Perjeta Drug Information

Metastatic Breast Cancer (MBC) PERJETA is indicated for use in combination with trastuzumab and docetaxel for the treatment of adults with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease.

Early Breast Cancer (EBC) PERJETA is indicated for use in combination with trastuzumab and chemotherapy for the neoadjuvant treatment of adults 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. the adjuvant treatment of adults with HER2-positive early breast cancer at high risk of recurrence.

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.

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: 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.

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 30 to 60 minutes. Administer 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 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. In patients receiving an anthracycline-based regimen, administer Perjeta and trastuzumab or trastuzumab hyaluronidase-oysk after 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 Administer Perjeta every 3 weeks for 3 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 2 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.

Adjuvant Treatment of Breast Cancer 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 1 of the first taxane-containing cycle.

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 if trastuzumab or trastuzumab hyaluronidase-oysk treatment is discontinued. Dose reductions are not recommended for Perjeta.

For chemotherapy dose modifications, see relevant prescribing information.

The recommended dosage modifications for LVEF decrease are listed in Table 2. Table 2: Dose Modifications for Left Ventricular Dysfunction Infusion-Related Reactions The infusion rate of Perjeta may be slowed or interrupted if the patient develops an infusion-related reaction. Hypersensitivity Reactions/Anaphylaxis The infusion should be discontinued immediately if the patient experiences a serious hypersensitivity reaction.

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, 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.

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) CLEOPATRA The safety of PERJETA in combination with trastuzumab and docetaxel was evaluated in a randomized trial (CLEOPATRA) in patients with HER2-positive metastatic breast cancer. The median duration of study treatment was 18.1 months for patients in the PERJETA-treated group.

Permanent discontinuation of PERJETA, trastuzumab, and docetaxel due to adverse reactions occurred in 6% of patients. Adverse reactions that led to permanent discontinuation of PERJETA, trastuzumab, and docetaxel in >1% of patients were left ventricular dysfunction. 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%) with PERJETA in combination with trastuzumab and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy. The most common 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 3 summarizes the adverse reactions in CLEOPATRA that occurred ≥ 10% of patients in the PERJETA-treated group. Neoadjuvant Treatment of Breast Cancer NeoSphere The safety of PERJETA was evaluated in a randomized trial (NeoSphere) in patients with operable, locally advanced, or inflammatory HER2-positive breast cancer (T2-4d) who were scheduled for neoadjuvant therapy.

After surgery, patients in the PERJETA plus trastuzumab arm received docetaxel every 3 weeks for 4 cycles prior to FEC. Permanent discontinuation of neoadjuvant PERJETA due to an adverse reaction occurred in 0.9% of patients. Table 4 summarizes the adverse reactions in NeoSphere that occurred ≥ 10% of patients who received neoadjuvant PERJETA with trastuzumab and docetaxel followed by FEC.

Table 4: Adverse Reactions (≥ 10%) in Patients who Received Neoadjuvant PERJETA in NeoSphere 0 Clinically relevant adverse reactions in < 10% of patients receiving neoadjuvant PERJETA with trastuzumab and docetaxel followed by FEC included anemia, febrile neutropenia, dizziness, upper respiratory tract infection, and increased lacrimation. 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.

For PERJETA 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 Grade 3 – 4 adverse reactions (> 2%) were neutropenia, leukopenia, febrile neutropenia, diarrhea, left ventricular dysfunction, anemia, dyspnea, nausea, and vomiting. For PERJETA 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 Grade 3 – 4 adverse reactions (> 2%) were neutropenia, febrile neutropenia, anemia, leukopenia, diarrhea, thrombocytopenia, vomiting, fatigue, ALT increased, hypokalemia, and hypersensitivity. Table 5 summarizes the adverse reactions in TRYPHAENA that occurred in > 10% of patients who received neoadjuvant PERJETA with trastuzumab and docetaxel following FEC or who received neoadjuvant PERJETA in combination with TCH. Table 5: Adverse Reactions (≥ 10%) in Patients Receiving Neoadjuvant Treatment with PERJETA in TRYPHAENA 3 Clinically relevant adverse reactions in < 10% of patients who received neoadjuvant PERJETA with trastuzumab and docetaxel following FEC or who received neoadjuvant PERJETA in combination with TCH included nail disorder, paronychia, pruritus, upper respiratory tract infection, and nasopharyngitis.

