Pertuzumab

>10%

Diarrhea (66.8%)

Alopecia (60.9%)

Neutropenia (52.8%)

Nausea (42.3%)

Fatigue (37.6%)

Rash (33.7%)

Peripheral neuropathy (32.4%)

Decreased appetite (29.2%)

Mucosal inflammation (27.8%)

Asthenia (26%)

Vomiting (24.1%)

Anemia (23.1%)

Peripheral edema (23.1%)

Nail disorder (22.9%)

Myalgia (22.9%)

Headache (20.9%)

Stomatitis (18.9%)

Pyrexia (18.7%)

Dysgeusia (18.4%)

Leukopenia (18.2%)

Upper respiratory tract infection (16.7%)

Arthralgia (15.5%)

Constipation (15%)

Pruritus (14%)

Dyspnea (14%)

Increased lacrimation (14%)

Febrile neutropenia (13.8%)

Insomnia (13.3%)

Dizziness (12.5%)

Nasopharyngitis (11.8%)

Dry skin (10.6%)

1-10%

Hypersensitivity (10%)

Paronychia (7.1%)

Pleural effusion (5.2%)

Left ventricular dysfunction (4.4%)

Congestive heart failure (1%)

Postmarketing Reports

Thrombocytopenia

Infusion reactions

Note: Adverse reaction were reported less frequently after discontinuing docetaxel; all adverse reactions in the pertuzumab/trastuzumab treatment group occurred in <10% of patients with the exception of diarrhea (19.1%), UTI (12.8%), rash (11.75%), headache (11.4%), and fatigue (11.1%)

Solution for intravenous infusion: 420 mg/14 mL (30 mg/mL) single-use vial

Pertuzumab vials should be refrigerated at 2 C to 8 C (36 F to 46 F) until it is used.

The following adverse reactions are discussed in greater detail in other sections of the label:

• Left Ventricular Dysfunction [see WARNINGS AND PRECAUTIONS]
• Embryo-Fetal Toxicity [see WARNINGS AND PRECAUTIONS]
• Infusion-Related Reactions [see WARNINGS AND PRECAUTIONS]
• Hypersensitivity Reactions/Anaphylaxis [see WARNINGS AND PRECAUTIONS]

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.

The adverse reactions described in Table 1 were identified in 804 patients with HER2-positive metastatic breast cancer treated in Study 1. 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. The rates of adverse events resulting in permanent discontinuation of all study therapy were 6.1% for patients in the PERJETA-treated group and 5.3% for patients in the placebo-treated group. Adverse events led to discontinuation of docetaxel alone in 23.6% of patients in the PERJETA-treated group and 23.2% of patients in the placebo-treated group. Table 1 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 followup of 50 months) in Study 1.

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%).

Table 1 : Summary of Adverse Reactions Occurring in ≥ 10% of Patients on the PERJETA Treatment Arm in Study 1

The following clinically relevant adverse reactions were reported in < 10% of patients in the PERJETA-treated group in Study 1:

Skin and subcutaneous tissue disorders: Paronychia (7.1% in the PERJETA-treated group vs. 3.5% in the placebo-treated group)

Respiratory, thoracic and mediastinal disorders: Pleural effusion (5.2% in the PERJETAtreated group vs. 5.8% in the placebo-treated group)

Cardiac disorders: Left ventricular dysfunction (4.4% in the PERJETA-treated group vs. 8.3% in the placebo-treated group) including symptomatic left ventricular systolic dysfunction (CHF) (1.0% in the PERJETA-treated group vs. 1.8% in the placebo-treated group)

Immune system disorders: Hypersensitivity (10.1% in the PERJETA-treated group vs. 8.6% in placebo-treated group)

In Study 1, 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 (19.1%), upper respiratory tract infection (12.8%), rash (11.7%), headache (11.4%), and fatigue (11.1%).

In Study 2, 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 PERJETAtreated group in Study 1. 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 2 reports the adverse reactions that occurred in patients who received neoadjuvant treatment with PERJETA for breast cancer in Study 2.

