ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following adverse reactions are discussed elsewhere in the labeling:Ocular Disorders [see Warnings and Precautions (5.1)].Pneumonitis [see Warnings and Precautions (5.2)].Peripheral Neuropathy [see Warnings and Precautions (5.3)].. Ocular Disorders [see Warnings and Precautions (5.1)].. Pneumonitis [see Warnings and Precautions (5.2)].. Peripheral Neuropathy [see Warnings and Precautions (5.3)].. The most common (>=20 %) adverse reactions, including laboratory abnormalities, were vision impairment, fatigue, increased aspartate aminotransferase, nausea, increased alanine aminotransferase, keratopathy, abdominal pain, decreased lymphocytes, peripheral neuropathy, diarrhea, decreased albumin, constipation, increased alkaline phosphatase, dry eye, decreased magnesium, decreased leukocytes, decreased neutrophils, and decreased hemoglobin. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact ImmunoGen at 1-833-486-4646 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The pooled safety population described in WARNINGS AND PRECAUTIONS reflect exposure to ELAHERE in 464 patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer at mg/kg AIBW administered intravenously once every weeks until disease progression or unacceptable toxicity in Study 0417; Study 0403 (NCT02631876), and Study 0401 (NCT01609556). The median duration of treatment was 4.3 months (range: 0.7 to 30.4).. Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer. Study 0417The safety of ELAHERE was evaluated in Study 0417, single-arm, open-label study in patients (n=106) with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer [see Clinical Studies (14)]. Patients received ELAHERE mg/kg AIBW once every weeks until disease progression or unacceptable toxicity. The median duration of treatment was 4.2 months (range: 0.7 to 13.3).Serious adverse reactions occurred in 31% of patients. The most common (>=2%) serious adverse reactions were intestinal obstruction (8%), ascites (4%), infection (3%), and pleural effusion (3%). Fatal adverse reactions occurred in 2% of patients, including small intestinal obstruction (1%) and pneumonitis (1%).Permanent discontinuation of ELAHERE due to adverse reactions occurred in 11% of patients. 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).Dosage delays of ELAHERE due to an adverse reaction occurred in 39% of patients treated with ELAHERE. Adverse reactions which required dosage delays in >=3% of patients included visual impairment (15%), keratopathy (11%), neutropenia (6%), dry eye (5%), cataracts (3%), and increased gamma-glutamyltransferase (3%).Dose reductions of ELAHERE due to an adverse reaction occurred in 20% of patients. Adverse reactions which required dose reductions in >=3% of patients included visual impairment (9%) and keratopathy (7%).The most common (>=20%) adverse reactions, including laboratory abnormalities, were vision impairment, fatigue, increased aspartate aminotransferase, nausea, increased alanine aminotransferase, keratopathy, abdominal pain, decreased lymphocytes, peripheral neuropathy, diarrhea, decreased albumin, constipation, increased alkaline phosphatase, dry eye, decreased magnesium, decreased leukocytes, decreased neutrophils, and decreased hemoglobin.Table summarizes the adverse reactions (>=10%) in patients treated with ELAHERE in Study 0417.Table 4: Adverse Reactions (>=10%) in Patients with Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer Who Received ELAHERE in Study 0417Adverse ReactionAll GradesN=106(%)Grade 3-4N=106(%) Fatigue includes fatigue and asthenia.Eye disordersVision impairmentVisual Impairment includes vision blurred, vitreous floaters, visual acuity reduced, diplopia, presbyopia, accommodation disorder, visual impairment, and refraction disorder. 507KeratopathyKeratopathy includes corneal disorder, corneal epithelial microcysts, corneal epithelial defect, keratitis, keratopathy, corneal deposits, and punctate keratitis. 379Dry eyeDry eye includes dry eye and lacrimation increased. 272Cataract183Photophobia170Eye PainEye pain includes eye pain and ocular discomfort. 100General disordersFatigue493Gastrointestinal disordersNausea400Abdominal PainAbdominal pain includes abdominal pain, abdominal pain upper, abdominal pain lower, abdominal discomfort. 367Diarrhea313Constipation301Vomiting190Abdominal distension110Nervous system disordersPeripheral neuropathyPeripheral neuropathy includes neuropathy peripheral, peripheral sensory neuropathy, peripheral motor neuropathy, paresthesia, hypoesthesia, polyneuropathy, and neurotoxicity. 332Metabolism and nutrition disordersDecreased appetite181Musculoskeletal and connective tissue disordersArthralgia170Myalgia100Respiratory, thoracic, and mediastinal disordersDyspneaDyspnea includes dyspnea and exertional dyspnea. 120Clinically relevant adverse reactions occurring in <10% of patients who received ELAHERE in Study 0417 included infusion related reactions/hypersensitivity (9%), pneumonitis (8%), thrombocytopenia (5%), and uveitis (1%).Table summarizes the laboratory abnormalities in Study 0417.Table 5: Select Laboratory Abnormalities >=10% for All Grades, or >=2% for Grades 3-4 in Patients Who Received ELAHERELaboratory AbnormalityELAHEREThe denominator used to calculate the rate varied from 98 to 101 based on the number of patients with baseline value and at least one post-treatment value. All Grades(%)Grade 3-4(%)Liver Function TestsIncreased aspartate aminotransferase502Increased alanine aminotransferase392Increased alkaline phosphatase301Hematology Decreased lymphocytes357Decreased leukocytes261Decreased neutrophils263Decreased hemoglobin253Decreased platelets182ChemistryDecreased albumin311Decreased magnesium272Increased creatinine160Decreased potassium154.

BOXED WARNING SECTION.

