Margenza Drug Information

is indicated, in combination with chemotherapy, for the treatment of adult patients with metastatic HER2-positive breast cancer who have received two or more prior anti-HER2 regimens, at least one of which was for metastatic disease. MARGENZA is a HER2/neu receptor antagonist indicated, in combination with chemotherapy, for the treatment of adult patients with metastatic HER2-positive breast cancer who have received two or more prior anti-HER2 regimens, at least one of which was for metastatic disease.

Recommended Doses and Schedules

The recommended dose of MARGENZA is 15 mg/kg, administered as an intravenous infusion every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity. Administer MARGENZA as an intravenous infusion at 15 mg/kg over 120 minutes for the initial dose, then over a minimum of 30 minutes every 3 weeks for all subsequent doses. On days when both MARGENZA and chemotherapy are to be administered, MARGENZA may be administered immediately after chemotherapy completion.

Refer to the respective Prescribing Information for each therapeutic agent administered in combination with MARGENZA for the recommended dosage information, as appropriate.

Dose Modification or Important Dosing Considerations

If a patient misses a dose of MARGENZA, administer the scheduled dose as soon as possible. Adjust the administration schedule to maintain a 3-week interval between doses. Left Ventricular Dysfunction Assess left ventricular ejection fraction (LVEF) before starting MARGENZA and regularly during treatment.

Withhold MARGENZA dosing for at least 4 weeks for any of the following: ≥ 16% absolute decrease in LVEF from pretreatment values LVEF below institutional limits of normal (or 50% if no limits are available) and ≥ 10% absolute decrease in LVEF from pretreatment values. MARGENZA dosing may be resumed if, within 8 weeks, LVEF returns to normal limits and absolute decrease from baseline is ≤ 15%. Permanently discontinue MARGENZA if LVEF decline persists for greater than 8 weeks, or if dosing is interrupted on greater than 3 occasions for LVEF decline. Infusion-Related Reactions Decrease the rate of infusion for mild or moderate infusion-related reactions (IRRs). Interrupt the infusion for dyspnea or clinically significant hypotension.

Permanently discontinue MARGENZA dosing in patients with severe or life-threatening IRRs.

Preparation for

Administration Administer as an intravenous infusion after dilution. Preparation for Intravenous Infusion Prepare solution for infusion, using aseptic technique, as follows: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The solution is clear to slightly opalescent, colorless to pale yellow or pale brown.

Some visible, translucent, inherent proteinaceous particles may be present. Swirl the vial(s) gently. Do not shake the vial(s). Calculate the required volume of MARGENZA needed to obtain the appropriate dose according to patient's body weight.

The calculated total dose volume should be rounded to the nearest 0.1 mL. Withdraw appropriate volume of MARGENZA solution from the vial(s) using a syringe. Transfer MARGENZA into an intravenous bag containing 100 mL or 250 mL 0.9% Sodium Chloride Injection, USP. Polyvinyl chloride (PVC) intravenous bags or intravenous bags made with polyolefins (polyethylene and polypropylene) and polyamide or polyolefins only or copolymer of olefins may be used. Do not use 5% Dextrose Injection, USP solution.

The final concentration of the diluted solution should be between 0.5 mg/mL to 7.2 mg/mL. Gently invert the intravenous bag to mix the diluted solution. Do not shake the intravenous bag. Discard any unused portion left in the vial(s). Do not administer as an intravenous push or bolus.

Do not mix MARGENZA with other drugs. Storage of Diluted Solution The product does not contain a preservative. If diluted infusion solution is not used immediately, it can be stored at room temperature up to 4 hours or stored refrigerated at 2°C to 8°C (36°F to 46°F) up to 24 hours.

If refrigerated, allow the diluted solution to come to room temperature prior to administration. Do not freeze. Administration Administer diluted infusion solution intravenously over 120 minutes for the initial dose, then over a minimum of 30 minutes every 3 weeks for all subsequent doses.

Administer through an intravenous line containing a sterile, non-pyrogenic, low-protein binding polyethersulfone (PES) 0.2 micron in-line or add-on filter. Do not co-administer other drugs through the same infusion line.

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 rates observed in practice. The safety of MARGENZA was evaluated in HER2-positive breast cancer patients who received two or more prior anti-HER2 regimens in SOPHIA. Patients were randomized (1:1) to receive either MARGENZA 15 mg/kg every 3 weeks plus chemotherapy or trastuzumab plus chemotherapy. Among patients who received MARGENZA, 40% were exposed for 6 months or longer and 11% were exposed for greater than one year.