Table 2 : Summary of Adverse Reactions Occurring in ≥ 10% in the Neoadjuvant Setting for Patients Receiving PERJETA in Study 2

The following adverse reactions were reported in < 10% of patients receiving neoadjuvant treatment and occurred more frequently in PERJETA-treated groups in Study 2: (Ptz=pertuzumab; T=trastuzumab; D=docetaxel)

Blood and lymphatic system disorders: Anemia (6.5% in the T+D arm, 2.8% in the Ptz+T+D arm, 4.6% in the Ptz+T arm and 8.5% in the Ptz+D arm), Febrile neutropenia (6.5% in the T+D arm, 8.4% in the Ptz+T+D arm, 0.0% in the Ptz+T arm and 7.4% in the Ptz+D arm)

Immune system disorders: Hypersensitivity (1.9% in the T+D arm, 5.6% in the Ptz+T+D arm, 5.6% in the Ptz+T arm and 5.3% in the Ptz+D arm)

Nervous system disorders: Dizziness (3.7% in the T+D arm, 2.8% in the Ptz+T+D arm, 5.6% in the Ptz+T arm and 3.2% in the Ptz+D arm)

Infections and infestations: Upper respiratory tract infection (2.8% in the T+D arm, 4.7% in the Ptz+T+D arm, 1.9% in the Ptz+T arm and 7.4% in the Ptz+D arm)

Respiratory, thoracic and mediastinal disorders: Dyspnea (3.7% in the T+D arm, 4.7% in the Ptz+T+D arm, 2.8% in the Ptz+T arm and 2.1% in the Ptz+D arm)

Cardiac disorders: Left ventricular dysfunction (0.9% in the T+D arm, 2.8% in the Ptz+T+D arm, 0.0% in the Ptz+T arm, and 1.1% in the Ptz+D arm) including symptomatic left ventricular dysfunction (CHF) (0.9% in the Ptz+T arm and 0.0% in the T+D arm, Ptz+T+D arm, and Ptz+D arm)

Eye disorders: Lacrimation increased (1.9% in the T+D arm, 3.7% in the Ptz+T+D arm, 0.9% in the Ptz+T arm, and 4.3% in the Ptz+D arm)

In Study 3, 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.

The rates of adverse events resulting in permanent discontinuation of any component of neoadjuvant treatment were 6.7% for patients receiving PERJETA in combination with trastuzumab and docetaxel following FEC and 7.9% for patients receiving PERJETA in combination with TCH. Table 3 reports the adverse reactions that occurred in patients who received neoadjuvant treatment with PERJETA for breast cancer in Study 3.

Table 3 : Summary of Adverse Reactions Occurring in ≥ 10% of Patients Receiving Neoadjuvant Treatment with PERJETA in Study 3

The following selected adverse reactions were reported in < 10% of patients receiving neoadjuvant treatment in Study 3: (Ptz=pertuzumab; T=trastuzumab; D=docetaxel; FEC= fluorouracil, epirubicin, and cyclophosphamide; TCH=docetaxel, carboplatin, and trastuzumab)

Skin and subcutaneous tissue disorders: Nail disorder (9.7% in the Ptz+T+FEC/Ptz+T+D arm, 6.7% in the FEC/Ptz+T+D arm, and 9.2% in the Ptz+TCH arm), Paronychia (0% in the Ptz+T+FEC/Ptz+T+D and 1.3% in both the FEC/Ptz+T+D and Ptz+TCH arms), Pruritis (2.8% in the Ptz+T+FEC/Ptz+T+D arm, 4.0% in the FEC/Ptz+T+D arm, and 3.9% in the Ptz+TCH arm)

Infections and infestations: Upper respiratory tract infection (8.3% in the Ptz+T+FEC/Ptz+T+D arm, 4.0% in the FEC/Ptz+T+D arm, and 2.6% in the Ptz+TCH arm), Nasopharyngitis (6.9% in the Ptz+T+FEC/Ptz+T+D arm, 6.7% in the FEC/Ptz+T+D arm, and 7.9% in the Ptz+TCH arm)

Respiratory, thoracic, and mediastinal disorders: Pleural effusion (1.4% in the Ptz+T+FEC/Ptz+T+D arm and 0% in the FEC/Ptz+T+D and Ptz+TCH arm)

Cardiac disorders: Left ventricular dysfunction (5.6% in the Ptz+T+FEC/PTZ+T+D arm, 4.0% in the FEC/Ptz+T+D arm, and 2.6% in the Ptz+TCH arm) including symptomatic left ventricular systolic dysfunction (CHF) (2.7% in the FEC/Ptz+T+D arm and 0% in the Ptz+T+FEC/Ptz+T+D and Ptz+TCH arms)

Immunogenicity

As with all therapeutic proteins, there is the potential for an immune response to PERJETA.

