Enfortumab Vedotin-ejfv Monograph for Professionals - Drugs.com

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# Enfortumab Vedotin-ejfv

Brand name: Padcev
Drug class: Antineoplastic Agents
Chemical name: Complex with N-[[[4-[[N-[6-(3-mercapto-2,5-dioxo-1-pyrrolidinyl)-1- oxohexyl]-l-valyl-N5-(aminocarbonyl)-l-ornithyl]amino]phenyl]methoxy]carbonyl]-N-methyl-l-valyl-N- [(1S,2R)-4-[(2S)-2-[(1R,2R)-3-[[(1R,2S)-2-hydroxy-1-methyl-2-phenylethyl]amino]-1-methoxy-2- methyl-3-oxopropyl]-1-pyrrolidinyl]-2-methoxy-1-[(1S)-1-methylpropyl]-4-oxobutyl]-N-methyl-l-valinamide, dimer, disulfide with human monoclonal AGS- 22M6 k-chain, anti-(human PVRL4 (poliovirus receptor-related 4, nectin 4) (human monoclonal AGS-22M6 γ1-chain), immunoglobulin G1
Molecular formula: C6642H10284N1742O2063S46
CAS number: 1346452-25-2

Medically reviewed by Drugs.com on Oct 10, 2022. Written by ASHP.

## Introduction

Antineoplastic agent; an anti-nectin-4 antibody conjugated with a microtubule inhibitor (monomethyl auristatin E [MMAE]).

## Uses for Enfortumab Vedotin-ejfv

### Urothelial Carcinoma

Treatment of locally advanced or metastatic urothelial carcinoma in patients who have previously received platinum-containing therapy in the neoadjuvant, adjuvant, or locally advanced or metastatic setting and either an anti-programmed-death receptor-1 (anti-PD-1) or anti-programmed-death ligand-1 (anti-PD-L1) antibody.

Accelerated approval based on objective response rate. Continued approval may be contingent on verification and description of clinical benefit in confirmatory studies.

## Enfortumab Vedotin-ejfv Dosage and Administration

### General

- Consult specialized references for procedures for proper handling and disposal of antineoplastics. Contact manufacturer for additional information.

#### Restricted Distribution

- Obtain through designated specialty distributors.

### Administration

#### IV Administration

Administer by IV infusion. Do not administer by rapid IV injection (e.g., IV push or bolus).

Enfortumab vedotin-ejfv powder for injection must be reconstituted and diluted prior to administration.

Do not mix with or administer through the same IV line with other drugs.

##### Reconstitution

Reconstitute vial containing 20 or 30 mg of enfortumab vedotin with 2.3 or 3.3 mL, respectively, of sterile water for injection to provide a solution containing 10 mg/mL; direct diluent toward the wall of the vial. Gently swirl vial and allow solution to stand for at least 1 minute to allow bubbles to dissipate. Do not shake reconstituted solution.

Reconstituted solution should be clear to slightly opalescent, colorless to light yellow, and free of visible particulates. Do not use if discoloration or particulate matter is present.

##### Dilution

Dilute dose in appropriate volume of 0.9% sodium chloride injection, 5% dextrose injection, or lactated Ringer's injection to yield a final concentration of 0.3–4 mg/mL. Mix diluted solution by gentle inversion.

Do not use if discoloration or particulate matter is present.

Discard any partially used vial or infusion bag.

##### Rate of Administration

Administer by IV infusion over 30 minutes.

### Dosage

#### Adults

##### Urothelial Carcinoma

###### IV

1.25 mg/kg (up to a maximum dose of 125 mg) on days 1, 8, and 15 of each 28-day cycle.

Continue therapy until disease progression or unacceptable toxicity occurs.

##### Dosage Modification for Toxicity

###### IV

Temporary interruption, dosage reduction, and/or permanent discontinuance may be necessary for adverse reactions. If dosage reduction is required, reduce dosage as described in Table 1.

Table 1: Recommended Dosage Reduction for Enfortumab Vedotin Toxicity1
Dosage Reduction Level | Dosage Reduction after Recovery from Toxicity (Initial Dose = 1.25 mg/kg [maximum dose 125 mg])
--- | ---
First | Resume at 1 mg/kg (up to a maximum dose of 100 mg)
Second | Resume at 0.75 mg/kg (up to a maximum dose of 75 mg)
Third | Resume at 0.5 mg/kg (up to a maximum dose of 50 mg)

If an adverse reaction occurs, modify dosage accordingly (see Table 2).

