERJETA compared
with patients randomized to receive placebo. The efficacy results from APHINITY are
summarized in Tables 10 and 11 and in Figure 3.

Page 33 of 36
 Table 10 Efficacy Results from APHINITY
PERJETA + Placebo +
trastuzumab + trastuzumab +
chemotherapy chemotherapy
N=2400 N=2404
Invasive Disease Free Survival (IDFS)
Number (%) of patients with event 171 (7.1%) 210 (8.7%)
1
HR [95% CI] 0.82 [0.67, 1.00]
p-value (Log-Rank test, stratified1) 0.047
3 year event-free rate2, % [95% CI] 94.1 [93.1, 95.0] 93.2 [92.2, 94.3]
IDFS including second primary non-breast cancer
Number (%) of patients with event 189 (7.9%) 230 (9.6%)
HR [95% CI] 1 0.83 [0.68, 1.00]
2
3 year event-free rate , % [95% CI] 93.5 [92.5, 94.5] 92.5 [91.4, 93.6]
Disease Free Survival (DFS)
Number (%) of patients with event 192 (8.0%) 236 (9.8%)
HR [95% CI] 1 0.82 [0.68, 0.99]
2
3 year event-free rate , % [95% CI] 93.4 [92.4, 94.4] 92.3 [91.2, 93.4]
3
Overall Survival (OS)
Number (%) of patients with event 80 (3.3%) 89 (3.7%)
1
HR [95% CI] 0.89 [0.66, 1.21]
2
3 year event-free rate , % [95% CI] 97.7 [97.0, 98.3] 97.7 [97.1, 98.3]
HR=Hazard Ratio, CI=Confidence Interval
1
All analyses stratified by nodal status, protocol version, central hormone receptor status, and adjuvant chemotherapy regimen.
Stratification factors are defined according to the randomization data for IDFS.
2
3-year event-free rate derived from Kaplan-Meier estimates
3
Data from first interim analysis

Page 34 of 36
Figure 3 Kaplan-Meier Curve of Invasive Disease Free Survival from APHINITY (ITT
Population)

Table 11 Efficacy Results by Baseline Disease Characteristics and Adjuvant Chemotherapy

from APHINITY1
Population Number of events/Total N (%) IDFS at 3 year Unstratified
(%, 95% CI) HR (95% CI)
PERJETA + Placebo + PERJETA + Placebo +
trastuzumab + trastuzumab + trastuzumab + trastuzumab +
chemotherapy chemotherapy chemotherapy chemotherapy

Hormone Receptor Status

Negative 71/864 91/858 92.8 91.2 0.76 (0.56, 1.04)
(8.2%) (10.6%) (90.8, 94.3) (89.0, 92.9)
Positive 100/1536 119/1546 94.8 94.4 0.86 (0.66, 1.13)
(6.5%) (7.7%) (93.5, 95.8) (93.1, 95.4)
Nodal Status
Negative 32/897 29/902 97.5 98.4 1.13 (0.68, 1.86)
(3.6%) (3.2%) (96.3, 98.4) (97.3, 99.0)
Positive 139/1503 181/1502 92.0 90.2 0.77 (0.62, 0.96)
(9.2%) (12.1%) (90.5, 93.3) (88.5, 91.6)
Adjuvant Chemotherapy Regimen
Anthracycline 139/1865 171/1877 93.8 93.0 0.82 (0.66, 1.03)
(7.4%) (9.1%) (92.6, 94.8) (91.8, 94.1)
Non-Anthracycline 32/535 39/527 94.9 94.0 0.82 (0.51, 1.31)
(6.0%) (7.4%) (92.6, 96.6) (91.5, 95.8)
1
Exploratory analyses without adjusting multiple comparisons, therefore, results are considered descriptive.

Page 35 of 36
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1 How Supplied
PERJETA injection is supplied as a 420 mg/14 mL (30 mg/mL) single-dose vial containing
preservative-free solution. NDC 50242-145-01.
Store vials in a refrigerator at 2°C to 8°C (36°F to 46°F) until time of use.
Keep vial in the outer carton in order to protect from light.
DO NOT FREEZE. DO NOT SHAKE.
17 PATIENT COUNSELING INFORMATION
Left Ventricular Dysfunction
• Advise patients to contact a health care professional immediately for any of the following:
new onset or worsening shortness of breath, cough, swelling of the ankles/legs, swelling of
the face, palpitations, weight gain of more than 5 pounds in 24 hours, dizziness or loss of
consciousness [see Warnings and Precautions (5.1)].
Embryo-Fetal Toxicity
• Advise pregnant women and females of reproductive potential that exposure to PERJETA in
combination with trastuzumab during pregnancy or within 7 months prior to conception can
result in fetal harm. Advise female patients to contact their healthcare provider with a known
or suspected pregnancy [see Use in Specific Populations (8.1)].
• Advise women who are exposed to PERJETA in combination with trastuzumab during
pregnancy or within 7 months prior to conception that there is a pregnancy
pharmacovigilance program that monitors pregnancy outcomes. Encourage these patients to
report their pregnancy to Genentech [see Use in Specific Populations (8.1)].
• Advise females of reproductive potential to use effective contraception during treatment and
for 7 months following the last dose of PERJETA in combination with trastuzumab [see Use
in Specific Populations (8.3)].

PERJETA® (pertuzumab)

Manufactured by: PERJETA is a registered trademark of Genentech, Inc.

©
Genentech, Inc. 2021 Genentech, Inc.
A Member of the Roche Group
1 DNA Way
South San Francisco, CA 94080-4990
U.S. License No. 1048

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