Pertuzumab (Monograph)

Brand name: Perjeta
Drug class: Antineoplastic Agents
- HER2/neu Receptor Antagonists
- HER2 Dimerization Inhibitors
VA class: AN900
Chemical name: Immunoglobulin G1, anti-(human neu (receptor)) (human-mouse monoclonal 2C4 heavy chain), disulfide with human-mouse monoclonal 2C4 κ-chain, dimer
CAS number: 380610-27-5

Medically reviewed by Drugs.com on Sep 3, 2024. Written by ASHP.

Warning

Risk of subclinical and clinical cardiac failure manifesting as decreased LVEF and CHF. (See Left Ventricular Dysfunction under Cautions.)
Evaluate cardiac function before and during treatment.
Discontinue pertuzumab in patients with a confirmed clinically significant decrease in LVEF. (See Left Ventricular Dysfunction under Dosage and Administration.)

Risk of embryofetal death and birth defects.
Oligohydramnios, delayed fetal kidney development, and embryofetal death reported in animals. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)
Inform patients of risk of fetal harm. Advise females of reproductive potential to use effective contraceptive methods during therapy and for 7 months after discontinuance of drug. (See Advice to Patients.)

Introduction

Antineoplastic agent; a recombinant humanized anti-human epidermal growth factor receptor type 2 (anti-HER2/ERBB2) monoclonal antibody.

Uses for Pertuzumab

Breast Cancer

In combination with trastuzumab and docetaxel for the treatment of HER2-positive metastatic breast cancer in patients who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease.

In combination with trastuzumab and chemotherapy for the neoadjuvant treatment of HER2-positive locally advanced, inflammatory, or early-stage breast cancer.

In combination with trastuzumab and chemotherapy for the adjuvant treatment of HER2-positive early-stage breast cancer at high risk of recurrence.

Pertuzumab Dosage and Administration

General

Select patients based on HER2 protein overexpression or HER2 gene amplification in tumor specimens.
Do not substitute for or use single-entity pertuzumab and trastuzumab preparations with fixed-combination pertuzumab/trastuzumab/hyaluronidase (Phesgo).
Because of risk of infusion or hypersensitivity reactions, closely observe patients for 60 minutes after first infusion and for 30 minutes after subsequent infusions. (See Infusion-related Reactions and also see Hypersensitivity Reactions under Cautions.) Do not administer subsequent drugs until after the 30- to 60-minute observation period.
May administer pertuzumab and trastuzumab (IV or sub-Q) in any order. Administration of a taxane should occur after pertuzumab and trastuzumab (IV or sub-Q). In patients receiving an anthracycline-based regimen, administer pertuzumab and trastuzumab (IV or sub-Q) after completion of the anthracycline.
Consult specialized references for procedures for proper handling (e.g., use of gloves) and disposal of antineoplastics.

Restricted Distribution

Available only through select specialty distributors. Contact manufacturer for additional information.

Administration

IV Administration

For solution compatibility information, see Compatibility under Stability.

Administer by IV infusion only. Do not administer by rapid IV injection (e.g., IV push or bolus).

Pertuzumab injection concentrate must be diluted prior to administration. Use within 24 hours following dilution. (See Storage under Stability.)

Do not mix with any other drug.

Dilution

Use aseptic technique since drug product contains no preservative.

Dilute appropriate dose in a PVC or non-PVC polyolefin infusion bag containing 250 mL of 0.9% sodium chloride injection; do not dilute in 5% dextrose injection. Mix the diluted solution by gentle inversion; do not shake. Discard any partially used vial.

Rate of Administration

Initial dose: Administer over 60 minutes.

Subsequent doses: Administer over 30–60 minutes.

Dosage

Consult published protocols for information on the dosage, method of administration, and administration sequence of other antineoplastic agents used in combination regimens with pertuzumab.

Discontinue pertuzumab if trastuzumb is discontinued. If a dose of pertuzumab and trastuzumab is missed or delayed, and the time between 2 sequential infusions of the combination is <6 weeks, administer maintenance dose of pertuzumab and trastuzumab as soon as possible; do not wait until the next scheduled dose. If the time between 2 sequential infusions of the combination is ≥6 weeks, re-administer initial pertuzumab and trastuzumab (IV only) dose (see Table 1).

