Elahere Drug Information

ELAHERE ® is indicated for the treatment of adult patients with folate receptor-alpha (FRα) positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have received one to three prior systemic treatment regimens. Select patients for therapy based on an FDA-approved test.

Patient Selection

Select patients for the treatment of platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer with ELAHERE based on the presence of FRα tumor expression using an FDA-approved test. Information on FDA-approved tests for the measurement of FRα tumor expression is available at http://www.fda.gov/CompanionDiagnostics.

Recommended Dosage

The recommended dosage of ELAHERE is 6 mg/kg adjusted ideal body weight (AIBW) administered once every 3 weeks (21-day cycle) as an intravenous infusion until disease progression or unacceptable toxicity. Dosing based on AIBW reduces exposure variability for patients who are either under or overweight. The total dose of ELAHERE is calculated based on each patient’s AIBW using the following formula: AIBW = Ideal Body Weight (IBW ) + 0.4*(Actual weight – IBW) Female IBW = 0.9*height – 92

Premedication and Required Eye Care

Premedica tion Administer the premedications in Table 1 prior to each infusion of ELAHERE to reduce the incidence and severity of infusion related reactions (IRRs), nausea, and vomiting. Table 1: Consider additional premedications including corticosteroids the day prior to ELAHERE administration for patients who experienced IRRs. Ophthalmic Exams and Premedication Ophthalmic E xam: Conduct an ophthalmic exam including visual acuity and slit lamp exam prior to initiation of ELAHERE, every other cycle for the first 8 cycles, and as clinically indicated.

Ophthalmic Topical Steroids: The use of ophthalmic topical steroids is recommended. The initial prescription and renewals of any corticosteroid medication should be made only after examination with a slit lamp. Administer one drop of ophthalmic topical steroids in each eye 6 times daily starting the day prior to each infusion until day 4; then administer one drop in each eye 4 times daily for days 5-8 of each cycle of ELAHERE.

Lubricating Eye Drops: The use of lubricating eye drops at least four times daily and as needed is recommended during treatment with ELAHERE. Instruct patients to use lubricating eye drops and advise to wait at least 10 minutes after ophthalmic topical steroid administration before instilling lubricating eye drops.

Dosage Modifications Table 2 provides dose reduction levels and Table 3 provides dosage modifications for ELAHERE due to adverse reactions. Table 3: Infusion-Related Reactions/Hypersensitivity Grade 2 Interrupt infusion and administer supportive treatment. After recovery from symptoms, resume the infusion at 50% of the previous rate, and if no further symptoms appear, increase rate as appropriate until infusion is completed.

Administer additional premedication for future cycles. Unless otherwise specified, National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0.

Instructions for Preparation and Administration Preparation ELAHERE is a hazardous drug. Follow applicable special handling and disposal procedures 1. Calculate the dose (mg) (based on the patient’s AIBW), total volume (mL) of solution required, and the number of vials of ELAHERE needed.

More than one vial will be needed for a full dose. Remove the vials of ELAHERE from the refrigerator and allow to warm to room temperature. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

ELAHERE is a clear to slightly opalescent, colorless solution. Gently swirl and inspect each vial prior to withdrawing the calculated dose volume of ELAHERE. Do not shake the vial.

Using aseptic technique, withdraw the calculated dose volume of ELAHERE for subsequent dilution. ELAHERE contains no preservatives and is intended for single-dose only. Discard any unused drug remaining in the vial.

Dilution ELAHERE must be diluted prior to administration with 5% Dextrose Injection, USP to a final concentration of 1 mg/mL to 2 mg/mL. ELAHERE is incompatible with 0.9% Sodium Chloride Injection. ELAHERE must not be mixed with any other drugs or intravenous fluids.

Determine the volume of 5% Dextrose Injection, USP required to achieve the final diluted drug concentration. Either remove excess 5% Dextrose Injection, USP from a prefilled intravenous bag or add the calculated volume of 5% Dextrose Injection, USP to a sterile empty intravenous bag. Then add the calculated dose volume of ELAHERE to the intravenous bag.