Patients in Study 1 were tested at multiple time-points for antibodies to PERJETA. Approximately 2.8% (11/386) of patients in the PERJETA-treated group and 6.2% (23/372) of patients in the placebo-treated group tested positive for anti-PERJETA antibodies. Of these 34 patients, none experienced anaphylactic/hypersensitivity reactions that were clearly related to the anti-therapeutic antibodies (ATA). The presence of pertuzumab in patient serum at the levels expected at the time of ATA sampling can interfere with the ability of this assay to detect antipertuzumab 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.

Immunogenicity data are highly dependent on the sensitivity and specificity of the test methods used. Additionally, the observed incidence of a positive result in a test method may be influenced by several factors, including sample handling, timing of sample collection, drug interference, concomitant medication, and the underlying disease. For these reasons, comparison of the incidence of antibodies to PERJETA with the incidence of antibodies to other products may be misleading.

Follow your doctor's instructions about any restrictions on food, beverages, or activity.

Serious side effects have been reported with pertuzumab including the following:

• Most Serious Side Effect: Receiving pertuzumab during pregnancy can result in the death of an unborn baby and birth defects.
  • If you are exposed to pertuzumab during pregnancy, you are encouraged to enroll in the MotHER Pregnancy Registry by contacting 1 (800) 690-6720.
• Other possible side effects of pertuzumab therapy include:
  • Heart problems: Pertuzumab can result in 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 pertuzumab.
  • Infusion-related reactions: Pertuzumab is a medicine that is delivered into a vein through a needle. This process can cause reactions known as infusion-related reactions. The most common infusion-related reactions when receiving pertuzumab, trastuzumab, and docetaxel (chemotherapy) were fatigue, loss of taste, allergic reactions, muscle pain, and vomiting.
  • Severe allergic reactions: Some people receiving pertuzumab may have severe allergic reactions, called hypersensitivity reactions or anaphylaxis. This reaction may be severe, may happen quickly, and may affect many areas of the body.

Contraindications

• Manufacturer states none known.1

Warnings/Precautions

Warnings

May cause fetal harm.1 Embryotoxicity and fetotoxicity demonstrated in animals.1 Oligohydramnios, delayed fetal kidney development, and embryo-fetal death observed following administration of pertuzumab to pregnant cynomolgus monkeys at dosages producing concentrations 2.5–20 times that of human clinical exposure (based on peak plasma concentrations).1

Embryotoxic and fetotoxic effects likely to be present during all trimesters of pregnancy.1

Verify pregnancy status prior to initiation of pertuzumab.1 Advise women of childbearing potential to use effective contraceptive methods during and for 6 months after discontinuance of drug.1

If used during pregnancy or if patient becomes pregnant during therapy, apprise of potential fetal hazard.1 (See Pregnancy under Cautions.) Monitor for development of oligohydramnios in patients who become pregnant during therapy; perform appropriate fetal testing if oligohydramnios occurs.1 Efficacy of IV hydration in the management of oligohydramnios secondary to pertuzumab exposure unknown.1

Sensitivity Reactions

Infusion reactions, including hypersensitivity and anaphylaxis, reported.1 Most common infusion reactions reported were pyrexia, chills, fatigue, headache, asthenia, hypersensitivity, vomiting, dysgeusia, and myalgia.1

Closely observe patients for 60 minutes after first infusion and for 30 minutes after subsequent infusions.1 If infusion or hypersensitivity reactions occur, may need to reduce infusion rate or temporarily or permanently discontinue therapy.1 (See Infusion or Hypersensitivity Reactions under Dosage and Administration.)