Table 1. Recommendations for Continuation of Pertuzumab and Trastuzumab Following Treatment Interruption for ≥6 Weeks1
Time Between Sequential Doses	Pertuzumab	Trastuzumab (IV)
≥6 Weeks	Administer 840 mg by IV infusion over 60 minutes, followed by 420 mg by IV infusion over 30–60 minutes every 3 weeks thereafter	Administer 8 mg/kg by IV infusion over approximately 90 minutes, followed by 6 mg/kg by IV infusion over 30 or 90 minutes every 3 weeks thereafter

Adults

Breast Cancer

Pertuzumab, Trastuzumab, and Docetaxel for HER2-positive Metastatic Breast Cancer

Initially, pertuzumab 840 mg in combination with trastuzumab (IV infusion or sub-Q injection) and docetaxel (IV infusion), followed every 3 weeks thereafter by pertuzumab 420 mg in combination with trastuzumab (IV infusion or sub-Q injection) and docetaxel (IV infusion).

Pertuzumab in Combination with Neoadjuvant Chemotherapy for HER2-positive Early-stage Breast Cancer

Initially, pertuzumab 840 mg in combination with trastuzumab (IV infusion or sub-Q injection) followed by pertuzumab 420 mg in combination with trastuzumab (IV infusion or sub-Q injection) every 3 weeks for 3–6 cycles as part of one of the following 4 treatment regimens:

Regimen: 4 preoperative cycles of pertuzumab in combination with trastuzumab (IV or sub-Q) and docetaxel, followed by 3 postoperative cycles of fluorouracil, epirubicin, and cyclophosphamide.

Regimen: 3 or 4 preoperative cycles of fluorouracil, epirubicin, and cyclophosphamide alone, followed by 3 or 4 preoperative cycles of pertuzumab in combination with docetaxel and trastuzumab (IV or sub-Q).

Regimen: 6 preoperative cycles of pertuzumab in combination with docetaxel (dose escalation above 75 mg/m² is not recommended), carboplatin, and trastuzumab (IV or sub-Q).

Regimen: 4 preoperative cycles of dose-dense doxorubicin and cyclophosphamide alone followed by 4 preoperative cycles of pertuzumab in combination with paclitaxel and trastuzumab (IV or sub-Q).

Following surgery, continue pertuzumab and trastuzumab to complete 1 year of therapy (up to 18 cycles).

Pertuzumab in Combination with Adjuvant Chemotherapy for HER2-positive Early-stage Breast Cancer

Initially, pertuzumab 840 mg in combination with trastuzumab (IV infusion or sub-Q injection) on day 1 of the first taxane-containing cycle, followed by pertuzumab 420 mg in combination with trastuzumab (IV infusion or sub-Q injection) every 3 weeks for a total of 1 year (up to 18 cycles) or until disease recurrence or intolerable toxicity occurs.

Dosage Modification for Toxicity and Contraindications to Continued Therapy

Dosage reductions not recommended. If toxicities occur, reduce infusion rate or temporarily or permanently discontinue therapy based on causality.

Discontinue pertuzumab if trastuzumab is discontinued; however, if other chemotherapy is discontinued, may continue pertuzumab and trastuzumab therapy.

Consult prescribing information for individual chemotherapy agents used in combination with pertuzumab for detailed information on dosage modifications.

Left Ventricular Dysfunction

Metastatic breast cancer: Baseline LVEF must be ≥50% prior to initiation of therapy. If LVEF decreases to <40% or to 40–45% with an absolute decrease from baseline of ≥10%, withhold pertuzumab and trastuzumab for at least 3 weeks. Reassess LVEF within approximately 3 weeks. If LVEF has recovered to >45% or to 40–45% with an absolute decrease from baseline of <10%, may resume pertuzumab and trastuzumab therapy. If LVEF has not improved or has declined further, strongly consider discontinuing pertuzumab and trastuzumab. (See Left Ventricular Dysfunction under Cautions.)

Early-stage breast cancer: Baseline LVEF should be ≥55% or, in those receiving anthracycline-based chemotherapy, ≥50%. If LVEF decreases to <50% with an absolute decrease from baseline of ≥10%, withhold pertuzumab and trastuzumab for at least 3 weeks. Reassess LVEF within approximately 3 weeks. If LVEF has recovered to >50% or to an absolute decrease from baseline of <10%, may resume pertuzumab and trastuzumab therapy. If LVEF has not improved or has declined further, strongly consider discontinuing pertuzumab and trastuzumab. (See Left Ventricular Dysfunction under Cautions.)