WARNING: OCULAR TOXICITY. ELAHERE can cause severe ocular toxicities, including visual impairment, keratopathy, dry eye, photophobia, eye pain, and uveitis [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)]. Conduct an ophthalmic exam including visual acuity and slit lamp exam prior to initiation of ELAHERE, every other cycle for the first cycles, and as clinically indicated [see Dosage and Administration (2.3)]. Administer prophylactic artificial tears and ophthalmic topical steroids [see Dosage and Administration (2.3) and Warnings and Precautions (5.1)]. Withhold ELAHERE for ocular toxicities until improvement and resume at the same or reduced dose [see Dosage and Administration (2.4) and Warnings and Precautions (5.1)]. Discontinue ELAHERE for Grade ocular toxicities [see Dosage and Administration (2.4) and Warnings and Precautions (5.1)]. ELAHERE can cause severe ocular toxicities, including visual impairment, keratopathy, dry eye, photophobia, eye pain, and uveitis [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)]. Conduct an ophthalmic exam including visual acuity and slit lamp exam prior to initiation of ELAHERE, every other cycle for the first cycles, and as clinically indicated [see Dosage and Administration (2.3)]. Administer prophylactic artificial tears and ophthalmic topical steroids [see Dosage and Administration (2.3) and Warnings and Precautions (5.1)]. Withhold ELAHERE for ocular toxicities until improvement and resume at the same or reduced dose [see Dosage and Administration (2.4) and Warnings and Precautions (5.1)]. Discontinue ELAHERE for Grade ocular toxicities [see Dosage and Administration (2.4) and Warnings and Precautions (5.1)]. WARNING: OCULAR TOXICITYSee full prescribing information for complete boxed warning.ELAHERE can cause severe ocular toxicities, including visual impairment, keratopathy, dry eye, photophobia, eye pain, and uveitis. (5.1, 6.1)Conduct an ophthalmic exam including visual acuity and slit lamp exam prior to initiation of ELAHERE, every other cycle for the first cycles, and as clinically indicated. (2.3)Administer prophylactic artificial tears and ophthalmic topical steroids. (2.3, 5.1)Withhold ELAHERE for ocular toxicities until improvement and resume at the same or reduced dose. (2.4, 5.1)Discontinue ELAHERE for Grade ocular toxicities. (2.4, 5.1). ELAHERE can cause severe ocular toxicities, including visual impairment, keratopathy, dry eye, photophobia, eye pain, and uveitis. (5.1, 6.1). Conduct an ophthalmic exam including visual acuity and slit lamp exam prior to initiation of ELAHERE, every other cycle for the first cycles, and as clinically indicated. (2.3). Administer prophylactic artificial tears and ophthalmic topical steroids. (2.3, 5.1). Withhold ELAHERE for ocular toxicities until improvement and resume at the same or reduced dose. (2.4, 5.1). Discontinue ELAHERE for Grade ocular toxicities. (2.4, 5.1).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenicity studies have not been conducted with mirvetuximab soravtansine-gynx or DM4.DM4 and the metabolite, S-methyl DM4, were clastogenic in the in vivo rat bone marrow micronucleus study. DM4 and S-methyl DM4 were not mutagenic in the bacterial reverse mutation (Ames) assay.Fertility studies have not been conducted with mirvetuximab soravtansine-gynx or DM4.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Mirvetuximab soravtansine-gynx is an antibody-drug conjugate (ADC). The antibody is chimeric IgG1 directed against folate receptor alpha (FR). The small molecule, DM4, is microtubule inhibitor attached to the antibody via cleavable linker. Upon binding to FR, mirvetuximab soravtansine-gynx is internalized followed by intracellular release of DM4 via proteolytic cleavage. DM4 disrupts the microtubule network within the cell, resulting in cell cycle arrest and apoptotic cell death.. 12.2 Pharmacodynamics. Exposure-Response RelationshipsAn exposure-response relationship between mirvetuximab soravtansine-gynx and overall response rates was observed. Higher incidence of Grade >=2 ocular adverse reactions and Grade >=2 peripheral neuropathy occurred with increasing mirvetuximab soravtansine-gynx exposure.. Cardiac ElectrophysiologyAt the approved recommended dose, ELAHERE did not cause large mean increases (>10 msec) in the QTc interval.. 12.3 Pharmacokinetics. The pharmacokinetics were characterized after patients were administered mirvetuximab soravtansine-gynx 0.161 mg/kg to 8.71 mg/kg adjusted ideal body weight (AIBW) dosages, (0.0268 times to 1.45 times the approved recommended dosage of mg/kg AIBW), unless otherwise noted.Table summarizes the exposure parameters of mirvetuximab soravtansine-gynx, unconjugated DM4, and its metabolite S-methyl-DM4 following administration after the first cycle (3-weeks) of mirvetuximab soravtansine-gynx mg/kg to patients. Peak mirvetuximab soravtansine-gynx concentrations were observed near the end of intravenous infusion, while peak unconjugated DM4 concentrations were observed on the second day after administration of mirvetuximab soravtansine-gynx, and the peak S-methyl-DM4 concentrations were observed approximately days after administration of mirvetuximab soravtansine-gynx. Steady state concentrations of mirvetuximab soravtansine-gynx, DM4, and S-methyl-DM4 were reached after treatment cycle. Accumulation of the mirvetuximab soravtansine-gynx, DM4, and S-methyl-DM4 was minimal following repeat administration of mirvetuximab soravtansine-gynx.Table 6: Exposure Parameters of Mirvetuximab Soravtansine-gynx, Unconjugated DM4, and S-methyl DM4 After First Treatment Cycle of mg/kg of Mirvetuximab Soravtansine-gynxMirvetuximab Soravtansine-gynxMean (+-SD)Unconjugated DM4Mean (+-SD)S-methyl-DM4Mean (+-SD)Cmax maximum concentration, AUCtau area under the concentration vs. time curve over the dosing interval (21 days).Cmax 137.3 (+-62.3) ug/mL4.11 (+-2.29) ng/mL6.98 (+-6.79) ng/mLAUCtau 20.65 (+-6.84) hmg/mL530 (+-245) hng/mL1848 (+-1585) hng/mL. DistributionThe mean (+-SD) steady state volume of distribution of mirvetuximab soravtansine-gynx was 2.63 (+-2.98) L.Human plasma protein binding of DM4 and S-methyl DM4 was >99%, in vitro.. EliminationTotal plasma clearance (geometric mean [CV%]) of mirvetuximab soravtansine-gynx was 18.9 mL/hour (51.9%). The geometric mean terminal phase half-life of mirvetuximab soravtansine-gynx after the first dose was 4.8 days leading to steady state at approximately 24 days. For the unconjugated DM4, the total plasma clearance (geometric mean [CV%]) was 13.8 L/hour (31.1%) and the geometric mean terminal phase half-life was 2.8 days. For S-methyl-DM4, the total plasma clearance (geometric mean [CV%]) was 4.3 L/hour (63.6%) and the geometric mean terminal phase half-life was 5.0 days.. MetabolismThe monoclonal antibody portion of mirvetuximab soravtansine-gynx is expected to be metabolized into small peptides by catabolic pathways. Unconjugated DM4 and S-methyl-DM4 undergo metabolism by CYP3A4. In human plasma, DM4 and S-methyl DM4 were identified as the main circulating metabolites, accounting for approximately 0.4% and 1.4% of mirvetuximab soravtansine-gynx AUCs, respectively.. ExcretionS-methyl DM4 and DM4-sulfo-SPDB-lysine were detected in urine within 24 hours of infusion as the main metabolites.. Specific PopulationsNo clinically significant differences in the pharmacokinetics of mirvetuximab soravtansine-gynx were observed based on age (34 to 89 years), body weight (36 to 136 kg), mild hepatic impairment (total bilirubin <=ULN and any AST >ULN or total bilirubin >1 to 1.5 times ULN and any AST), or mild to moderate renal impairment (CLcr >=30 and <90 mL/min).The pharmacokinetics of ELAHERE in patients with moderate to severe hepatic impairment (total bilirubin >1.5 ULN with any AST) or severe renal impairment (CLcr 15 to 30 mL/min) is unknown.. Drug Interaction Studies. Clinical studies and model informed approachesNo clinical studies evaluating the drug-drug interaction potential of mirvetuximab soravtansine-gynx have been conducted.However, in clinical trials, there were no differences in exposure between patients who received concomitant weak or moderate CYP3A4 inhibitors or P-glycoprotein (P-gp) inhibitors and those who did not.. In Vitro Studies. Cytochrome P450 (CYP) Enzymes: Unconjugated DM4 is time-dependent inhibitor of CYP3A4. Unconjugated DM4 and S-methyl DM4 are not direct inhibitors