Table 2. Recommended Dosage Modification for Enfortumab Vedotin Toxicity1
Adverse Reaction and Severity | Dosage Modification
--- | ---
Hyperglycemia |
Blood glucose concentration >250 mg/dL | Withhold therapy; when blood glucose concentration improves to ≤250 mg/dL, resume at same dosage
Peripheral Neuropathy |
Grade 2 | First occurrence: Withhold therapy; when peripheral neuropathy improves to grade 1 or less, resume at same dosage
| Subsequent occurrence: Withhold therapy; when peripheral neuropathy improves to grade 1 or less, resume at next lower dosage (see Table 1)
Grade 3 or greater | Permanently discontinue therapy
Dermatologic Reactions |
Grade 3 | First occurrence: Withhold therapy; when toxicity improves to grade 1 or less, resume at same dosage or at next lower dosage (see Table 1) Subsequent occurrence: Permanently discontinue therapy
Grade 4 | Permanently discontinue therapy
Hematologic Toxicity |
Grade 2 thrombocytopenia | Withhold therapy; when toxicity improves to grade 1 or less, resume at same dosage or at next lower dosage (see Table 1)
Grade 3 hematologic toxicity | Withhold therapy; when toxicity improves to grade 1 or less, resume at same dosage or at next lower dosage (see Table 1)
Grade 4 hematologic toxicity | Withhold therapy; when toxicity improves to grade 1 or less, resume at next lower dosage (see Table 1) or discontinue therapy
Other Nonhematologic Toxicity |
Grade 3 | Withhold therapy; when toxicity improves to grade 1 or less, resume at same dosage or at next lower dosage (see Table 1)
Grade 4 | Permanently discontinue therapy

### Special Populations

#### Hepatic Impairment

Mild hepatic impairment (Child-Pugh class A): No dosage adjustment necessary.

Moderate or severe hepatic impairment (Child-Pugh class B or C): Avoid use. (See Hepatic Impairment under Cautions.)

#### Renal Impairment

Mild, moderate, or severe renal impairment (Clcr ≤90 mL/minute): No dosage adjustment necessary. (See Renal Impairment under Cautions.)

Detailed Enfortumab vedotin dosage information

## Cautions for Enfortumab Vedotin-ejfv

### Contraindications

- No known contraindications.

### Warnings/Precautions

#### Hyperglycemia

Hyperglycemia and diabetic ketoacidosis, sometimes fatal, reported in patients with or without preexisting diabetes mellitus.

Monitor blood glucose concentrations in patients with diabetes mellitus or hyperglycemia and in those at risk for such disease. Interrupt therapy for blood glucose >250 mg/dL. (See Dosage Modification for Toxicity under Dosage and Administration.)

#### Peripheral Neuropathy

Peripheral neuropathy, mainly sensory neuropathy, reported in patients with or without preexisting peripheral neuropathy.

Monitor patients for new or worsening peripheral neuropathy. Interruption of therapy, dosage reduction, and/or permanent discontinuance of therapy may be necessary. (See Dosage Modification for Toxicity under Dosage and Administration.)

#### Ocular Effects

Ocular disorders reported. Most events affected the cornea and included blurred vision, keratitis, limbal stem cell deficiency, and dry eye.

Monitor patients for ocular disorders. Consider prophylaxis with artificial tear substitutes for dry eye and ophthalmologic evaluation if ocular symptoms occur or do not resolve. Consider treatment with topical ophthalmic corticosteroid therapy as clinically indicated. Interruption of therapy or dosage reduction may be necessary.

#### Dermatologic Reactions

Cutaneous reactions, including pruritus, maculopapular rash, symmetrical drug-related intertriginous and flexural exanthema (SDRIFE), bullous dermatitis, exfoliative dermatitis, and palmar-plantar erythrodysesthesia, reported.

Monitor patients for dermatologic reactions. Interruption of therapy, dosage reduction, and/or permanent discontinuance of therapy may be necessary. (See Dosage Modification for Toxicity under Dosage and Administration.) Consider appropriate treatment (e.g., topical corticosteroid, antihistamine) as clinically indicated.

#### Extravasation

Skin and soft tissue reactions secondary to extravasation observed following administration. Reactions may be delayed. Erythema, swelling, increased temperature, and pain worsened up to 2–7 days after extravasation and resolved within 1–4 weeks of peaking. Secondary cellulitis, bullae, or exfoliation occurred rarely.

Ensure adequate venous access prior to initiation of infusion and carefully monitor the infusion site during administration. If extravasation occurs, discontinue infusion immediately.

#### Fetal/Neonatal Morbidity and Mortality

May cause fetal harm. Embryofetal toxicity, teratogenicity, and maternal toxicity observed in animals.

Perform pregnancy test prior to initiating enfortumab vedotin therapy in women of reproductive potential. Avoid pregnancy during therapy. Women of childbearing potential should use effective contraception while receiving the drug and for 2 months after the last dose. Men who are partners of such women should use effective contraception while receiving the drug and for 4 months after the last dose.

