PECTUNA

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).

It consists of two heavy chains and two lights chains that have and 214 residues respectively.

It was first approved by the FDA in for use with docetaxel and another HER2-targeted monoclonal antibody, trastuzumab, in the treatment of metastatic HER2-positive breast cancer.

Its indicated conditions have since expanded to include use as both a neoadjuvant therapy and an adjuvant therapy in the treatment of HER2-positive breast cancers at high risk of recurrence. 5, 8.

Pertuzumab is indicated for intravenous administration 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.

It is also indicated in combination with trastuzumab and other chemotherapies for the neoadjuvant treatment of HER2-positive locally advanced, inflammatory, or early-stage breast cancer as part of a complete treatment regimen and as adjuvant treatment in patients with HER2-positive early-stage breast cancer at high risk of recurrence.

Pertuzumab is also indicated for subcutaneous injection.

• in combination with trastuzumab and hyaluronidase.

• in the treatment of HER2-positive breast cancers in adults.

Pertuzumab exerts its antineoplastic effects by binding to and inhibiting the activity of HER2, an oncogene that has been implicated in the formation of numerous cancers.

As with other therapeutic monoclonal antibodies, pertuzumab has a relatively long duration of action necessitating dosing every 3 weeks.

Drugs that block

HER2 activity, including pertuzumab, have been implicated in the development of cardiotoxicity (specifically left ventricular dysfunction).

• a baseline assessment of left ventricular ejection fraction (LVEF) should be conducted prior to beginning therapy with pertuzumab and at regular intervals throughout therapy to ensure LVEF remains within normal limits.

Consider indefinite suspension of therapy if

LVEF declines and does not improve.

Intravenous administered pertuzumab, given as a loading dose of 840 mg followed by a maintenance dose of 420 mg every 3 weeks, reaches steady-state concentration following the first maintenance dose.

In its subcutaneous formulation, in combination with, the absolute bioavailability of pertuzumab is approximately 0.7 and the median T max is 4 days.

This subcutaneous formulation leverages the benefits of co-administration with hyaluronidase.

• this enzyme breaks down hylauronic acid, thereby decreasing the viscosity of the extracellular matrix (ECM) and allowing for greater bioavailability with subcutaneous administration.

The average steady-state volume of distribution following intravenous administration is 3.53-7.5 L.

The metabolism of pertuzumab has not been studied directly.

Monoclonal antibodies are typically subject to catabolism to smaller peptides and proteins prior to elimination.

The median half-life of pertuzumab was determined to be 18 days based on a population pharmacokinetic analysis.

The median clearance of pertuzumab was determined to be 0.24 L/day based on a population pharmacokinetic analysis.

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There are no data regarding overdose of pertuzumab.

Single doses higher than 25 mg/kg have not been tested.

Symptoms of overdose are likely to be consistent with pertuzumab's adverse effect profile, and may therefore involve significant diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and/or peripheral neuropathy.

Pertuzumab has been associated with the development of left ventricular dysfunction (i.e. cardiotoxicity) that may be exacerbated in instances of overdose.

is contraindicated in patients with known hypersensitivity to pertuzumab or to any of its excipients.

PERJETA is contraindicated in patients with known hypersensitivity to pertuzumab or to any of its excipients.

For intravenous infusion only.

Do not administer as an intravenous push or bolus.

HER2 testing: Perform using FDA-approved tests by laboratories with demonstrated proficiency.

The initial

PERJETA dose is 840 mg administered as a 60-minute intravenous infusion, followed every 3 weeks thereafter by 420 mg administered as a to 60 minute intravenous infusion.

Administer PERJETA, trastuzumab or trastuzumab hyaluronidase-oysk, and docetaxel every 3 weeks.

Administer PERJETA, trastuzumab or trastuzumab hyaluronidase-oysk, and chemotherapy preoperatively every 3 weeks for to 6 cycles.

Administer PERJETA, trastuzumab or trastuzumab hyaluronidase-oysk, and chemotherapy postoperatively every 3 weeks for a total of 1 year (up to 18 cycles). 2.1 Evaluation and Testing Before Initiating Perjeta Assess left ventricular ejection fraction (LVEF) prior to initiation of PERJETA and at regular intervals during treatment.

Verify the pregnancy status of females of reproductive potential prior to the initiation of PERJETA. 2.2 Patient Selection Select patients based on HER2 protein overexpression or HER2 gene amplification in tumor specimens.

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: 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. 2.3 Recommended Dosage and Administration 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 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 to 90 minutes.

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 to 5 minutes once every three weeks irrespective of the patient's body weight.

PERJETA, trastuzumab or trastuzumab hyaluronidase-oysk, and taxane sequentially.

PERJETA and trastuzumab or trastuzumab hyaluronidase-oysk can be given in any order.

Administer taxane after

PERJETA and trastuzumab or trastuzumab hyaluronidase-oysk.

An observation period of to 60 minutes is recommended after each PERJETA infusion and before commencement of any subsequent administration of trastuzumab or trastuzumab hyaluronidase-oysk, or taxane.

In patients receiving an anthracycline-based regimen, administer PERJETA and trastuzumab or trastuzumab hyaluronidase-oysk after completion of the anthracycline.