of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A. DM4 and S-methyl DM4 are not inducers of CYP1A2, CYP2B6, or CYP3A4.. Transporter Systems: Unconjugated DM4 and S-methyl DM4 are substrates of P-gp but are not inhibitors of P-gp.. 12.6 Immunogenicity. As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation against mirvetuximab soravtansine-gynx is highly dependent on the sensitivity and specificity of the assay. The observed incidence of anti-drug antibodies (including neutralizing antibody) is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies to mirvetuximab soravtansine-gynx in other studies.With median duration of treatment of 4.3 months in Studies 0417, 0401, and 0403, total of 55/423 (13%) ovarian cancer patients treated with mirvetuximab soravtansine-gynx at mg/kg AIBW had at least post-baseline positive sample for anti-mirvetuximab soravtansine-gynx antibodies. Of those patients, 28/423 patients (7%) had developed treatment-emergent ADA and 3/423 patients (0.7%) had treatment-enhanced ADA. Neutralizing antibodies were detected in 24/423 (6%) of patients.Because of the low occurrence of anti-mirvetuximab soravtansine-gynx antibodies, the effect of these antibodies on the pharmacokinetics, efficacy, and/or safety of mirvetuximab soravtansine-gynx is unknown.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. The efficacy of ELAHERE was evaluated in Study 0417 (NCT04296890), single-arm trial of patients with FR positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer (n=106). Patients were permitted to receive up to three prior lines of systemic therapy. All patients were required to have received prior bevacizumab. The trial enrolled patients whose tumors were positive for FR expression as determined by the VENTANA FOLR1 (FOLR1-2.1) RxDx Assay. Patients were excluded if they had corneal disorders, ocular conditions requiring ongoing treatment, Grade >1 peripheral neuropathy, or noninfectious interstitial lung disease.Patients received ELAHERE mg/kg (based on adjusted ideal body weight) as an intravenous infusion every weeks until disease progression or unacceptable toxicity. Tumor response assessments occurred every weeks for the first 36 weeks and every 12 weeks thereafter.The major efficacy outcome measures were investigator-assessed overall response rate (ORR) and duration of response (DOR) evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1.The efficacy evaluable population included 104 patients with platinum-resistant disease, who had measurable disease, and received at least one dose of ELAHERE. In these 104 patients, the median age was 62 years (range: 35 to 85); 96% were White, 2% were Asian, and 2% did not have race reported. Two percent of patients were Hispanic or Latino. All patients had an ECOG PS of (57%) or (43%). Ten percent of patients had received prior line of systemic therapy, 39% of patients had received prior lines of systemic therapy, and 50% of patients had received prior lines of systemic therapy. All patients had received prior bevacizumab and 47% had received prior PARP inhibitor.Efficacy results for Study 0417 are summarized in Table 7.Table 7: Efficacy Results in Study 0417ELAHERE(N=104)Confirmed Overall Response RateInvestigator assessment.(95% CI)31.7%(22.9, 41.6) Complete response rate4.8% Partial response rate26.9%Duration of ResponseN=33 Median duration of response, months (95% CI)6.9(5.6, 9.7)Response assessment results using independent radiology review were consistent with investigator assessment.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The pooled safety population described in WARNINGS AND PRECAUTIONS reflect exposure to ELAHERE in 464 patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer at mg/kg AIBW administered intravenously once every weeks until disease progression or unacceptable toxicity in Study 0417; Study 0403 (NCT02631876), and Study 0401 (NCT01609556). The median duration of treatment was 4.3 months (range: 0.7 to 30.4).. Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer. Study 0417The safety of ELAHERE was evaluated in Study 0417, single-arm, open-label study in patients (n=106) with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer [see Clinical Studies (14)]. Patients received ELAHERE mg/kg AIBW once every weeks until disease progression or unacceptable toxicity. The median duration of treatment was 4.2 months (range: 0.7 to 13.3).Serious adverse reactions occurred in 31% of patients. The most common (>=2%) serious adverse reactions were intestinal obstruction (8%), ascites (4%), infection (3%), and pleural effusion (3%). Fatal adverse reactions occurred in 2% of patients, including small intestinal obstruction (1%) and pneumonitis (1%).Permanent discontinuation of ELAHERE due to adverse reactions occurred in 11% of patients. 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).Dosage delays of ELAHERE due to an adverse reaction occurred in 39% of patients treated with ELAHERE. Adverse reactions which required dosage delays in >=3% of patients included visual impairment (15%), keratopathy (11%), neutropenia (6%), dry eye (5%), cataracts (3%), and increased gamma-glutamyltransferase (3%).Dose reductions of ELAHERE due to an adverse reaction occurred in 20% of patients. Adverse reactions which required dose reductions in >=3% of patients included visual impairment (9%) and keratopathy (7%).The most common (>=20%) adverse reactions, including laboratory abnormalities, were vision impairment, fatigue, increased aspartate aminotransferase, nausea, increased alanine aminotransferase, keratopathy, abdominal pain, decreased lymphocytes, peripheral neuropathy, diarrhea, decreased albumin, constipation, increased alkaline phosphatase, dry eye, decreased magnesium, decreased leukocytes, decreased neutrophils, and decreased hemoglobin.Table summarizes the adverse reactions (>=10%) in patients treated with ELAHERE in Study 0417.Table 4: Adverse Reactions (>=10%) in Patients with Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer Who Received ELAHERE in Study 0417Adverse ReactionAll GradesN=106(%)Grade 3-4N=106(%) Fatigue includes fatigue and asthenia.Eye disordersVision impairmentVisual Impairment includes vision blurred, vitreous floaters, visual acuity reduced, diplopia, presbyopia, accommodation disorder, visual impairment, and refraction disorder. 507KeratopathyKeratopathy includes corneal disorder, corneal epithelial microcysts, corneal epithelial defect, keratitis, keratopathy, corneal deposits, and punctate keratitis. 379Dry eyeDry eye includes dry eye and lacrimation increased. 272Cataract183Photophobia170Eye PainEye pain includes eye pain and ocular discomfort. 100General disordersFatigue493Gastrointestinal disordersNausea400Abdominal PainAbdominal pain includes abdominal pain, abdominal pain upper, abdominal pain lower, abdominal discomfort. 367Diarrhea313Constipation301Vomiting190Abdominal distension110Nervous system disordersPeripheral neuropathyPeripheral neuropathy includes neuropathy peripheral, peripheral sensory neuropathy, peripheral motor neuropathy, paresthesia, hypoesthesia, polyneuropathy, and neurotoxicity. 332Metabolism and nutrition disordersDecreased appetite181Musculoskeletal and connective tissue disordersArthralgia170Myalgia100Respiratory, thoracic, and mediastinal disordersDyspneaDyspnea includes dyspnea and exertional dyspnea. 120Clinically relevant adverse reactions occurring in <10% of patients who received ELAHERE in Study 0417 included infusion related reactions/hypersensitivity (9%), pneumonitis (8%), thrombocytopenia (5%), and uveitis (1%).Table summarizes the laboratory abnormalities in Study 0417.Table 5: Select Laboratory Abnormalities >=10% for All Grades, or >=2% for Grades 3-4 in Patients Who Received ELAHERELaboratory AbnormalityELAHEREThe denominator used to calculate the rate varied from 98 to 101 based on the number of patients with baseline value and at least one post-treatment value. All Grades(%)Grade 3-4(%)Liver Function TestsIncreased aspartate aminotransferase502Increased alanine aminotransferase392Increased alkaline phosphatase301Hematology Decreased lymphocytes357Decreased leukocytes261Decreased neutrophils263Decreased hemoglobin253Decreased platelets182ChemistryDecreased albumin311Decreased magnesium272Increased creatinine160Decreased potassium154.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. None.. None. (4). None. (4).

