Mirvetuximab Soravtansine-gynx (Monograph)

Brand name: Elahere
Drug class: Antineoplastic Agents

Introduction

Folate receptor alpha (FRα)-directed antibody and microtubule inhibitor conjugate; an antineoplastic agent.¹

Uses for Mirvetuximab Soravtansine-gynx

Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

Treatment of adults with folate receptor-alpha (FRα) positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have received 1 to 3 prior systemic treatment regimens.^{1 3 5 6}

Mirvetuximab Soravtansine-gynx Dosage and Administration

General

Pretreatment Screening

• Select patients for treatment based on the presence of folate receptor alpha (FRα) tumor expression using an FDA-approved test.¹ FDA-approved tests for measurement of FRα tumor expression are available at [Web].¹

• Perform ophthalmic exam including visual acuity and slit lamp exam prior to treatment initiation.¹

• Verify pregnancy status in females of reproductive potential.¹

Patient Monitoring

• Perform ophthalmic exam including visual acuity and slit lamp exam every other cycle for the first 8 cycles and as clinically indicated.¹

• Monitor for ocular toxicity and withhold, reduce, or permanently discontinue mirvetuximab soravtansine-gynx based on severity and persistence of ocular adverse reactions.¹

• Avoid use of contact lenses during treatment unless directed by a healthcare provider.¹

• Monitor for pulmonary signs and symptoms of pneumonitis (e.g., hypoxia, cough, dyspnea, or interstitial infiltrates on radiologic exams).¹

• Monitor for signs and symptoms of neuropathy (e.g., paresthesia, tingling or burning sensation, neuropathic pain, muscle weakness, or dysesthesia).¹

Premedication and Prophylaxis

• Premedicate to reduce the incidence and severity of infusion related reactions (IRRs), nausea, and vomiting.¹

Dispensing and Administration Precautions

Handling and Disposal

• Mirvetuximab soravtansine-gynx is classified as a hazardous drug.¹ Follow applicable special handling and disposal procedures.¹

• Based on the Institute for Safe Medication Practices (ISMP), mirvetuximab soravtansine-gynx is a high-alert medication that has a heightened risk of causing significant patient harm when used in error.⁹

Administration

IV Administration

Administer by IV infusion after dilution.¹

Administer using a 0.2 or 0.22 µm polyethersulfone (PES) in-line filter.¹ Do not substitute other membrane materials.¹

After the infusion, flush IV line with 5% dextrose injection to ensure delivery of full dose.¹ Do not use any other IV fluids.¹

Administer premedications prior to mirvetuximab soravtansine-gynx administration (see Premedications under Dosage and Administration).¹

Dilute commercially available injection concentrate with 5% dextrose injection prior to administration; do not use 0.9% sodium chloride injection.¹ Do not mix with any other drugs or IV fluids.¹

Dilution

Dilute commercially available injection concentrate with 5% dextrose injection to a final concentration of 1 to 2 mg/mL according to the following procedures.¹

Calculate the dose (mg) based on patient's adjusted ideal body weight (AIBW), total volume (mL) of solution required, and the number of vials needed.¹ More than one vial will be needed for a full dose.¹

Remove vials from the refrigerator and allow to warm to room temperature.¹ Visually inspect vials for particulate matter and discoloration prior to administration.¹ Solution should be a clear to slightly opalescent, colorless solution.¹ Gently swirl each vial prior to withdrawing the calculated dose volume.¹ Do not shake vial.¹

Using aseptic technique, withdraw the calculated dose volume for subsequent dilution.¹ Discard any unused drug remaining in the vial.¹

Determine the volume of 5% dextrose injection, USP required to achieved the final diluted drug concentration.¹ Remove excess 5% dextrose injection from a prefilled IV bag or add the calculated volume of 5% dextrose injection to a sterile empty IV bag.¹ Add calculated dose volume of mirvetuximab soravtansine-gynx to the IV bag.¹ Gently mix the diluted drug solution by slowly inverting the bag several times.¹ Do not shake or agitate.¹

Rate of Administration

Administer initial IV infusion at a rate of 1 mg/min.¹

If well tolerated after 30 minutes at 1 mg/min, can increase infusion rate to 3 mg/min.¹ If well tolerated after 30 minutes at 3 mg/min, can increase infusion rate to 5 mg/min.¹

If no infusion-related reactions occur with 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.¹

Premedications

Administer the premedications in Table 1 prior to each infusion to reduce the incidence and severity of infusion related reactions (IRRs), nausea, and vomiting.¹