Gently mix the diluted drug solution by slowly inverting the bag several times to assure uniform mixing. Do not shake or agitate. • If the diluted infusion solution is not used immediately, store solution either at ambient temperature for no more than 8 hours (including infusion time), or under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 24 hours. If refrigerated, allow the infusion bag to reach room temperature prior to administration.

After refrigeration, administer diluted infusion solutions within 8 hours (including infusion time). Do not freeze prepared infusion solution. Administration Inspect the ELAHERE intravenous infusion bag visually for particulate matter and discoloration prior to administration.

Administer pre-medications prior to ELAHERE administration. Administer ELAHERE as an intravenous infusion only, using a 0.2 or 0.22 µm polyethersulfone (PES) in-line filter. Do not substitute other membrane materials.

Administer the initial dose as an intravenous infusion at the rate of 1 mg/min. If well tolerated after 30 minutes at 1 mg/min, the infusion rate can be increased to 3 mg/min. If no infusion-related reactions occur with the previous dose, subsequent infusions should be started at the maximally tolerated rate and may be increased up to a maximum infusion rate of 5 mg/min, as tolerated.

Following the infusion, flush the intravenous line with 5% Dextrose Injection, USP to ensure delivery of the full dose. Do not use any other intravenous fluids for flushing.

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 practice. The median duration of treatment was 4.4 months (range: 1.0 to 30.0). In the pooled safety population, the most common (≥20%) adverse reactions, including laboratory abnormalities, were increased aspartate aminotransferase, fatigue, increased alanine aminotransferase, blurred vision, nausea, increased alkaline phosphatase, diarrhea, abdominal pain, keratopathy, peripheral neuropathy, musculoskeletal pain, decreased lymphocytes, decreased platelets, decreased magnesium, decreased hemoglobin, dry eye, constipation, decreased leukocytes, vomiting, decreased albumin, decreased appetite, and decreased neutrophils.

Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer Study 0416 The safety of ELAHERE was evaluated in Study 0416, a multicenter, open-label, active-controlled, randomized, two-arm, study in patients (n=453) with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer. Patients received ELAHERE 6 mg/kg AIBW once every 3 weeks until disease progression or unacceptable toxicity. The median duration of treatment was 5 months (range: 0.69 to 27.4).

Serious adverse reactions occurred in 24% of patients treated with ELAHERE. Fatal adverse reactions occurred in 3% of patients, including intestinal obstruction, dyspnea in the setting of subileus, neutropenic sepsis, cardiopulmonary failure, respiratory failure, ischemic stroke, and pulmonary embolus. Permanent discontinuation of ELAHERE due to adverse reactions occurred in 9% of patients.

Dosage delays of ELAHERE due to an adverse reaction occurred in 54% of patients treated with ELAHERE. Dose reductions of ELAHERE due to an adverse reaction occurred in 34% of patients. Table 4: Adverse Reactions Occurring in ≥10% of Patients with Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer Who Received ELAHERE in Study 0 0 ¥ Chemotherapy: paclitaxel, pegylated liposomal doxorubicin (PLD), topotecan. ※ Blurred vision includes vision blurred, vitreous floaters, visual acuity reduced, diplopia, accommodation disorder, and visual impairment. Keratopathy includes corneal disorder, corneal epithelial microcysts, keratitis, keratopathy, corneal deposits, punctate keratitis, and corneal opacity. Dry eye includes dry eye and lacrimation increased. ˄ Cataract includes cataract and cataract nuclear. ⸙ Fatigue includes fatigue and asthenia. Abdominal pain includes abdominal pain, abdominal pain upper, abdominal pain lower, and abdominal discomfort. ¶ Peripheral neuropathy includes neuropathy peripheral, peripheral sensory neuropathy, peripheral motor neuropathy, paresthesia, hypoesthesia, polyneuropathy, neurotoxicity, and peripheral sensorimotor neuropathy. ♦ Musculoskeletal pain includes back pain, myalgia, neck pain, arthralgia, musculoskeletal pain, non-cardiac chest pain, bone pain, pain in extremity, musculoskeletal stiffness, musculoskeletal chest pain, and musculoskeletal discomfort. ± Pneumonitis includes pneumonitis, interstitial lung disease, respiratory failure, and organizing pneumonia.