DESCRIPTION SECTION.

11 DESCRIPTION. Mirvetuximab soravtansine-gynx is folate receptor alpha (FR)-directed antibody-drug conjugate (ADC) consisting of three components: 1) an anti-FR monoclonal antibody of IgG1 subtype 2) the small molecule anti-tubulin agent DM4 (a maytansine derivative) and 3) linker, sulfo-SPDB (1-(2,5-dioxopyrrolidin-1-yl)oxy-1-oxo-4-(pyridin-2-yldisulfanyl)butane-2-sulfonic acid) that covalently attaches DM4 to the mirvetuximab antibody. Mirvetuximab soravtansine-gynx has an approximate molecular weight of 150 kDa. An average of 3.4 molecules of DM4 are attached to each antibody molecule. Mirvetuximab soravtansine-gynx is produced by chemical conjugation of the antibody and small molecule components. The antibody is produced by mammalian (Chinese hamster ovary) cells, and the small molecule components are produced by chemical synthesis.Mirvetuximab soravtansine-gynx has the following structure:ELAHERE (mirvetuximab soravtansine-gynx) injection is supplied as sterile, preservative-free, clear to slightly opalescent, colorless solution containing 100 mg/20 mL of mirvetuximab soravtansine-gynx in single-dose vials. Each mL of solution contains mg of mirvetuximab soravtansine-gynx, and glacial acetic acid (0.22 mg), polysorbate 20 (0.1 mg), sodium acetate (0.53 mg), sucrose (90 mg), and Water for Injection. The pH is approximately 5.0.The ELAHERE vial stoppers are not made with natural rubber latex.. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Administer ELAHERE as an intravenous infusion only after dilution in 5% Dextrose Injection, USP. ELAHERE is incompatible with normal saline. (2.5)The recommended dose of ELAHERE is mg/kg adjusted ideal body weight administered as an intravenous infusion every weeks until disease progression or unacceptable toxicity. (2.2)Premedicate with corticosteroid, antihistamine, and antipyretic. (2.3)Premedicate with an antiemetic, ophthalmic topical steroids, and lubricating eye drops. (2.3, 5.1)See full Prescribing Information for preparation and administration instructions and dose modifications for adverse reactions. (2). Administer ELAHERE as an intravenous infusion only after dilution in 5% Dextrose Injection, USP. ELAHERE is incompatible with normal saline. (2.5). The recommended dose of ELAHERE is mg/kg adjusted ideal body weight administered as an intravenous infusion every weeks until disease progression or unacceptable toxicity. (2.2). Premedicate with corticosteroid, antihistamine, and antipyretic. (2.3). Premedicate with an antiemetic, ophthalmic topical steroids, and lubricating eye drops. (2.3, 5.1). See full Prescribing Information for preparation and administration instructions and dose modifications for adverse reactions. (2). 2.1 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 FR tumor expression [see Indications Usage (1) and Clinical Studies (14)] using an FDA-approved test.Information on FDA-approved tests for the measurement of FR tumor expression is available at http://www.fda.gov/CompanionDiagnostics.. 2.2 Recommended Dosage. The recommended dose of ELAHERE is mg/kg adjusted ideal body weight (AIBW) administered once every weeks (21-day cycle) as an intravenous infusion until disease progression or unacceptable toxicity [see Dosage and Administration (2.5)].The total dose of ELAHERE is calculated based on each patients AIBW using the following formula:AIBW Ideal Body Weight (IBW [kg]) 0.4(Actual weight [kg] IBW)Female IBW (kg) 0.9height(cm) 92. 2.3 Premedication and Required Eye Care. PremedicationAdminister the premedications in Table prior to each infusion of ELAHERE to reduce the incidence and severity of infusion related reactions (IRRs), nausea, and vomiting.Table 1: Premedication Prior to Each ELAHERE InfusionPremedicationRoute of AdministrationExamples (or equivalent)Administration Time Prior to ELAHERE InfusionCorticosteroidintravenousdexamethasone 10 mgAt least 30 minutes priorAntihistamineoral or intravenousdiphenhydramine 25 mg to 50 mgAntipyreticoral or intravenousacetaminophen 325 mg to 650 mgAntiemeticoral or intravenous5-HT3 serotonin receptor antagonist or appropriate alternativesBefore each dose and thereafter as neededConsider additional premedications including corticosteroids the day prior to ELAHERE administration for patients who experienced IRRs.. Ophthalmic Exams and Premedication. Ophthalmic exam: Conduct an ophthalmic exam including visual acuity and slit lamp exam prior to initiation of ELAHERE, every other cycle for the first 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 slit lamp. Administer one drop of ophthalmic topical steroids in each eye times daily starting the day prior to each infusion until day 4; then administer one drop in each eye times daily for days 5-8 of each cycle of ELAHERE [see Warnings and Precautions (5.1)]. 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 [see Warnings and Precautions (5.1)].. 2.4 Dosage Modifications. Table provides dose reductions and modifications for adverse reactions. Adjust the schedule of administration to maintain 3-week interval between doses.Table 2: Dosage Reduction ScheduleELAHERE Dose LevelsStarting Dose6 mg/kg AIBWFirst Dose Reduction5 mg/kg AIBWSecond Dose Reduction4 mg/kg AIBWPermanently discontinue in patients who cannot tolerate mg/kg AIBW. Table 3: Dosage Modifications for Adverse ReactionsAdverse ReactionSeverity of Adverse ReactionUnless otherwise specified, National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. Dosage ModificationKeratitis/Keratopathy[see Warnings and Precautions (5.1) and Adverse Reactions (6.1)]Nonconfluent superficial keratitisMonitor.Confluent superficial keratitis, cornea epithelial defect, or 3-line or more loss in best corrected visual acuityWithhold dose until improved or resolved, then maintain at same dose level or consider dose reduction.Corneal ulcer or stromal opacity or best corrected distance visual acuity 20/200 or worseWithhold dose until improved or resolved, then reduce by one dose level.Corneal perforationPermanently discontinue.Uveitis[see Warnings and Precautions (5.1) and Adverse Reactions (6.1)]Grade 1/ Rare cell in anterior chamberMonitor.Grade 2/ 1-2+ Cell or Flare in anterior chamberWithhold dose until Grade or less, then maintain dose at same dose level.Grade 3/ 3+ Cell or Flare in anterior chamberWithhold dose until Grade or less, then reduce dose by one dose level.Grade 4/ HypopyonPermanently discontinue.Pneumonitis[see Warnings and Precautions (5.2) and Adverse Reactions (6.1)]Grade 1Monitor.Grade 2Withhold dose until Grade or less, then resume at same dose level or one lower dose level at the discretion of the healthcare provider.Grade or 4Permanently discontinue.Peripheral Neuropathy[see Warnings and Precautions (5.3) and Adverse Reactions (6.1)]Grade 2Withhold dose until Grade or less, then reduce by one dose level.Grade or 4Permanently discontinue.Infusion-Related Reactions/Hypersensitivity[see Adverse Reactions (6.1)]Grade 1Maintain infusion rate.Grade 2Interrupt 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 [see Dosage and Administration (2.5)]. Administer additional premedication for future cycles [see Dosage and Administration (2.3)]. Grade or 4Immediately stop infusion and administer supportive treatment.Advise patient to seek emergency treatment and immediately notify their healthcare provider if the infusion-related symptoms recur.Permanently discontinue.Other Adverse Reactions[see Adverse Reactions (6.1)]Grade 3Withhold dose until Grade or less, then resume at one lower dose level.Grade 4Permanently discontinue.. 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 [see Dosage and Administration (2.5)]. Administer additional premedication for future cycles [see Dosage and Administration (2.3)]. Immediately stop infusion and administer supportive treatment.. Advise patient to seek emergency treatment and immediately notify their healthcare provider if the infusion-related symptoms recur.. Permanently discontinue.. 2.5 Instructions for Preparation and Administration. PreparationELAHERE is hazardous drug. Follow applicable special handling and disposal procedures1.Calculate the dose (mg) (based on the patients AIBW), total volume (mL) of solution required, and the number of vials of ELAHERE needed [see Recommended Dosage (2.2) and Dose Modifications (2.4)]. More than one vial will be needed for 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 clear to slightly opalescent, colorless solution.Gently swirl and inspect each vial prior to withdrawing the calculated dose volume of ELAHERE for subsequent further dilution. Do not shake the vial.Using aseptic technique, withdraw the calculated dose volume of ELAHERE for subsequent further dilution.ELAHERE contains no preservatives and is intended for single-dose only. Discard any unused drug remaining in the vial.. ELAHERE is hazardous drug. Follow applicable special handling and disposal procedures1.. Calculate the dose (mg) (based on the patients AIBW), total volume (mL) of solution required, and the number of vials of ELAHERE needed [see Recommended Dosage (2.2) and Dose Modifications (2.4)]. More than one vial will be needed for 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 clear to slightly opalescent, colorless solution.. Gently swirl and inspect each vial prior to withdrawing the calculated dose volume of ELAHERE for subsequent further dilution. Do not shake the vial.. Using aseptic technique, withdraw the calculated dose volume of ELAHERE for subsequent further dilution.. ELAHERE contains no preservatives and is intended for single-dose only. Discard any unused drug remaining in the vial.. DilutionELAHERE must be diluted prior to administration with 5% Dextrose Injection, USP to final concentration of mg/mL to 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 prefilled intravenous bag or add the calculated volume of 5% Dextrose Injection, USP to 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 [(18C to 25C (64.4F to 77F)] for no more than hours (including infusion time), or under refrigeration at 2C to 8C (36F to 46F) for no more than 12 hours. If refrigerated, allow the infusion bag to reach room temperature prior to administration. After refrigeration, administer diluted infusion solutions within hours (including infusion time).Do not freeze prepared infusion solution.. ELAHERE must be diluted prior to administration with 5% Dextrose Injection, USP to final concentration of mg/mL to 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 prefilled intravenous bag or add the calculated volume of 5% Dextrose Injection, USP to 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 [(18C to 25C (64.4F to 77F)] for no more than hours (including infusion time), or under refrigeration at 2C to 8C (36F to 46F) for no more than 12 hours. If refrigerated, allow the infusion bag to reach room temperature prior to administration. After refrigeration, administer diluted infusion solutions within hours (including infusion time).. Do not freeze prepared infusion solution.. AdministrationInspect the ELAHERE intravenous infusion bag visually for particulate matter and discoloration prior to administration.Administer pre-medications prior to ELAHERE administration [see Premedication and Prophylactic Regimen (2.3)].Administer ELAHERE as an intravenous infusion only, using 0.2 or 0.22 um polyethersulfone (PES) in-line filter. Do not substitute other membrane materials.Administer the initial dose as an intravenous infusion at the rate of mg/min. If well tolerated after 30 minutes at mg/min, the infusion rate can be increased to mg/min. If well tolerated after 30 minutes at mg/min, the infusion rate can be increased to 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 maximum infusion rate of 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.. Inspect the ELAHERE intravenous infusion bag visually for particulate matter and discoloration prior to administration.. Administer pre-medications prior to ELAHERE administration [see Premedication and Prophylactic Regimen (2.3)].. Administer ELAHERE as an intravenous infusion only, using 0.2 or 0.22 um polyethersulfone (PES) in-line filter. Do not substitute other membrane materials.. Administer the initial dose as an intravenous infusion at the rate of mg/min. If well tolerated after 30 minutes at mg/min, the infusion rate can be increased to mg/min. If well tolerated after 30 minutes at mg/min, the infusion rate can be increased to 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 maximum infusion rate of 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.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Injection: 100 mg/20 mL (5 mg/mL) clear to slightly opalescent, colorless solution in single-dose vial.. Injection: 100 mg/20 mL (5 mg/mL) in single-dose vial. (3). Injection: 100 mg/20 mL (5 mg/mL) in single-dose vial. (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Strong CYP3A4 Inhibitors: Closely monitor for ELAHERE adverse reactions. (7.1). 7.1 Effects of Other Drugs on ELAHERE. Strong CYP3A4 InhibitorsDM4 is CYP3A4 substrate. Concomitant use of ELAHERE with strong CYP3A4 inhibitors may increase unconjugated DM4 exposure [see Clinical Pharmacology (12.3)], which may increase the risk of ELAHERE adverse reactions [see Adverse Reactions (6)]. Closely monitor patients for adverse reactions with ELAHERE when used concomitantly with strong CYP3A4 inhibitors [see Warnings and Precautions (5)].

