DRUG INTERACTIONS-(summary)

 Strong CYP3A4 Inhibitors: Closely monitor for ELAHERE adverse reactions. 

 DRUG INTERACTIONS (details)

1. 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.

BRIEF SUMMARY

MIRVENTUXIMAB- (Nov 2022)

Indn-   To treat patients with recurrent Ovarian cancer  that is resistent to platinum therapy     

Comp-   Injection: 100 mg/20 mL (5 mg/mL) in a single-dose vial.  Administer as an intravenous infusion only after dilution in 5% Dextrose Injection, USP. is incompatible with normal saline

ADR- The most common (=20 %) adverse reactions, including laboratory abnormalities, were vision impairment, fatigue, increased aspartate aminotransferase, nausea, increased alanine aminotransferase, keratopathy, abdominal pain.

CI- None.

WARNINGS -                                                                                                    Pneumonitis:                                                                                                             Withhold  for persistent or recurrent Grade 2 pneumonitis and consider dose reduction. Permanently discontinue  for Grade 3 or 4 pneumonitis.

 Peripheral Neuropathy: Monitor patients for new or worsening peripheral neuropathy. Withhold dosage, dose reduce, or permanently discontinue  based on the severity of peripheral neuropathy.

 Embryo-Fetal Toxicity:  can cause fetal harm. Advise of the potential risk to a fetus and to use effective contraception.

Pat Inform-

Ocular Disorders Inform patients about the need for eye exams before and during treatment with . 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

Pneumonitis -Advise patients to immediately report new or worsening respiratory symptoms.

Embryo-Fetal Toxicity- Advise pregnant women and females of reproductive potential of the potential risk to a fetus.

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U.S.  APPROVED DRUGS SURING 2022                                        

Serial No 29

Name-        ELAHERE

Active  Ingredient -  Mirvetuximab Soravtansine -gymx

Pharmacological clssificiation-        To treat patients with recurrent Ovarian                                                                           cancer  that is resistent to platinum therapy                                                                                                                                                                                                                                                                                              

 Date of Approved-         11/14/2022 

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use                                 ELAHERE safely and effectively.                                                                                  See full prescribing information for ELAHERE. ELAHERETM (mirvetuximab soravtansine-gynx) injection, for intravenous use

Initial U.S. Approval: 2022

WARNING: OCULAR TOXICITY                                                                                   See full prescribing information for complete boxed warning.

• ELAHERE can cause severe ocular toxicities, including visual impairment, keratopathy, dry eye, photophobia, eye pain, and uveitis.

 • 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.

 • Administer prophylactic artificial tears and ophthalmic topical steroids.

 • Withhold ELAHERE for ocular toxicities until improvement and resume at the same or reduced dose.

 • Discontinue ELAHERE for Grade 4 ocular toxicities.

INDICATIONS AND USAGE

 ELAHERE is a folate receptor alpha (FRa)-directed antibody and microtubule inhibitor conjugate indicated for the treatment of adult patients with FRa 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.

 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 a confirmatory trial. 

ADVERSE REACTIONS

 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.

CONTRAINDICATIONS-                                                                                                    • None.

WARNINGS AND PRECAUTIONS-                                                                                   • Pneumonitis:                                                                                                             Withhold ELAHERE for persistent or recurrent Grade 2 pneumonitis and consider dose reduction. Permanently discontinue ELAHERE for Grade 3 or 4 pneumonitis.

 • 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.

 • Embryo-Fetal Toxicity: ELAHERE can cause fetal harm. Advise of the potential risk to a fetus and to use effective contraception.

DOSAGE AND ADMINISTRATION

 • Administer ELAHERE as an intravenous infusion only after dilution in 5% Dextrose Injection, USP. ELAHERE is incompatible with normal saline

 • The recommended dose of ELAHERE is 6 mg/kg adjusted ideal body weight administered as an intravenous infusion every 3 weeks until disease progression or unacceptable toxicity.

 • Premedicate with a corticosteroid, antihistamine, and antipyretic.

 • Premedicate with an antiemetic, ophthalmic topical steroids, and lubricating eye drops.

 • See full Prescribing Information for preparation and administration instructions and dose modifications for adverse reactions. 

DOSAGE FORMS AND STRENGTHS

 • Injection: 100 mg/20 mL (5 mg/mL) in a single-dose vial.

PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Ocular Disorders Inform 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

Pneumonitis -Advise patients to immediately report new or worsening respiratory symptoms].

Embryo-Fetal Toxicity- Advise pregnant women and females of reproductive potential of the potential risk to a fetus.

Advise female patients to inform their healthcare provider of a known or suspected pregnancy .

Advise females of reproductive potential to use effective contraception during treatment with ELAHERE and for 7 months after the last dose .

Lactation- Advise women not to breastfeed during treatment with ELAHERE and for 1 month after the last dose

Manufactured by: ImmunoGen, Inc. Waltham, MA 02451 1-781-895-0600 U.S. License XXXX Reference ID: 5077370

CLINICAL PHARMACOLOGY

1. Mechanism of Action

Mirvetuximab soravtansine-gynx is an antibody-drug conjugate (ADC). The antibody is a chimeric IgG1 directed against folate receptor alpha (FRa).

2. Pharmacodynamics Exposure-                                                                              Response Relationships An 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 Electrophysiology-                                                                                           At the approved recommended dose, ELAHERE did not cause large mean increases (>10 msec) in the QTc interval.

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 6 mg/kg AIBW), unless otherwise noted.

Distribution-                                                                                                                  The 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.

Elimination-                                                                                                                     Total 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 a steady state at approximately 24 days.

Metabolism-                                                                                                                  The monoclonal antibody portion of mirvetuximab soravtansine-gynx is expected to be metabolized into small peptides by catabolic pathways.

Excretion-                                                                                                                        S-methyl DM4 and DM4-sulfo-SPDB-lysine were detected in urine within 24 hours of infusion as the main metabolites

5.Specific Populations-                                                                                                    No 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 approaches No clinical studies evaluating the drug-drug interaction potential of mirvetuximab soravtansine-gynx have been conducted.

However, in 3 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 a time-dependent inhibitor of CYP3A4.

Transporter Systems:                                                                                              Unconjugated DM4 and S-methyl DM4 are substrates of P-gp but are not inhibitors of Pgp.

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 a median duration of treatment of 4.3 months in Studies 0417, 0401, and 0403, a total of 55/423 (13%) ovarian cancer patients treated with mirvetuximab soravtansine-gynx at 6 mg/kg AIBW had at least 1 postbaseline positive sample for anti-mirvetuximab soravtansine-gynx antibodies. Of those patients, 28/423 patients (7%) had developed treatment-emergent ADA and 3/423 patients (

 USE IN SPECIFIC POPULATIONS

1. 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.

 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.

2. Lactation Risk Summary-                                                                                     There 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 a breastfed child, advise women not to breastfeed during treatment with ELAHERE and for 1 month after the last dose.

3. Females and Males of Reproductive Potential-                                                     ELAHERE can cause embryo-fetal harm when administered to a pregnant woman

Pregnancy Testing-                                                                                                           Verify 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 7 months after the last dose.

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

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 a clinically meaningful effect on the pharmacokinetics of ELAHERE.

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

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)