Other Warnings and Precautions

Decreases in LVEF reported with inhibitors of HER2, including pertuzumab.1 6 9 In principal efficacy study, pertuzumab not associated with increased incidence of symptomatic left ventricular systolic dysfunction (LVSD, congestive heart failure [CHF]) or decrease in LVEF compared with placebo.1 2 Median time to development of LVSD appears to be around cycle 4.6

Safety not established in patients with baseline LVEF ≤50%, prior history of CHF, decreases in LVEF to <50% during prior trastuzumab therapy, or conditions that could impair left ventricular function (e.g., uncontrolled hypertension, recent MI, serious cardiac arrhythmia requiring treatment, cumulative prior anthracycline exposure >360 mg/m2 of doxorubicin or its equivalent).1

Risk of LVSD possibly increased in patients who received prior anthracycline therapy or had prior radiation therapy to the chest area.1

Assess LVEF prior to initiation of therapy and at regular intervals (e.g., every 3 months) during treatment.1

If substantial decreases in LVEF occur, may need to temporarily or permanently discontinue therapy.1 (See Left Ventricular Dysfunction under Dosage and Administration.)

Assess breast tumors for HER2 overexpression prior to initiation of therapy because safety and efficacy of pertuzumab established only in patients with HER2-overexpressing tumors.1

Immunohistochemistry (IHC) assays (e.g., Dako Herceptest), which measure overexpression of the HER2 protein, and fluorescent in situ hybridization (FISH) (e.g., Dako HER2 FISH PharmDx), which measures amplification of the HER2 oncogene, are tests most commonly used.1 3 5

In principal efficacy study, patients were required to have disease demonstrating an IHC score of 3+ or a FISH amplification ratio of ≥2.1 2 Limited data for patients with FISH-positive tumors that lack HER2 overexpression.1

Select laboratories with demonstrated proficiency in the specific technology being used; improper assay performance can lead to unreliable results.1

Specific Populations

Category D.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

If used during pregnancy or if patient becomes pregnant while receiving therapy, apprise of potential fetal hazard.1 Encourage patient to enroll in the MotHER Pregnancy Registry (800-690-6720), and immediately notify Genentech Adverse Event Line (888-835-2555).1

Not known whether pertuzumab is distributed into milk.1 Discontinue nursing or the drug.1

Safety and efficacy not established.1

No overall differences in safety, efficacy, and pharmacokinetics relative to younger adults.1

Pharmacokinetics not studied in patients with hepatic impairment.1

Systemic exposure not altered by mild or moderate renal impairment; no dosage adjustment required.1 (See Renal Impairment under Dosage and Administration and also see Special Populations under Pharmacokinetics.)

Limited data in patients with severe renal impairment.1

Common Adverse Effects

Diarrhea,1 2 alopecia,1 2 neutropenia,1 2 nausea,1 2 fatigue,1 2 rash,1 2 peripheral neuropathy.1

Absorption

Bioavailability

Steady-state concentrations achieved after first maintenance dose.1

Special Populations

Age, gender, or ethnicity (Japanese versus non-Japanese): No effects on pertuzumab pharmacokinetics.1 12

Baseline serum albumin concentration or lean body weight: Minor influence on pertuzumab pharmacokinetics.1 (See Special Populations under Dosage and Administration.)

Mild (Clcr of 60–90 mL/minute) or moderate (Clcr of 30–60 mL/minute) renal impairment: Systemic exposure is similar to that in patients with normal renal function.1 (See Renal Impairment under Dosage and Administration.)

Severe renal impairment (Clcr <30 mL/minute): Limited data.1

No relationship between Clcr and pertuzumab exposure observed over Clcr range of 27–244 mL/minute.1

Elimination

Half-life

Median half-life: 18 days.1

• Tell all of your health care providers that you take this medicine. This includes your doctors, nurses, pharmacists, and dentists.
• You may have more chance of getting an infection. Wash hands often. Stay away from people with infections, colds, or flu.
• If you have upset stomach, throwing up, loose stools (diarrhea), or are not hungry, talk with your doctor. There may be ways to lower these side effects.
• Some patients have very bad side effects during the infusion. Tell your doctor if you have any bad effects during the infusion.
• This medicine may raise the chance of a very bad and sometimes deadly heart problem (myocarditis). The chance may be higher if you are getting certain other chemo drugs. Talk with your doctor.
• If you are able to get pregnant, a pregnancy test will be done to show that you are NOT pregnant before starting pertuzumab. Talk with your doctor.

Use this medicine as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• It is given as an infusion into a vein over a period of time.

What do I do if I miss a dose?

• Call your doctor to find out what to do.