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3 Females and Males of Reproductive Potential. ELAHERE can cause embryo-fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)].. Pregnancy TestingVerify pregnancy status in females of reproductive potential prior to initiating ELAHERE.. Contraception. Females: Advise females of reproductive potential to use effective contraception during treatment with ELAHERE and for months after the last dose.

GERIATRIC USE SECTION.

8.5 Geriatric Use. Of the 106 patients who were treated in Study 0417, 44% of patients were >=65 years old. Grade >=3 adverse reactions occurred in 49% of patients >=65 years and in 51% <65 years. No clinically meaningful differences in efficacy or safety were observed between patients >=65 years of age compared to younger patients.Population pharmacokinetic analysis indicates that age does not have clinically meaningful effect on the pharmacokinetics of ELAHERE [see Clinical Pharmacology (12.3)].

HEPATIC IMPAIRMENT SUBSECTION.

8.7 Hepatic Impairment. Avoid use of ELAHERE in patients with moderate or severe hepatic impairment (total bilirubin >1.5 ULN).No dosage adjustment of ELAHERE is recommended for patients with mild hepatic impairment (total bilirubin <=ULN and AST >ULN or total bilirubin >1 to 1.5 times ULN and any AST) [see Clinical Pharmacology (12.3)].

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. How SuppliedEach ELAHERE (mirvetuximab soravtansine-gynx) injection carton (NDC 72903-853-01) contains:One single-dose vial containing 100 mg of mirvetuximab soravtansine-gynx in 20 mL (5 mg/mL) of clear to slightly opalescent, colorless sterile solution.. One single-dose vial containing 100 mg of mirvetuximab soravtansine-gynx in 20 mL (5 mg/mL) of clear to slightly opalescent, colorless sterile solution.. Storage and HandlingStore ELAHERE vials upright in refrigerator at 2C to 8C (36F to 46F) until the time of preparation in the original carton to protect from light.Do not freeze or shake.ELAHERE is hazardous drug. Follow applicable special handling and disposal procedures1.

IMMUNOGENICITY.

12.6 Immunogenicity. As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation against mirvetuximab soravtansine-gynx is highly dependent on the sensitivity and specificity of the assay. The observed incidence of anti-drug antibodies (including neutralizing antibody) is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies to mirvetuximab soravtansine-gynx in other studies.With median duration of treatment of 4.3 months in Studies 0417, 0401, and 0403, total of 55/423 (13%) ovarian cancer patients treated with mirvetuximab soravtansine-gynx at mg/kg AIBW had at least post-baseline positive sample for anti-mirvetuximab soravtansine-gynx antibodies. Of those patients, 28/423 patients (7%) had developed treatment-emergent ADA and 3/423 patients (0.7%) had treatment-enhanced ADA. Neutralizing antibodies were detected in 24/423 (6%) of patients.Because of the low occurrence of anti-mirvetuximab soravtansine-gynx antibodies, the effect of these antibodies on the pharmacokinetics, efficacy, and/or safety of mirvetuximab soravtansine-gynx is unknown.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. ELAHERE(TM) is indicated for the treatment of adult patients with folate receptor-alpha (FR) 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 [see Dosage and Administration (2.1)].This indication is approved under accelerated approval based on tumor response rate and durability of response [see Clinical Studies (14)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial.. ELAHERE is folate receptor alpha (FR)-directed antibody and microtubule inhibitor conjugate indicated for the treatment of adult patients with FR 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. (1, 2.1)This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial. (1, 14).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Medication Guide).. Ocular DisordersInform patients about the need for eye exams before and during treatment with ELAHERE.Advise patients to contact their healthcare provider promptly if they experience any visual changes. Advise patients to use steroid eye drops and artificial tear substitutes [see Dosage and Administration (2.3) and Warnings and Precautions (5.1)].. PneumonitisAdvise patients to immediately report new or worsening respiratory symptoms [see Dosage and Administration (2.3) and Warnings and Precautions (5.2)].. Embryo-Fetal ToxicityAdvise pregnant women and females of reproductive potential of the potential risk to fetus. Advise female patients to inform their healthcare provider of known or suspected pregnancy [see Use in Specific Populations (5.4, 8.1, 8.3)].Advise females of reproductive potential to use effective contraception during treatment with ELAHERE and for months after the last dose [see Use in Specific Populations (8.1, 8.3)]. LactationAdvise women not to breastfeed during treatment with ELAHERE and for month after the last dose [see Use in Specific Populations (8.2)].

LACTATION SECTION.