If used during pregnancy or patient becomes pregnant, apprise of potential fetal hazard.

#### Immunogenicity

Potential for immunogenicity. Development of anti-enfortumab vedotin antibodies does not appear to affect pharmacokinetics, efficacy, or safety of the antibody-drug conjugate.

#### Infertility

Results of animal studies suggest enfortumab vedotin may impair male fertility.

#### Specific Populations

##### Pregnancy

May cause fetal harm. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

##### Lactation

Not known whether enfortumab vedotin is distributed into milk, affects nursing infants, or affects milk production. Discontinue nursing during therapy and for at least 3 weeks after the last dose.

##### Pediatric Use

Safety and efficacy not established.

##### Geriatric Use

In clinical trials, 60% of patients were ≥65 years of age and 26% were ≥75 years of age. No overall differences in safety or efficacy were observed between geriatric patients and younger adults.

##### Hepatic Impairment

Systemic exposure may be increased in patients with mild hepatic impairment; no dosage adjustment necessary. (See Special Populations under Pharmacokinetics.)

Not studied in patients with moderate or severe hepatic impairment; however, incidence of grade 3 or 4 adverse reactions and death is increased in patients with moderate (Child-Pugh class B) or severe (Child-Pugh class C) hepatic impairment who received an MMAE-containing antibody-drug conjugate similar in structure to enfortumab vedotin. Avoid use in patients with moderate or severe hepatic impairment.

##### Renal Impairment

Systemic exposure not affected by mild, moderate, or severe renal impairment. Not studied in patients with end-stage renal disease, including those requiring dialysis.

No dosage adjustment necessary in patients with mild, moderate, or severe renal impairment.

### Common Adverse Effects

Fatigue, peripheral neuropathy, decreased appetite, rash, alopecia, nausea, dysgeusia, diarrhea, dry eye, pruritus, dry skin, anemia, lymphopenia, hypophosphatemia, elevated concentrations of lipase, hyperglycemia, hyponatremia, hyperuricemia, neutropenia.

## Interactions for Enfortumab Vedotin-ejfv

No formal drug interaction studies performed; however, pharmacokinetic interactions with MMAE (the microtubule-inhibiting component of enfortumab vedotin) have been studied with an MMAE-containing antibody-drug conjugate similar in structure to enfortumab vedotin.

MMAE is a substrate of P-glycoprotein (P-gp), but not an inhibitor of P-gp in vitro.

### Drugs Affecting Hepatic Microsomal Enzymes

Potent CYP3A4 inhibitors: Increased peak plasma concentration and AUC of MMAE and increased risk of enfortumab vedotin toxicity expected. No dosage adjustment necessary. Monitor closely for adverse effects.

Potent CYP3A4 inducers: Decreased peak plasma concentration and AUC of MMAE expected. No dosage adjustment necessary.

### Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP3A4: Pharmacokinetic interaction not expected.

### Specific Drugs

Drug | Interaction | Comments
--- | --- | ---
Ketoconazole | Similar MMAE-containing antibody-drug conjugate: AUC and peak concentration of MMAE increased by 34 and 25%, respectively; no change in exposure of antibody-drug conjugate | Similar interaction expected with enfortumab vedotin Dosage adjustment not required Monitor for enfortumab vedotin adverse effects
Midazolam | No change in systemic exposure of midazolam expected |
Rifampin | Similar MMAE-containing antibody-drug conjugate: AUC and peak concentration of MMAE decreased by 46 and 44%, respectively; no change in exposure of antibody-drug conjugate | Similar interaction expected with enfortumab vedotin Dosage adjustment not required

Enfortumab vedotin drug interactions (more detail)

## Enfortumab Vedotin-ejfv Pharmacokinetics

### Absorption

#### Bioavailability

Peak plasma concentrations of the antibody-drug conjugate are attained near the end of IV infusion; peak plasma concentrations of MMAE are attained approximately 2 days after IV administration of enfortumab vedotin.

Minimal accumulation of enfortumab vedotin and MMAE following repeated administration.

Steady-state concentrations of the antibody-drug conjugate and MMAE achieved after one treatment cycle (i.e., 3 doses).

#### Special Populations

Mild hepatic impairment (bilirubin concentration not exceeding the ULN with AST concentration exceeding the ULN, or bilirubin concentration exceeding the ULN, but ≤1.5 times the ULN, with AST not exceeding the ULN): AUC of MMAE increased by 48%.

Moderate or severe hepatic impairment (ALT or AST >2.5 times the ULN or total bilirubin concentration >1.5 times the ULN) or those who have undergone liver transplantation: Pharmacokinetics not studied.

Mild, moderate, or severe renal impairment (Clcr ≤ 90 mL/minute): No substantial effects on AUC of enfortumab vedotin or MMAE.