Serious adverse reactions occurred in 16% of patients who received MARGENZA. Serious adverse reactions in > 1% of patients included febrile neutropenia (1.5%), neutropenia/neutrophil count decrease (1.5%) and infusion related reactions (1.1%). Fatal adverse reactions occurred in 1.1% of patients who received MARGENZA, including viral pneumonia (0.8%) and aspiration pneumonia (0.4%). Permanent discontinuation due to an adverse reaction occurred in 3% of patients who received MARGENZA. Adverse reactions which resulted in permanent discontinuation in > 1% of patients who received MARGENZA included left ventricular dysfunction and infusion-related reactions. Dosage interruptions due to an adverse reaction occurred in 11% of patients who received MARGENZA. Adverse reactions which required dosage interruption in > 5% of patients who received MARGENZA included infusion-related reactions. Table 1 summarizes the adverse reactions in SOPHIA. Table 1 Adverse Reactions (>10%) in Patients with Metastatic HER2-Positive Breast Cancer Who Received MARGENZA in SOPHIA Adverse Reaction MARGENZA + Chemotherapy (n = 264) Trastuzumab + Chemotherapy (n = 266) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) General disorders and administration site conditions Fatigue/Asthenia 57 7 47

Pyrexia 19 0.4 14 0.4 Gastrointestinal disorders Nausea 33 1.1 32 0.4

Diarrhea 25 2.3 25

Vomiting 21 0.8 14 1.5 Constipation 19 0.8 17 0.8 Abdominal pain

Includes abdominal pain, abdominal discomfort, lower abdominal pain and upper abdominal pain 17 1.5 21

Skin and Subcutaneous tissue Alopecia 18 0 15 0 Palmar-plantar erythrodysesthesia 13

0 15 3 Nervous System Disorders Headache Includes headache and migraine 19 0 16 0 Peripheral neuropathy Includes peripheral neuropathy, peripheral sensory neuropathy, peripheral motor neuropathy, and neuropathy 16 1.1 15

Respiratory, thoracic and mediastinal disorders Cough 14 0.4 12 0 Dyspnea 13

1.1 11

Metabolism and nutrition disorders Decreased appetite 14 0.4 14 0.4 Musculoskeletal and

connective tissue disorders Arthralgia/Myalgia 14 0.4 12

Extremity pain 11 0.8 9 0 Injury, poisoning and procedural complications Infusion-related

reaction 13 1.5 3 0 Clinically relevant adverse reactions in ≤10% of patients who received MARGENZA in combination with chemotherapy included: dizziness and stomatitis (10%) each, decreased weight, dysgeusia, rash, and insomnia (6%) each, hypertension (5%), and syncope (1.5%). Table 2 summarizes the laboratory abnormalities in SOPHIA. Table 2 Select Laboratory Abnormalities (≥20%) That Worsened from Baseline in Patients with Metastatic HER2-Positive Breast Cancer Who Received MARGENZA in SOPHIA Laboratory Abnormality MARGENZA + Chemotherapy The denominator used to calculate the rate varied from 229 to 253 based on the number of patients with a baseline value and at least one post-treatment value. Trastuzumab + Chemotherapy All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) aPTT: activated partial thromboplastin time; INR: prothrombin international normalized ratio; ALT: alanine aminotransferase; AST: aspartate aminotransferase Hematology Decreased hemoglobin 52 3.2 43

Decreased leukocytes 40 5 36 3.2 Decreased neutrophils 34 9 28 9

Increased aPTT 32 3.4 34

Decreased lymphocytes 31 4.4 38 4.4 Increased

INR 24 1.2 25

Chemistry Increased creatinine 68 0.4 60 0 Increased

ALT 32 2 30

Increased lipase 30 6 24 3.2 Increased

AST 23 2 22

Anthracyclines Patients who receive anthracyclines less than 4 months after stopping MARGENZA may be at increased risk of cardiac dysfunction. While this interaction has not been studied with MARGENZA, clinical data from other HER2-directed antibodies warrants consideration. Avoid anthracycline-based therapy for up to 4 months after stopping MARGENZA. If concomitant use is unavoidable, closely monitor patient's cardiac function.

Pregnancy Risk Summary Based on findings in animals and mechanism of action, MARGENZA can cause fetal harm when administered to a pregnant woman. There are no available data on use of MARGENZA in pregnant women to inform the drug-associated risk. In postmarketing reports, use of a HER2-directed antibody during pregnancy resulted in cases of oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death.

In an animal reproduction study, intravenous administration of margetuximab-cmkb to pregnant cynomolgus monkeys once every 3 weeks, starting at gestational day (GD) 20 until delivery, resulted in oligohydramnios and delayed infant kidney development. Animal exposures were ≥ 3 times the human exposures at the recommended dose, based on C max (see Data ). Advise patients of potential risks to a fetus. There are clinical considerations if MARGENZA is used during pregnancy or within 4 months prior to conception (see Clinical Considerations ). Estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

In the U.S. general population, background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2 - 4% and 15 - 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Monitor women who received MARGENZA during pregnancy or within 4 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 In an enhanced pre- and post-natal development study, pregnant cynomolgus monkeys received intravenous doses of 50 or 100 mg/kg margetuximab-cmkb once every 3 weeks starting on GD 20 and until delivery. Animal exposures at doses of 50 and 100 mg/kg were 3 and 6 times, respectively, the human exposures at the recommended dose, based on C max. Treatment with 50 and 100 mg/kg margetuximab-cmkb resulted in oligohydramnios beginning on GD 75. An infant mortality occurred on post-natal day 63 following maternal exposure to 100 mg/kg margetuximab-cmkb.

Clinical findings included tubular degeneration/necrosis and tubular dilatation in the kidney. Maternal doses of 50 and 100 mg/kg resulted in decreased infant kidney weights and histologic immature nephrons. Measurable serum concentrations of margetuximab-cmkb were observed in infant animals, which is consistent with margetuximab-cmkb crossing the placenta.

Pediatric Use Safety and effectiveness of MARGENZA have not been established in pediatric patients.