8.2 Lactation. Risk SummaryThere are no data on the presence of mirvetuximab soravtansine-gynx in human milk or the effects on the breastfed child or milk production. Because of the potential for serious adverse reactions in breastfed child, advise women not to breastfeed during treatment with ELAHERE and for month after the last dose.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Mirvetuximab soravtansine-gynx is an antibody-drug conjugate (ADC). The antibody is chimeric IgG1 directed against folate receptor alpha (FR). The small molecule, DM4, is microtubule inhibitor attached to the antibody via cleavable linker. Upon binding to FR, mirvetuximab soravtansine-gynx is internalized followed by intracellular release of DM4 via proteolytic cleavage. DM4 disrupts the microtubule network within the cell, resulting in cell cycle arrest and apoptotic cell death.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenicity studies have not been conducted with mirvetuximab soravtansine-gynx or DM4.DM4 and the metabolite, S-methyl DM4, were clastogenic in the in vivo rat bone marrow micronucleus study. DM4 and S-methyl DM4 were not mutagenic in the bacterial reverse mutation (Ames) assay.Fertility studies have not been conducted with mirvetuximab soravtansine-gynx or DM4.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 20 mL Vial Carton. Rx OnlyNDC: 72903-853-01ELAHERE(TM)mirvetuximab soravtansine-gynxInjection100 mg/20 mL(5 mg/mL)For Intravenous Infusion afterDilution in 5% Dextrose Injection, USPSingle-dose vial.Discard unused portionWarning: Hazardous DrugDispense the enclosedMedication Guide to each patient.immunogen(R) PRINCIPAL DISPLAY PANEL 20 mL Vial Carton.

PEDIATRIC USE SECTION.

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

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Exposure-Response RelationshipsAn exposure-response relationship between mirvetuximab soravtansine-gynx and overall response rates was observed. Higher incidence of Grade >=2 ocular adverse reactions and Grade >=2 peripheral neuropathy occurred with increasing mirvetuximab soravtansine-gynx exposure.. Cardiac ElectrophysiologyAt the approved recommended dose, ELAHERE did not cause large mean increases (>10 msec) in the QTc interval.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The pharmacokinetics were characterized after patients were administered mirvetuximab soravtansine-gynx 0.161 mg/kg to 8.71 mg/kg adjusted ideal body weight (AIBW) dosages, (0.0268 times to 1.45 times the approved recommended dosage of mg/kg AIBW), unless otherwise noted.Table summarizes the exposure parameters of mirvetuximab soravtansine-gynx, unconjugated DM4, and its metabolite S-methyl-DM4 following administration after the first cycle (3-weeks) of mirvetuximab soravtansine-gynx mg/kg to patients. Peak mirvetuximab soravtansine-gynx concentrations were observed near the end of intravenous infusion, while peak unconjugated DM4 concentrations were observed on the second day after administration of mirvetuximab soravtansine-gynx, and the peak S-methyl-DM4 concentrations were observed approximately days after administration of mirvetuximab soravtansine-gynx. Steady state concentrations of mirvetuximab soravtansine-gynx, DM4, and S-methyl-DM4 were reached after treatment cycle. Accumulation of the mirvetuximab soravtansine-gynx, DM4, and S-methyl-DM4 was minimal following repeat administration of mirvetuximab soravtansine-gynx.Table 6: Exposure Parameters of Mirvetuximab Soravtansine-gynx, Unconjugated DM4, and S-methyl DM4 After First Treatment Cycle of mg/kg of Mirvetuximab Soravtansine-gynxMirvetuximab Soravtansine-gynxMean (+-SD)Unconjugated DM4Mean (+-SD)S-methyl-DM4Mean (+-SD)Cmax maximum concentration, AUCtau area under the concentration vs. time curve over the dosing interval (21 days).Cmax 137.3 (+-62.3) ug/mL4.11 (+-2.29) ng/mL6.98 (+-6.79) ng/mLAUCtau 20.65 (+-6.84) hmg/mL530 (+-245) hng/mL1848 (+-1585) hng/mL. DistributionThe mean (+-SD) steady state volume of distribution of mirvetuximab soravtansine-gynx was 2.63 (+-2.98) L.Human plasma protein binding of DM4 and S-methyl DM4 was >99%, in vitro.. EliminationTotal plasma clearance (geometric mean [CV%]) of mirvetuximab soravtansine-gynx was 18.9 mL/hour (51.9%). The geometric mean terminal phase half-life of mirvetuximab soravtansine-gynx after the first dose was 4.8 days leading to steady state at approximately 24 days. For the unconjugated DM4, the total plasma clearance (geometric mean [CV%]) was 13.8 L/hour (31.1%) and the geometric mean terminal phase half-life was 2.8 days. For S-methyl-DM4, the total plasma clearance (geometric mean [CV%]) was 4.3 L/hour (63.6%) and the geometric mean terminal phase half-life was 5.0 days.. MetabolismThe monoclonal antibody portion of mirvetuximab soravtansine-gynx is expected to be metabolized into small peptides by catabolic pathways. Unconjugated DM4 and S-methyl-DM4 undergo metabolism by CYP3A4. In human plasma, DM4 and S-methyl DM4 were identified as the main circulating metabolites, accounting for approximately 0.4% and 1.4% of mirvetuximab soravtansine-gynx AUCs, respectively.. ExcretionS-methyl DM4 and DM4-sulfo-SPDB-lysine were detected in urine within 24 hours of infusion as the main metabolites.. Specific PopulationsNo clinically significant differences in the pharmacokinetics of mirvetuximab soravtansine-gynx were observed based on age (34 to 89 years), body weight (36 to 136 kg), mild hepatic impairment (total bilirubin <=ULN and any AST >ULN or total bilirubin >1 to 1.5 times ULN and any AST), or mild to moderate renal impairment (CLcr >=30 and <90 mL/min).The pharmacokinetics of ELAHERE in patients with moderate to severe hepatic impairment (total bilirubin >1.5 ULN with any AST) or severe renal impairment (CLcr 15 to 30 mL/min) is unknown.. Drug Interaction Studies. Clinical studies and model informed approachesNo clinical studies evaluating the drug-drug interaction potential of mirvetuximab soravtansine-gynx have been conducted.However, in clinical trials, there were no differences in exposure between patients who received concomitant weak or moderate CYP3A4 inhibitors or P-glycoprotein (P-gp) inhibitors and those who did not.. In Vitro Studies. Cytochrome P450 (CYP) Enzymes: Unconjugated DM4 is time-dependent inhibitor of CYP3A4. Unconjugated DM4 and S-methyl DM4 are not direct inhibitors of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A. DM4 and S-methyl DM4 are not inducers of CYP1A2, CYP2B6, or CYP3A4.. Transporter Systems: Unconjugated DM4 and S-methyl DM4 are substrates of P-gp but are not inhibitors of P-gp.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryBased on its mechanism of action, ELAHERE can cause embryo-fetal harm when administered to pregnant woman because it contains genotoxic compound (DM4) and affects actively dividing cells [see Clinical Pharmacology (12.1), Nonclinical Toxicology (13.1)]. Human immunoglobulin (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 drug-associated risk. No reproductive or developmental animal toxicity studies were conducted with mirvetuximab soravtansine-gynx. Advise patients of the potential risk to 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.. Data. Animal Data: No reproductive or developmental animal toxicity studies have been conducted with mirvetuximab soravtansine-gynx. 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.

REFERENCES SECTION.

15 REFERENCES. 1OSHA Hazardous Drugs. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html.

RENAL IMPAIRMENT SUBSECTION.

8.6 Renal Impairment. No dosage adjustment of ELAHERE is recommended for patients with mild to moderate renal impairment (CLcr 30 to 90 mL/min). The effect of severe renal impairment (CLcr 15 to 30 mL/min) or end-stage renal disease on ELAHERE is unknown [see Clinical Pharmacology (12.3)].

SPL MEDGUIDE SECTION.