Known hypersensitivity to pertuzumab or any component of the formulation

Note: For pertuzumab, trastuzumab, and docetaxel combination regimens, pertuzumab and trastuzumab may be administered in any order; however, docetaxel should be given after pertuzumab and trastuzumab. Observe patients for 30 to 60 minutes after each pertuzumab infusion and before subsequent infusions of trastuzumab or docetaxel.

Breast cancer, metastatic HER2+: IV: 840 mg over 60 minutes followed by a maintenance dose of 420 mg over 30 to 60 minutes every 3 weeks until disease progression or unacceptable toxicity (in combination with trastuzumab and docetaxel) (Baselga, 2012; Swain, 2015).

Breast cancer, neoadjuvant treatment HER2+: Adults: IV: 840 mg over 60 minutes followed by a maintenance dose of 420 mg over 30 to 60 minutes every 3 weeks for 3 to 6 cycles; may be administered as one of the regimens below. Postoperatively, continue trastuzumab to complete 1 year of treatment.

Four preoperative cycles of pertuzumab, trastuzumab, and docetaxel, followed by 3 postoperative cycles of fluorouracil, epirubicin, and cyclophosphamide (FEC) (Gianni, 2012) or

Three preoperative cycles of FEC (alone) followed by 3 preoperative cycles of pertuzumab, trastuzumab, and docetaxel (Schneeweiss, 2013) or

Six preoperative cycles of pertuzumab, trastuzumab, docetaxel, and carboplatin (Schneeweiss, 2013)

Missed doses or delays: If <6 weeks has elapsed, administer the 420 mg maintenance dose; do not wait until the next planned dose. If ≥6 weeks has elapsed, readminister the 840 mg initial dose (over 60 minutes), and then follow with a maintenance dose of 420 mg (over 30 to 60 minutes) every 3 weeks.

Dilute in 250 mL NS only (do not use dextrose 5% solutions) in PVC or non-PVC (polyolefin) bags. Gently invert to mix (avoid foaming); do not shake. Do not mix with other medications.

Commonly reported side effects of pertuzumab include: anaphylaxis, cytokine release syndrome, hypersensitivity, and infusion related reaction. See below for a comprehensive list of adverse effects.

Applies to pertuzumab: intravenous solution

Cardiovascular

Common (1% to 10%): Left ventricular dysfunction (including congestive heart failure)[Ref]

Dermatologic

Very Common (10% or more): Alopecia (up to 61%), rash (up to 34%), nail disorder (up to 23%), pruritus (up to 14%)
Common (1% to 10%): Dry skin, palmar-plantar erythrodysesthesia syndrome[Ref]

Gastrointestinal

Very common (10% or more): Diarrhea (up to 67%), nausea (up to 42%), mucositis/mucosal inflammation (up to 28%), constipation (up to 25%), vomiting (up to 24%), stomatitis (up to 19%), dyspepsia (up to 12%)[Ref]

Hematologic

Very common (10% or more): Neutropenia (up to 53%), anemia (up to 23%), leucopenia (up to 20%), febrile neutropenia (up to 13%)[Ref]

Hypersensitivity

Very common (10% or more): Hypersensitivity/anaphylactic reaction, infusion reaction/cytokine release syndrome[Ref]

Metabolic

Very common (10% or more): Decreased appetite (up to 29%)[Ref]

Musculoskeletal

Very common (10% or more): Myalgia (up to 24%), arthralgia (up to 15%), pain in extremity (up to 15%)[Ref]

Nervous system

Very common (10% or more): Peripheral neuropathy (up to 21%), headache (up to 21%), dysgeusia (up to 18%), peripheral sensory neuropathy (up to 14%), dizziness (up to 13%)[Ref]

Ocular

Very common (10% or more): Increased lacrimation (up to 14%)[Ref]

Psychiatric

Very common (10% or more): Insomnia (up to 13%)[Ref]

Respiratory

Very common (10% or more): Cough (up to 21%), upper respiratory tract infection (up to 17%), dyspnea (up to 16%), nasopharyngitis (up to 13%)
Common (1% to 10%): Paronychia, pleural effusion, epistaxis
Uncommon (0.1% to 1%): Interstitial lung disease[Ref]

Other

Very common (10% or more): Fatigue (up to 38%), peripheral edema (up to 30%), asthenia (up to 30%), pyrexia (up to 19%), pain
Common (1% to 10%): Chills[Ref]

Some side effects of pertuzumab may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.