Neoadjuvant Treatment of Breast Cancer BERENICE The safety of PERJETA was evaluated in a two-arm non-randomized study (BERENICE) in patient with HER2-positive locally advanced, inflammatory, or early-stage HER2-positive breast cancer. 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 peripheral neuropathy, decreased ejection fraction, diarrhea, neutropenia and infusion-related reaction.

For PERJETA 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, decreased neutrophil count, decreased white blood cell count, anemia, diarrhea, peripheral neuropathy, increased ALT, and nausea. The most common Grade 3 – 4 adverse reactions (> 2%) were febrile neutropenia, diarrhea, neutropenia, decreased neutrophil count stomatitis, fatigue, vomiting, mucosal inflammation, neutropenic sepsis and anemia.

Table 6 summarizes the adverse reactions in BERENICE that occurred in ≥ 10% of patients who received neoadjuvant PERJETA with trastuzumab and paclitaxel following ddAC or who received neoadjuvant PERJETA with trastuzumab and docetaxel following FEC. Table 6: Adverse Reactions (≥ 10%) of Patients Receiving Neoadjuvant PERJETA in Combination with Trastuzumab and Taxane Chemotherapy Following ddAC or FEC in BERENICE 1 2 0 Clinically relevant adverse reactions in < 10% of patients who received PERJETA in combination with trastuzumab and paclitaxel following ddAC or patients receiving PERJETA in combination with trastuzumab and docetaxel following FEC included pruritus, nail disorder, paronychia, upper respiratory tract infection, and nasopharyngitis. Adjuvant Treatment of Breast Cancer APHINITY The safety of PERJETA was evaluated in a multicenter, randomized, double-blind, placebo-controlled study (APHINITY) conducted in patients with HER2-positive early breast cancer who had their primary tumor excised prior to randomization.

Patients were randomized to receive either PERJETA in combination with trastuzumab and chemotherapy or placebo in combination with trastuzumab and chemotherapy. Investigators selected one of three anthracycline-based or non-anthracycline-based chemotherapy regimens for patients. 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.

Serious adverse reactions (hospitalization) due to diarrhea in the PERJETA-treated group was 2.4%. The incidence of diarrhea was higher when chemotherapy was administered with PERJETA (61%) and was higher when administered with non-anthracycline based therapy (85%) than with anthracycline based therapy (67%). The median duration of diarrhea was 8 days.

The median duration of Grade ≥3 diarrhea was 20 days. The incidence of diarrhea during the period PERJETA and trastuzumab were administered without chemotherapy was 18% in the PERJETA-treated group. Adverse reactions resulting in permanent discontinuation of any study therapy were 13% for patients in the PERJETA-treated group.

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. 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.

Table 7 summarizes the adverse reactions that occurred in ≥ 10% of patients who received adjuvant PERJETA in combination with trastuzumab and chemotherapy followed by PERJETA and trastuzumab for a total of 52 weeks (up to 18 cycles) or until recurrence, withdrawal of consent, or unmanageable toxicity. Table 7: Adverse Reactions (≥ 10%) of Patients Receiving Adjuvant PERJETA in Combination with Trastuzumab and Chemotherapy Followed by PERJETA and Trastuzumab in APHINITY Clinically relevant adverse reactions in < 10% of patients who received PERJETA in combination with trastuzumab and anthracycline-based or non-anthracycline-based chemotherapy regimens included l eukopenia, upper respiratory tract infection, and paronychia Adverse Reactions in Patients Receiving PERJETA and Trastuzumab After Discontinuation of Chemotherapy In APHINITY, adverse reactions that occurred after discontinuation of chemotherapy in >10% included diarrhea (18%), arthralgia (15%), radiation skin injury (12%), and hot flush (12%).

Pregnancy 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. 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.

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. 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.

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.

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

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