MEDICATION GUIDE ELAHERE (el-ah-HERE)(mirvetuximab soravtansine-gynx)injection, for intravenous useThis Medication Guide has been approved by the U.S. Food and Drug Administration.Issued 11 2022 What is the most important information should know about ELAHEREELAHERE can cause serious side effects, including:Eye problems. Eye problems are common with ELAHERE and can also be severe. Tell your healthcare provider right away if you develop any eye problems during treatment with ELAHERE, including blurred vision, dry eyes, sensitivity to light, eye pain, or new or worsening vision changes.Your healthcare provider will send you to see an eye care professional to check your eyes before you start treatment with ELAHERE, during treatment with ELAHERE, and as needed for any worsening signs and symptoms of eye problems.Your healthcare provider will prescribe steroid eye drops and lubricating eye drops before you start and during your treatment with ELAHERE. You should use eye drops as directed by your healthcare provider.Do not wear contact lenses throughout your treatment with ELAHERE unless you are told to use them by your healthcare provider.See What are the possible side effects of ELAHERE for more information about side effects.What is ELAHEREELAHERE is prescription medicine used to treat adults with folate receptor-alpha positive ovarian cancer, fallopian tube cancer, or primary peritoneal cancer who:have not responded to or are no longer responding to treatment with platinum-based chemotherapy and have received to prior types of chemotherapy.Your healthcare provider will perform test to make sure that ELAHERE is right for you.It is not known if ELAHERE is safe and effective in children.Before receiving ELAHERE, tell your healthcare provider about all of your medical conditions, including if you:have vision or eye problems.have liver problems.are pregnant or plan to become pregnant. ELAHERE can harm your unborn baby. Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with ELAHERE. Females who are able to become pregnant: Your healthcare provider should do pregnancy test before you start treatment with ELAHERE.You should use an effective birth control (contraception) during treatment and for months after your last dose of ELAHERE. are breastfeeding or plan to breastfeed. It is not known if ELAHERE passes into your breast milk. Do not breastfeed during treatment and for month after your last dose of ELAHERE.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking certain other medicines during treatment with ELAHERE may cause side effects.How will receive ELAHEREELAHERE will be given to you by infusion into your vein (intravenous or IV).Before each dose of ELAHERE you will receive medicines to help prevent infusion related reactions, nausea, and vomiting.ELAHERE is usually given every weeks (21-day cycle). Your healthcare provider will decide how many cycles you need.What are the possible side effects of ELAHEREELAHERE can cause serious side effects, including:See What is the most important information should know about ELAHERE Lung problems (pneumonitis). ELAHERE can cause severe or life-threatening inflammation of the lungs that may lead to death. Tell your healthcare provider right away if you get new or worsening symptoms, including trouble breathing, shortness of breath, cough, or chest pain.Peripheral neuropathy. You may develop nerve problems called peripheral neuropathy during treatment with ELAHERE. Your healthcare provider will monitor you for signs and symptoms of nerve problems. Tell your healthcare provider if you get new or worsening numbness or tingling in your hands or feet or muscle weakness.The most common side effects of ELAHERE include:feeling tiredincreased liver enzymes in the bloodnauseastomach-area (abdominal) paindecreased red or white blood cell countsdiarrheadecreased albumin level in the bloodconstipationdecreased magnesium level in the bloodYour healthcare provider may change your dose of ELAHERE, delay treatment, or completely stop treatment if you have certain side effects.These are not all of the possible side effects of ELAHERE.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.General information about the safe and effective use of ELAHERE.Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. If you would like more information about ELAHERE, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about ELAHERE that is written for healthcare professionals.What are the ingredients in ELAHEREActive ingredient: mirvetuximab soravtansine-gynx Inactive ingredients: glacial acetic acid, polysorbate 20, sodium acetate, sucrose, Water for Injection.Manufactured by: ImmunoGen, Inc., Waltham, MA 02451U.S. License 2288ELAHERE(TM) is trademark owned by ImmunoGen, Inc. (C)2022 ImmunoGen, Inc. For more information, go to www.immunogen.com or call 1-833-486-4646.. Eye problems. Eye problems are common with ELAHERE and can also be severe. Tell your healthcare provider right away if you develop any eye problems during treatment with ELAHERE, including blurred vision, dry eyes, sensitivity to light, eye pain, or new or worsening vision changes.Your healthcare provider will send you to see an eye care professional to check your eyes before you start treatment with ELAHERE, during treatment with ELAHERE, and as needed for any worsening signs and symptoms of eye problems.Your healthcare provider will prescribe steroid eye drops and lubricating eye drops before you start and during your treatment with ELAHERE. You should use eye drops as directed by your healthcare provider.Do not wear contact lenses throughout your treatment with ELAHERE unless you are told to use them by your healthcare provider.. Your healthcare provider will send you to see an eye care professional to check your eyes before you start treatment with ELAHERE, during treatment with ELAHERE, and as needed for any worsening signs and symptoms of eye problems.. Your healthcare provider will prescribe steroid eye drops and lubricating eye drops before you start and during your treatment with ELAHERE. You should use eye drops as directed by your healthcare provider.. Do not wear contact lenses throughout your treatment with ELAHERE unless you are told to use them by your healthcare provider.. have not responded to or are no longer responding to treatment with platinum-based chemotherapy and have received to prior types of chemotherapy.. have vision or eye problems.. have liver problems.. are pregnant or plan to become pregnant. ELAHERE can harm your unborn baby. Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with ELAHERE. Females who are able to become pregnant: Your healthcare provider should do pregnancy test before you start treatment with ELAHERE.You should use an effective birth control (contraception) during treatment and for months after your last dose of ELAHERE. Your healthcare provider should do pregnancy test before you start treatment with ELAHERE.. You should use an effective birth control (contraception) during treatment and for months after your last dose of ELAHERE.. are breastfeeding or plan to breastfeed. It is not known if ELAHERE passes into your breast milk. Do not breastfeed during treatment and for month after your last dose of ELAHERE.. ELAHERE will be given to you by infusion into your vein (intravenous or IV).. Before each dose of ELAHERE you will receive medicines to help prevent infusion related reactions, nausea, and vomiting.. ELAHERE is usually given every weeks (21-day cycle). Your healthcare provider will decide how many cycles you need.. See What is the most important information should know about ELAHERE Lung problems (pneumonitis). ELAHERE can cause severe or life-threatening inflammation of the lungs that may lead to death. Tell your healthcare provider right away if you get new or worsening symptoms, including trouble breathing, shortness of breath, cough, or chest pain.. Peripheral neuropathy. You may develop nerve problems called peripheral neuropathy during treatment with ELAHERE. Your healthcare provider will monitor you for signs and symptoms of nerve problems. Tell your healthcare provider if you get new or worsening numbness or tingling in your hands or feet or muscle weakness.. feeling tired. increased liver enzymes in the blood. nausea. stomach-area (abdominal) pain. decreased red or white blood cell counts. diarrhea. decreased albumin level in the blood. constipation. decreased magnesium level in the blood.

SPL UNCLASSIFIED SECTION.

2.1 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 FR tumor expression [see Indications Usage (1) and Clinical Studies (14)] using an FDA-approved test.Information on FDA-approved tests for the measurement of FR tumor expression is available at http://www.fda.gov/CompanionDiagnostics.

STORAGE AND HANDLING SECTION.