Clinically relevant adverse reactions occurring in <10% of patients who received ELAHERE in Study 0416 included infusion related reactions/hypersensitivity (8%). Study 0417 The safety of ELAHERE was evaluated in Study 0417, a single-arm, open-label study in patients (n=106) with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer. The median duration of treatment was 4.2 months (range: 0.7 to 13.3).

Fatal adverse reactions occurred in 2% of patients, including small intestinal obstruction (1%) and pneumonitis (1%). The most common (≥2%) adverse reactions leading to permanent discontinuation were intestinal obstruction (2%) and thrombocytopenia (2%). One patient (0.9%) permanently discontinued ELAHERE due to visual impairment (unilateral decrease to BCVA ≤ 20/200 that resolved to baseline after discontinuation).

Adverse reactions which required dose reductions in ≥3% of patients included blurred vision (9%) and keratopathy (7%). Table 6 summarizes the adverse reactions (≥10%) in patients treated with ELAHERE in Study 0417. Table 6: Adverse Reactions (≥10%) in Patients with Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer Who Received ELAHERE in Study 0 0 ※ Blurred vision includes vision blurred, vitreous floaters, visual acuity reduced, diplopia, presbyopia, accommodation disorder, visual impairment, and refraction disorder. Keratopathy includes corneal disorder, corneal epithelial microcysts, corneal epithelial defect, keratitis, keratopathy, corneal deposits, and punctate keratitis. Dry eye includes dry eye and lacrimation increased. § Eye pain includes eye pain and ocular discomfort. ⸙ Fatigue includes fatigue and asthenia. Abdominal pain includes abdominal pain, abdominal pain upper, abdominal pain lower, and abdominal discomfort. ¶ Peripheral neuropathy includes neuropathy peripheral, peripheral sensory neuropathy, peripheral motor neuropathy, paresthesia, hypoesthesia, polyneuropathy, and neurotoxicity. ^ Dyspnea includes dyspnea and exertional dyspnea.

Table 7 summarizes the laboratory abnormalities in Study 0417. Immunogenicity: Anti-Drug Antibody-Associated Adverse Reactions In studies in patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer who received ELAHERE at 6 mg/kg AIBW administered intravenously once every 3 weeks, 9% (57/626) developed anti-drug antibodies. Infusion reactions (including bronchospasm, erythema, eyelid erythema, flushing, hypersensitivity, periorbital edema, rash, allergic rhinitis, face edema) occurred in 26% (15/57) of patients with anti-drug antibodies and in 7% (41/569) who did not develop anti-drug antibodies.

Effects of Other Drugs on ELAHERE Strong CYP3A4 Inhibitors DM4 is a CYP3A4 substrate. Concomitant use of ELAHERE with strong CYP3A4 inhibitors may increase unconjugated DM4 exposure, which may increase the risk of ELAHERE adverse reactions. Closely monitor patients for adverse reactions with ELAHERE when used concomitantly with strong CYP3A4 inhibitors.

Pregnancy Risk Summary Based on its mechanism of action, ELAHERE can cause embryo-fetal harm when administered to a pregnant woman because it contains a genotoxic compound (DM4) and affects actively dividing cells. Human immunoglobulin G (IgG) is known to cross the placental barrier; therefore, ELAHERE has the potential to be transmitted from the mother to the developing fetus. There are no available human data on ELAHERE use in pregnant women to inform a drug-associated risk.

No reproductive or developmental animal toxicity studies were conducted with mirvetuximab soravtansine-gynx. Advise patients of the potential risk to a fetus. 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. The cytotoxic component of ELAHERE, DM4, disrupts microtubule function, is genotoxic, and can be toxic to actively dividing cells, suggesting it has the potential to cause embryotoxicity and teratogenicity.

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