End-stage renal disease and dialysis: Pharmacokinetics not studied.

Age (range: 24–87 years), sex, and race or ethnicity do not have clinically important effects on pharmacokinetics of enfortumab vedotin.

### Distribution

#### Extent

Not known whether enfortumab vedotin is distributed into milk.

#### Plasma Protein Binding

MMAE: 68–82% in vitro.

### Elimination

#### Metabolism

Expected to undergo catabolism to small peptides, amino acids, free MMAE, and free MMAE-related catabolites.

MMAE is primarily metabolized by CYP3A4.

#### Elimination Route

Elimination route not fully characterized. Following administration of an MMAE-containing antibody-drug conjugate similar in structure to enfortumab vedotin, 17 or 6% of the total administered dose of MMAE was excreted over 1 week in feces or urine, respectively, mainly as unchanged drug.

#### Half-life

Antibody-drug conjugate: 3.4 days.

MMAE: 2.4 days; limited by rate of release from enfortumab vedotin.

## Stability

### Storage

#### Parenteral

##### Powder for Injection

2–8°C in original carton. Do not freeze or shake.

May store reconstituted drug in vial at 2–8°C for up to 4 hours after reconstitution. Protect from direct sunlight. Do not freeze or shake.

May store infusion solution at 2–8°C for up to 8 hours after dilution. Protect from direct sunlight. Do not freeze or shake.

### Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

#### Parenteral

##### Solution Compatibility

Compatible
Dextrose 5% in water
Ringer’s injection, lactated
Sodium chloride 0.9%

## Actions

- Enfortumab vedotin is an antinectin-4 antibody conjugated via a protease-cleavable maleimidocaproyl valine-citrulline linker with the microtubule inhibitor MMAE. Approximately 4 MMAE molecules attached to each antibody molecule.

- The antibody-drug conjugate binds to nectin-4 (also known as poliovirus receptor-related protein 4; PVRL4), a transmembrane adhesion protein located on the surface of cells. The resultant complex is internalized by the cell, and MMAE is released via proteolytic cleavage and disrupts the intracellular microtubule network, resulting in cell cycle arrest and apoptosis.

## Advice to Patients

- Importance of advising patients to read the manufacturer's patient information.

- Risk of hyperglycemia. Importance of informing clinician immediately if symptoms of hyperglycemia (e.g, frequent urination, increased thirst, blurred vision) occur.

- Risk of peripheral neuropathy. Importance of informing clinician if symptoms of peripheral neuropathy (e.g., tingling or numbness of the hands or feet, muscle weakness) occur.

- Risk of adverse ocular effects. Importance of informing clinician immediately if adverse ocular effects (e.g., blurry vision, dry eye) occur. Advise patients to use artificial tear substitutes to prevent or manage symptoms of dry eye.

- Risk of rash and severe cutaneous reactions. Importance of informing clinician if signs or symptoms of progressive or intolerable cutaneous reactions occur.

- Risk of extravasation. Importance of informing clinician immediately if signs or symptoms of an infusion-related reaction (e.g., redness, swelling, itching, discomfort at the infusion site) occur.

- Risk of fetal harm. Necessity of advising women of reproductive potential to use effective contraception during therapy and for at least 2 months after the last dose. Necessity of advising men who are partners of such women to use effective contraception during therapy and for 4 months after the last dose. Importance of women informing their clinicians if they become pregnant during therapy or think they may be pregnant. Advise pregnant women of potential risk to the fetus.

- Importance of advising women to avoid breast-feeding while receiving the drug and for 3 weeks after the last dose.

- Risk of impaired male fertility.

- Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses (e.g., diabetes mellitus, hyperglycemia, peripheral neuropathy).

- Importance of informing patients of other important precautionary information. (See Cautions.)

## 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.

Distribution of enfortumab vedotin is restricted. (See Restricted Distribution under Dosage and Administration.)

Enfortumab Vedotin-ejfv
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer
--- | --- | --- | --- | ---
Parenteral | For injection, for IV infusion only | 20 mg | Padcev | Seattle Genetics, (comarketed with Astellas)
|  | 30 mg | Padcev | Seattle Genetics, (comarketed with Astellas)

AHFS DI Essentials™. © Copyright 2023, Selected Revisions October 19, 2020. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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## More about enfortumab vedotin

- Check interactions
- Reviews (3)
- Side effects
- Dosage information
- During pregnancy
- Drug class: miscellaneous antineoplastics
- Breastfeeding
- En español

### Patient resources

- Drug Information
- Enfortumab vedotin-ejfv Intravenous (Advanced Reading)

### Professional resources

#### Other brands

Padcev

### Related treatment guides

- Urothelial Carcinoma

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