Storage and HandlingStore ELAHERE vials upright in refrigerator at 2C to 8C (36F to 46F) until the time of preparation in the original carton to protect from light.Do not freeze or shake.ELAHERE is hazardous drug. Follow applicable special handling and disposal procedures1.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Advise not to breastfeed. (8.2)Moderate or severe hepatic impairment: Avoid use. (8.7). Lactation: Advise not to breastfeed. (8.2). Moderate or severe hepatic impairment: Avoid use. (8.7). 8.1 Pregnancy. Risk SummaryBased on its mechanism of action, ELAHERE can cause embryo-fetal harm when administered to pregnant woman because it contains genotoxic compound (DM4) and affects actively dividing cells [see Clinical Pharmacology (12.1), Nonclinical Toxicology (13.1)]. Human immunoglobulin (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 drug-associated risk. No reproductive or developmental animal toxicity studies were conducted with mirvetuximab soravtansine-gynx. Advise patients of the potential risk to 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.. Data. Animal Data: No reproductive or developmental animal toxicity studies have been conducted with mirvetuximab soravtansine-gynx. 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.. 8.2 Lactation. Risk SummaryThere are no data on the presence of mirvetuximab soravtansine-gynx in human milk or the effects on the breastfed child or milk production. Because of the potential for serious adverse reactions in breastfed child, advise women not to breastfeed during treatment with ELAHERE and for month after the last dose.. 8.3 Females and Males of Reproductive Potential. ELAHERE can cause embryo-fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)].. Pregnancy TestingVerify pregnancy status in females of reproductive potential prior to initiating ELAHERE.. Contraception. Females: Advise females of reproductive potential to use effective contraception during treatment with ELAHERE and for months after the last dose.. 8.4 Pediatric Use. Safety and effectiveness of ELAHERE have not been established in pediatric patients.. 8.5 Geriatric Use. Of the 106 patients who were treated in Study 0417, 44% of patients were >=65 years old. Grade >=3 adverse reactions occurred in 49% of patients >=65 years and in 51% <65 years. No clinically meaningful differences in efficacy or safety were observed between patients >=65 years of age compared to younger patients.Population pharmacokinetic analysis indicates that age does not have clinically meaningful effect on the pharmacokinetics of ELAHERE [see Clinical Pharmacology (12.3)].. 8.6 Renal Impairment. No dosage adjustment of ELAHERE is recommended for patients with mild to moderate renal impairment (CLcr 30 to 90 mL/min). The effect of severe renal impairment (CLcr 15 to 30 mL/min) or end-stage renal disease on ELAHERE is unknown [see Clinical Pharmacology (12.3)].. 8.7 Hepatic Impairment. Avoid use of ELAHERE in patients with moderate or severe hepatic impairment (total bilirubin >1.5 ULN).No dosage adjustment of ELAHERE is recommended for patients with mild hepatic impairment (total bilirubin <=ULN and AST >ULN or total bilirubin >1 to 1.5 times ULN and any AST) [see Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Pneumonitis: Withhold ELAHERE for persistent or recurrent Grade pneumonitis and consider dose reduction. Permanently discontinue ELAHERE for Grade or pneumonitis. (2.4, 5.2)Peripheral Neuropathy: Monitor patients for new or worsening peripheral neuropathy. Withhold dosage, dose reduce, or permanently discontinue ELAHERE based on the severity of peripheral neuropathy. (2.4, 5.3)Embryo-Fetal Toxicity: ELAHERE can cause fetal harm. Advise of the potential risk to fetus and to use effective contraception. (5.4, 8.1, 8.3). Pneumonitis: Withhold ELAHERE for persistent or recurrent Grade pneumonitis and consider dose reduction. Permanently discontinue ELAHERE for Grade or pneumonitis. (2.4, 5.2). Peripheral Neuropathy: Monitor patients for new or worsening peripheral neuropathy. Withhold dosage, dose reduce, or permanently discontinue ELAHERE based on the severity of peripheral neuropathy. (2.4, 5.3). Embryo-Fetal Toxicity: ELAHERE can cause fetal harm. Advise of the potential risk to fetus and to use effective contraception. (5.4, 8.1, 8.3). 5.1 Ocular Disorders. ELAHERE can cause severe ocular adverse reactions, including visual impairment, keratopathy (corneal disorders), dry eye, photophobia, eye pain, and uveitis.Ocular adverse reactions occurred in 61% of patients with ovarian cancer treated with ELAHERE. Nine percent (9%) of patients experienced Grade ocular adverse reactions, including visual impairment, keratopathy/keratitis (corneal disorders), dry eye, photophobia, and eye pain; and one patient (0.2%) experienced Grade keratopathy. The most common (>=5%) ocular adverse reactions were visual impairment (49%), keratopathy (36%), dry eye (26%), cataract (15%), photophobia (13%), and eye pain (12%) [see Adverse Reactions (6.1)].The median time to onset for first ocular adverse reaction was 1.2 months (range: 0.03 to 12.9). Of the patients who experienced ocular events, 49% had complete resolution and 39% had partial improvement (defined as decrease in severity by one or more grades from the worst grade) at last follow up. Ocular adverse reactions led to permanent discontinuation of ELAHERE in 0.6% of patients.Premedication and use of lubricating and ophthalmic topical steroid eye drops during treatment with ELAHERE are recommended [see Dosage and Administration (2.3)]. Advise patients to avoid use of contact lenses during treatment with ELAHERE unless directed by healthcare provider.Refer patients to an eye care professional for an ophthalmic exam including visual acuity and slit lamp exam prior to treatment initiation, every other cycle for the first cycles, and as clinically indicated. Promptly refer patients to an eye care professional for any new or worsening ocular signs and symptoms.Monitor for ocular toxicity and withhold, reduce, or permanently discontinue ELAHERE based on severity and persistence of ocular adverse reactions. [see Dosage and Administration (2.4)]. 5.2 Pneumonitis. Severe, life-threatening, or fatal interstitial lung disease (ILD), including pneumonitis, can occur in patients treated with ELAHERE.Pneumonitis occurred in 10% of patients treated with ELAHERE, including 0.8% with Grade events, and patient (0.2%) with Grade event. One patient (0.2%) died due to respiratory failure in the setting of pneumonitis and lung metastases. Pneumonitis resulted in ELAHERE dose reduction in 1%, dose interruptions in 3%, and permanent discontinuation in 3% of patients.Monitor patients for pulmonary signs and symptoms of pneumonitis, which may include hypoxia, cough, dyspnea, or interstitial infiltrates on radiologic exams. Infectious, neoplastic, and other causes for such symptoms should be excluded through appropriate investigations. Withhold ELAHERE for patients who develop persistent or recurrent Grade pneumonitis until symptoms resolve to <= Grade and consider dose reduction. Permanently discontinue ELAHERE in all patients with Grade or pneumonitis [see Dosage and Administration (2.4)]. Patients who are asymptomatic may continue dosing of ELAHERE with close monitoring.. 5.3 Peripheral Neuropathy. Peripheral neuropathy occurred in 36% of patients with ovarian cancer treated with ELAHERE across clinical trials; 2% of patients experienced Grade peripheral neuropathy. Peripheral neuropathy adverse reactions included peripheral neuropathy (19%), peripheral sensory neuropathy (9%), paraesthesia (6%), neurotoxicity (3%), hypoaesthesia (2%), peripheral motor neuropathy (1%), neuralgia (0.4%), polyneuropathy (0.2%) and oral hypoesthesia (0.2%).The median time to onset of peripheral neuropathy was 1.3 months (range 0.03 to 29.1). Of the patients who experienced peripheral neuropathy, 28% had complete resolution and 13% had partial improvement (defined as decrease in severity by one or more grades from the worst grade) at last follow up. Peripheral neuropathy led to discontinuation of ELAHERE in 0.4% of patients.Monitor patients for signs and symptoms of neuropathy, such as paresthesia, tingling or burning sensation, neuropathic pain, muscle weakness, or dysesthesia. For patients experiencing new or worsening peripheral neuropathy, withhold dosage, dose reduce, or permanently discontinue ELAHERE based on the severity of peripheral neuropathy [see Dosage and Administration (2.4)]. 5.4 Embryo-Fetal Toxicity. Based on its mechanism of action, ELAHERE can cause embryo-fetal harm when administered to pregnant woman because it contains genotoxic compound (DM4) and affects actively dividing cells.Advise pregnant women of the potential risk to fetus. Advise females of reproductive potential to use effective contraception during treatment with ELAHERE and for months after the last dose [see Use in Specific Populations (8.1, 8.3)].