Consider additional premedications including corticosteroids the day prior to mirvetuximab soravtansine-gynx for patients who experienced IRRs.¹

The use of lubricating eye drops is also recommended.¹ Administer at least 4 times daily and as needed during treatment with mirvetuximab soravtansine-gynx.¹ Patients should wait at least 10 minutes after ophthalmic topical steroid administration before instilling lubricating eye drops.¹

Dosage

Adults

Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

IV

Recommended dosage: 6 mg/kg adjusted ideal body weight (AIBW) administered once every 3 weeks (21-day cycle) as an IV Infusion until disease progression or unacceptable toxicity.¹

Dose is calculated based on a patient's AIBW using the following formula:

AIBW=Ideal Body Weight (IBW [kg]) + 0.4*(Actual weight [kg]-IBW)¹

Female IBW [kg]=0.9*height[cm]-92¹

Dosage Modifications for Toxicity

If adverse reactions occur, dosage modifications or temporary interruption of therapy may be required based on the severity of the reaction (see Table 1 and Table 2).¹

Special Populations

Hepatic Impairment

No specific dosage recommendations.¹ Not recommended in patients with moderate or severe hepatic impairment.¹

Renal Impairment

No specific dosage recommendations for mild to moderate renal impairment (Cl_cr≥30 mL/minute).¹ No data for severe renal impairment (Cl_cr<30 mL/minute).¹

Geriatric Patients

No specific dosage recommendations.¹

Cautions for Mirvetuximab Soravtansine-gynx

Contraindications

• None.¹

Warnings/Precautions

Warnings

Ocular Disorders

Risk of severe ocular adverse reactions, including visual impairment, keratopathy (corneal disorders), dry eye, photophobia, eye pain, and uveitis.¹ (See Boxed Warning.)

Premedication and use of lubricating and ophthalmic topical steroid eye drops during treatment are recommended.¹ Advise patients to avoid use of contact lenses during treatment with mirvetuximab soravtansine-gynx unless directed by a healthcare provider.¹

Refer patients to an eye care professional for an ophthalmic exam prior to treatment initiation, every other cycle for the first 8 cycles, and as clinically indicated.¹ Promptly refer patients to an eye care professional for any new or worsening ocular signs and symptoms.¹

Monitor for ocular toxicity and withhold, reduce, or permanently discontinue mirvetuximab soravtansine-gynx based on severity and persistence of ocular adverse reactions.¹

Other Warnings and Precautions

Pneumonitis

Severe, life-threatening, or fatal interstitial lung disease (ILD) can occur.¹ Monitor patients for pulmonary signs and symptoms of pneumonitis, which may include hypoxia, cough, dyspnea, or interstitial infiltrates on radiologic exams.¹

Withhold therapy for patients who develop persistent or recurrent Grade 2 pneumonitis until symptoms resolve to ≤Grade 1 and consider dose reduction.¹ Permanently discontinue in patients with Grade 3 or 4 pneumonitis.¹

Peripheral Neuropathy

Monitor patients for signs and symptoms of neuropathy.¹ For patients experiencing new or worsening peripheral neuropathy, withhold dosage, reduce dosage, or permanently discontinue mirvetuximab soravtansine-gynx based on severity.¹

Fetal and Neonatal Morbidity and Mortality

Mirvetuximab soravtansine-gynx can cause embryo-fetal harm when administered to a pregnant woman.¹ Advise pregnant women of the potential risk to a fetus.¹

Advise females of reproductive potential to use effective contraception during treatment with mirvetuximab soravtansine-gynx and for 7 months after the last dose.¹

Specific Populations

Pregnancy

May cause embryo-fetal harm based on mechanism of action.¹ Human IgG is known to cross placental barrier and may be transmitted from the mother to developing fetus.¹

No available human data on use in pregnant women to inform a drug-associated risk.¹

Advise patients of the potential risk to a fetus.¹

Lactation

No data on presence in human milk or the effects on the breastfed child or milk production.¹ Advise women not to breastfeed during treatment and for 1 month after the last dose.¹

Females and Males of Reproductive Potential

Can cause embryo-fetal harm when administered to a pregnant woman.¹

Verify pregnancy status in females of reproductive potential prior to initiating mirvetuximab soravtansine-gynx.¹

Advise females of reproductive potential to use effective contraception during treatment and for 7 months after the last dose.¹

Pediatric Use

Safety and effectiveness not established.¹

Geriatric Use

No differences in safety or effectiveness in geriatric patients compared with younger adults.¹