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 Administer

PERJETA every 3 weeks for to 6 cycles as part of one of the following treatment regimens: 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) 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 Six preoperative cycles of PERJETA in combination with docetaxel, carboplatin, and trastuzumab (TCH) or trastuzumab hyaluronidase-oysk (escalation of docetaxel above 75 mg/m is not recommended) 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 Following surgery, administer PERJETA and trastuzumab or trastuzumab hyaluronidase-oysk to complete 1 year of treatment (up to 18 cycles) or until disease recurrence or unmanageable toxicity, whichever occurs first.

As part of a regimen including standard anthracycline.

• and/or taxane-based chemotherapy, administer PERJETA 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.

Administer PERJETA on

Day of the first taxane-containing cycle. 2.4 Important Dosing Considerations Missed Dose The recommended dosage modifications for delayed or missed doses are listed in Table 1.

Table 1: Recommendations for Delayed or Missed Doses Time between two sequential doses PERJETA Trastuzumab (intravenous) Trastuzumab hyaluronidase-oysk < 6 weeks Administer PERJETA 420 mg intravenously as soon as possible.

Do not wait until the next planned dose.

Administer trastuzumab 6 mg/kg intravenously as soon as possible.

Administer trastuzumab hyaluronidase-oysk 600 mg/10,000 units subcutaneously as soon as possible.

Do not wait until the next planned dose. ≥ 6 weeks Readminister PERJETA loading dose of 840 mg intravenously as a 60 minute infusion, followed by a maintenance dose of 420 mg administered intravenously over a period of to 60 minutes every 3 weeks thereafter.

Readminister trastuzumab loading dose of 8 mg/kg intravenously over approximately 90 minutes, followed by a maintenance dose of 6 mg/kg administered intravenously over a period of 30 or 90 minutes every 3 weeks thereafter.

Permanently discontinue

PERJETA if trastuzumab or trastuzumab hyaluronidase-oysk treatment is discontinued.

Dose reductions are not recommended for

For chemotherapy dose modifications, see relevant prescribing information. 2.5 Dosage Modification for Adverse Reactions Left Ventricular Dysfunction Assess left ventricular ejection fraction (LVEF) prior to initiation of PERJETA and at regular intervals during treatment.

The recommended dosage modifications for LVEF decrease are listed in Table 2.

Table 2: Dose Modifications for Left Ventricular Dysfunction Pre-treatment LVEF: Monitor LVEF every: Withhold PERJETA and trastuzumab or trastuzumab hyaluronidase-oysk for at least 3 weeks for an LVEF decrease to: Resume PERJETA and trastuzumab or trastuzumab hyaluronidase-oysk after 3 weeks if LVEF has recovered to: Metastatic Breast Cancer ≥ 50% ~12 weeks Either Either <40% 40%-45% with a fall of ≥10%-points below pre-treatment value >45% 40%-45% with a fall of <10%-points below pre-treatment value Early Breast Cancer ≥ 55% 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. ~12 weeks (once during neoadjuvant therapy) <50% with a fall of ≥10%-points below pre-treatment value Either ≥50% <10% points below pre-treatment value Infusion-Related Reactions The infusion rate of PERJETA may be slowed or interrupted if the patient develops an infusion-related reaction.

Reactions/Anaphylaxis The infusion should be discontinued immediately if the patient experiences a serious hypersensitivity reaction. 2.6 Preparation for Administration Administer as an intravenous infusion only.

Do not mix

PERJETA with other drugs.

Prepare the solution for infusion, using aseptic technique, as follows: Parenteral drug products should be inspected visually for particulates and discoloration prior to administration, whenever solution and container permit.

Withdraw the appropriate volume of

PERJETA solution from the vial(s) using a sterile needle and syringe.

Dilute into a 250 mL 0.45% Sodium Chloride Injection or 0.9% Sodium Chloride Injection 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 refrigerated at 2°C to 8°C (36 °F to 46 °F) for up to 24 hours.

Dilute with 0.45% Sodium Chloride Injection or 0.9% Sodium Chloride Injection only.

Do not use 5% Dextrose Injection.

PERJETA (pertuzumab) injection is supplied as a 420 mg/14 mL (30 mg/mL) single-dose vial containing sterile, preservative-free, clear to slightly opalescent, colorless to pale brown solution.

NDC 50242-145-01.

Store vials refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton until time of use to protect from light.

Do not freeze.

Do not shake.

Store vials refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton until time of use to protect from light.

Do not freeze.

Do not shake.

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.

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.

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.

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.

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 to 150 mg/kg pertuzumab, followed by bi-weekly doses of 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 C max.

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 C max ).

At Caesarean section on

GD100, oligohydramnios, decreased relative lung and kidney weights, and microscopic evidence of renal hypoplasia consistent with delayed renal 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.

The safety and effectiveness of

PERJETA have not been established in pediatric patients.

In CLEOPATRA, NeoSphere, TRYPHAENA, BERENICE, and APHINITY, 464 patients who received PERJETA were ≥ 65 years of age and were ≥ 75 years of age.

The incidence of adverse reactions was increased in patients aged ≥ 65 years of age compared to patients aged < 65 years of age for decreased appetite, anemia, decreased weight, asthenia, dysgeusia, peripheral neuropathy, and hypomagnesemia.

No overall differences in efficacy of

PERJETA were observed in patients aged ≥ 65 and <65 years of age.

Clinical studies did not include sufficient numbers of patients aged ≥ 75 years to determine if these patients respond differently than younger patients.

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).