Infusion-related Reactions

If clinically important infusion reactions occur, reduce infusion rate or interrupt infusion and administer appropriate medical therapy.

If severe infusion or hypersensitivity reactions occur, immediately discontinue infusion and consider permanent discontinuance of therapy.

Monitor patients carefully until signs and symptoms have completely resolved.

Hypersensitivity Reactions

If serious hypersensitivity reactions occur, immediately discontinue infusion and permanently discontinue drug.

Monitor patients carefully until signs and symptoms have completely resolved.

Special Populations

Dosage adjustment not necessary based on body weight or baseline albumin concentration. (See Special Populations under Pharmacokinetics.)

Hepatic Impairment

No specific dosage recommendations at this time. (See Hepatic Impairment under Cautions.)

Renal Impairment

Mild (Cl_cr 60–90 mL/minute) or moderate (Cl_cr 30–60 mL/minute) renal impairment: No dosage adjustment required.

Severe renal impairment (Cl_cr <30 mL/minute): No specific dosage recommendations at this time due to limited data. (See Renal Impairment under Cautions.)

Geriatric Patients

No specific dosage recommendations at this time. (See Geriatric Use under Cautions.)

Cautions for Pertuzumab

Contraindications

Known hypersensitivity to the drug or any ingredients in the formulation.

Warnings/Precautions

Warnings

Left Ventricular Dysfunction

Decreases in LVEF reported with inhibitors of HER2, including pertuzumab. Median time to development of left ventricular systolic dysfunction (LVSD) with pertuzumab appears to be around cycle 4.

In principal efficacy study in patients with metastatic breast cancer, pertuzumab not associated with increased incidence of symptomatic LVSD (CHF) or decrease in LVEF compared with placebo.

In patients receiving pertuzumab in combination with trastuzumab and docetaxel in the neoadjuvant setting, the combination was associated with an increased incidence of LVSD and decreased LVEF. Incidence of asymptomatic and symptomatic LVSD and decreased LVEF varied with each pertuzumab-containing neoadjuvant regimen.

In patients receiving pertuzumab-containing adjuvant therapy for early-stage breast cancer, incidence of symptomatic heart failure (NYHA class III/IV) with LVEF <50% and an absolute decrease in LVEF of ≥10% was similar in pertuzumab- or placebo-treated patients.

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).

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

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

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

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm based on mechanism of action and animal studies. Embryotoxicity and fetotoxicity demonstrated in animals. 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). Oligohydramnios and oligohydramnios sequence manifesting as pulmonary hyperplasia, skeletal abnormalities, and neonatal death reported with anti-HER2 antibody trastuzumab during pregnancy in postmarketing experience.

Perform pregnancy test prior to initiation of pertuzumab. Advise females of reproductive potential to use effective contraceptive methods during therapy and for 7 months after discontinuance of drug.

If used during pregnancy or if patient becomes pregnant during therapy, apprise of potential fetal hazard. (See Pregnancy under Cautions.) Monitor for development of oligohydramnios in patients who become pregnant during therapy; perform appropriate fetal testing if oligohydramnios occurs.

Sensitivity Reactions

Infusion-related Reactions

Infusion-related reactions, including fatal events, reported. Most common infusion reactions reported were pyrexia, chills, fatigue, headache, asthenia, hypersensitivity, vomiting, dysgeusia, and myalgia.

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

Hypersensitivity Reactions

Severe hypersensitivity, including anaphylaxis and fatal events, reported. Angioedema also described in postmarketing reports.

If serious hypersensitivity reactions occur, discontinue therapy. Administer in a setting where emergency equipment and appropriate medical support are available for management of potential infusion reactions. Closely observe patients for hypersensitivity reactions, including anaphylaxis. (See Hypersensitivity Reactions under Dosage and Administration.)

Other Warnings and Precautions

Evaluation of HER2

Select patients based on HER2 protein overexpression or HER2 gene amplification.

Assess HER2 status using FDA-approved tests specific for breast cancer. Select laboratories with demonstrated proficiency in the specific technology being used; improper assay performance can lead to unreliable results.