Hepatic Impairment

Avoid use in patients with moderate or severe hepatic impairment (total bilirubin >1.5 ULN).¹

Renal Impairment

No recommended dosage adjustment for patients with mild to moderate renal impairment (Cl_cr30 to 90 mL/minute).¹ Effect of severe renal impairment (Cl_cr15 to < 30 mL/minute) or end-stage renal disease is unknown.¹

Common Adverse Effects

Most common (≥20%) adverse reactions: 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, decreased hemoglobin.¹

Drug Interactions

Drug-drug interaction studies not performed.^{1 3}

Unconjugated DM4 and its S-methyl-DM4 metabolite undergo metabolism by CYP3A4.¹

Unconjugated DM4 demonstrates time-dependent inhibition of CYP3A4.^{1 3} S-methyl DM4 exhibits weak time-dependent inhibition of CYP2C8 and CYP2C9.³ DM4 and S-methyl DM4 do not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4/5.³ DM4 and S-methyl-DM4 do not induce CYP1A2, CYP2B6, or CYP3A4.^{1 3}

Unconjugated DM4 and S-methyl DM4 are substrates, but not inhibitors, of P-gp.^{1 3} DM4 and S-methyl DM4 are substrates, but not inhibitors, of multidrug resistance 1 (MDR1).³

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Strong CYP3A4 inhibitors: Concomitant use with strong CYP3A4 inhibitors may increase unconjugated DM4 exposure, which may increase the risk of adverse reactions.^{1 3} Closely monitor for adverse reactions.^{1 3}

Mirvetuximab Soravtansine-gynx Pharmacokinetics

Absorption

Onset

Steady state concentration of mirvetuximab soravtansine-gynx, DM4, and S-methyl-DM4 metabolite reached after one 3-week cycle.¹

Distribution

Plasma Protein Binding

DM4 and S-methyl DM4 metabolite: >99%.¹

Elimination

Metabolism

Monoclonal antibody portion of mirvetuximab soravtansine-gynx is expected to be metabolized into small peptides by catabolic pathways.¹ Unconjugated DM4 and S-methyl-DM4 undergo metabolism by CYP3A4.^{1 3}

Elimination Route

Biliary excretion is primary route of elimination for DM4.³ Urinary excretion accounts for approximately 0.7% of the mirvetuximab soravtansine-gynx dose.³

Half-life

Unconjugated DM4: 2.8 days¹

S-methyl-DM4 metabolite: 5 days¹

Stability

Storage

Parenteral

Injection concentrate

Store vials upright in a refrigerator at 2–8ºC until time of preparation in the original carton to protect from light.¹ Do not freeze or shake.¹

May store diluted solution at ambient temperature (18–25ºC) for no more than 8 hours (including infusion time), or under refrigeration at 2–8ºC for no more than 12 hours.¹ If refrigerated, allow infusion bag to reach room temperature prior to administration.¹ After refrigeration, administer diluted infusion solutions within 8 hours (including infusion time).¹

Actions

• Antibody-drug conjugate consisting of an IgG antibody directed against FRα linked to a microtubule inhibitor (DM4).¹

• Upon binding to FRα, mirvetuximab soravtansine-gynx is internalized followed by intracellular release of DM4 via proteolytic cleavage.¹

• DM4 inhibits tubulin polymerization and microtubule assembly within the cell, resulting in cell cycle arrest and apoptotic cell death.^{1 3}

Advice to Patients

• Advise patients to read the FDA-approved patient labeling (Medication Guide).¹

• Inform patients about the need for eye exams before and during treatment with mirvetuximab soravtansine-gynx.¹

• Advise patients to contact their healthcare provider promptly if they experience any visual changes.¹ Advise patients to use steroid eye drops and artificial tear substitutes.¹

• Risk of pneumonitis; advise patients to immediately report new or worsening respiratory symptoms.¹

• Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.¹

• Advise patients to inform their clinician if they are or plan to become pregnant or plan to breast-feed.¹ Advise pregnant women and females of reproductive potential of the potential risk to a fetus.¹ Advise females of reproductive potential to use effective contraception during treatment with mirvetuximab soravtansine-gynx and for 7 months after the last dose.¹ Advise patients not to breastfeed during treatment with mirvetuximab soravtansine-gynx and for 1 month after the last dose.¹

• Inform patients of other important precautionary information.¹

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Mirvetuximab soravtansine-gynx is obtained through designated specialty pharmacies.⁴ Contact manufacturer or consult the website ([Web]) for specific availability information.⁴

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