Immunogenicity

Potential for immunogenicity. Anaphylactic or hypersensitivity reactions related to presence of anti-pertuzumab antibodies not observed.

Tumor Lysis Syndrome

Tumor lysis syndrome reported during postmarketing experience. Increased risk in patients with high tumor burden (e.g., bulky metastases). Monitor and/or initiate treatment as clinically indicated.

Prolongation of QT Interval

In a subset of 20 patients enrolled in the CLEOPATRA study, no large (i.e., >20 msec) increases in the corrected QT (QT_c) interval observed in patients receiving pertuzumab in combination with trastuzumab and docetaxel.

Specific Populations

Pregnancy

May cause fetal harm. (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. Encourage patient to immediately notify manufacturer (888-835-2555).

Lactation

Not known whether pertuzumab is distributed into milk. Consider benefits of breast-feeding and the importance of pertuzumab to the woman as well as potential adverse effects on the breast-fed infant from the drug or underlying maternal condition.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

No overall differences in efficacy and pharmacokinetics relative to younger adults; however, insufficient data in patients ≥75 years of age to determine whether they respond differently than younger adults. Decreased appetite, anemia, decreased weight, asthenia, dysgeusia, peripheral neuropathy, and hypomagnesemia occurred more frequently in patients ≥65 years of age compared with younger adults.

Hepatic Impairment

Pharmacokinetics not studied in patients with hepatic impairment.

Renal Impairment

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

Limited data in patients with severe renal impairment.

Common Adverse Effects

Metastatic breast cancer: Diarrhea, alopecia, neutropenia, nausea, fatigue, rash, peripheral neuropathy.

Early-stage breast cancer: Alopecia, diarrhea, nausea, neutropenia, fatigue, vomiting, thrombocytopenia, anemia, constipation, peripheral neuropathy, headache, asthenia, mucosal inflammation, myalgia.

Drug Interactions

Specific Drugs

Drug	Interaction
Carboplatin	Drug interaction not observed
Docetaxel	Drug interaction not observed
Paclitaxel	Drug interaction not observed
Trastuzumab	Drug interaction not observed

Pertuzumab Pharmacokinetics

Absorption

Bioavailability

Steady-state concentrations achieved after first maintenance dose.

Special Populations

Age, sex, ethnicity (Japanese versus non-Japanese), or disease status (early-stage versus metastatic): No effects on pertuzumab pharmacokinetics.

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

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

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

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

Elimination

Half-life

Median half-life: 18 days.

Stability

Storage

Parenteral

Injection

2–8°C in original carton to protect from light. Do not freeze or shake.

Diluted solution: 2–8°C for up to 24 hours after dilution.

Compatibility

Parenteral

Solution Compatibility

Compatible
Sodium chloride 0.9%
Incompatible
Dextrose 5% in water

Actions

Binds specifically to extracellular dimerization domain (subdomain II) of HER2 protein, blocking heterodimerization of HER2 with other ligand-bound members of the HER family (i.e., epidermal growth factor receptor [EGFR]/HER1, HER3, HER4).
Blockade of HER2 heterodimerization (particularly with HER3) results in inhibition of ligand-activated intracellular signaling through 2 major signal pathways, mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K/Akt), potentially causing cell growth arrest and apoptosis, respectively.
Mediates antibody-dependent cell-mediated cytotoxicity (ADCC).
Exhibits complementary mechanisms of action with trastuzumab; therefore, combined use with trastuzumab may result in more comprehensive inhibition of HER2 signaling.

Advice to Patients

Risk of left ventricular dysfunction. Advise patients to contact a health care professional immediately if new-onset or worsening shortness of breath, cough, swelling of the ankles and/or legs, swelling of the face, palpitations, weight gain >5 pounds in 24 hours, dizziness, or loss of consciousness occurs.
Risk of fetal harm (e.g., embryo-fetal death, birth defects). Necessity of advising women of childbearing potential to use effective contraceptive methods during and for 7 months after discontinuance of drug. Encourage women who have been exposed to pertuzumab during pregnancy to report their pregnancy to manufacturer. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)
Risk of infusion or hypersensitivity reactions.
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.
Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Pertuzumab can only be obtained through select specialty distributors. Contact manufacturer for additional information.