enfortumab vedotin (Rx)

Brand and Other Names:Padcev, enfortumab vedotin-ejfv
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

injection, lyophilized powder for reconstitution

  • 20mg single-dose vial
  • 30mg single-dose vial

Urothelial Carcinoma

Indicated for locally advanced or metastatic urothelial cancer in patients who have received a PD-1/L1 inhibitor and platinum-containing chemotherapy in the neoadjuvant/adjuvant, locally advanced, or metastatic setting

1.25 mg/kg (up to 125 mg) IV on Days 1, 8, and 15 of a 28-day cycle

Weight ≥100kg: Not to exceed 125 mg/dose

Continue until disease progression or unacceptable toxicity

Dosage Modifications

Recommended dose reduction schedule

  • First dose reduction: 1 mg/kg up to 100 mg
  • Second dose reduction: 0.75 mg/kg up to 75 mg
  • Third dose reduction: 0.5 mg/kg up to 50 mg

Skin reactions

  • Suspected Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN), or Grade 3 (severe): Withhold until Grade ≤1, then resume at same dose level, or consider dose reduction by 1 dose level
  • Confirmed SJS or TEN; recurrent Grade 3 or Grade 4: Permanently discontinue

Hyperglycemia

  • Blood glucose (BG) >250 mg/dL: Withhold until BG improves to ≤250 mg/dL, then resume at same dose level

Peripheral neuropathy

  • Grade 2: Withhold until Grade ≤1, then resume at same dose level (if first occurrence)
  • If recurs, withhold until Grade ≤1 then, resume at reduced by 1 dose level
  • Grade ≥3: Permanently discontinue

Other nonhematologic toxicity

  • Grade 3: Withhold until Grade ≤1, then resume at same dose level or consider dose reduction by 1 dose level
  • Grade 4: Permanently discontinue

Hematologic toxicity

  • Grade 3, or Grade 2 thrombocytopenia: Withhold until Grade ≤1, then resume at the same dose level or consider reduction by 1 dose level
  • Grade 4: Withhold until Grade ≤1, then reduce by 1 dose level or discontinue treatment

Renal impairment

  • Mild, moderate, or severe (CrCl ≤90 mL/min): No dose adjustment required

Hepatic impairment

  • Mild (Child-Pugh A): No dose adjustment required
  • Moderate or severe (Child-Pugh B or C): Avoid use; not studied

Safety and efficacy not established

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Interactions

Interaction Checker

and enfortumab vedotin

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    No Interactions Found
    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

          Minor

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            Adverse Effects

            >10%

            All grades

            • Fatigue (56%)
            • Peripheral neuropathy (56%)
            • Decreased appetite (52%)
            • Rash (52%)
            • Alopecia (50%)
            • Nausea (45%)
            • Diarrhea (42%)
            • Dysgeusia (42%)
            • Dry eye (40%)
            • Dry skin (26%)
            • Pruritus (26%)
            • Vomiting (18%)

            Grade 3 or more

            • Rash (13%)

            Grade 2-4 laboratory abnormalities

            • Hemoglobin decreased (34%)
            • Phosphates decreased (34%)
            • Lymphocytes decreased (32%)
            • Creatinine increased (20%)
            • Potassium decreased (19%)
            • Neutrophils decreased (14%)
            • Leukocytes decreased (14%)
            • Lipase increased (14%)

            1-10%

            Grade 3 or more

            • Fatigue (6%)
            • Diarrhea (6%)
            • Peripheral neuropathy (4%)
            • Nausea (3%)
            • Decreased appetite (2%)
            • Pruritus (2%)
            • Vomiting (2%)

            Grade 2-4 laboratory abnormalities

            • Sodium decreased (8%)
            • Urate increased (7%)

            Grade 3-4 laboratory abnormalities

            • Hemoglobin decreased (10%)
            • Lymphocytes decreased (10%)
            • Phosphate decreased (10%)
            • Lipase increased (9%)
            • Glucose increased (8%)
            • Sodium decreased (8%)
            • Urate increased (7%)
            • Neutrophils decreased (5%)
            • Leukocytes decreased (4%)
            • Creatinine increased (2%)
            • Potassium decreased (1%)

            Postmarketing Reports

            Skin and subcutaneous tissue disorders: Epidermal necrosis, Stevens-Johnson syndrome, toxic epidermal necrolysis

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            Warnings

            Contraindications

            None

            Cautions

            Hyperglycemia occurred, including death; diabetic ketoacidosis can occur in patients with or without pre-existing diabetes mellitus; incidence of Grade 3-4 hyperglycemia increased consistently in patients with higher body mass index and with higher baseline A1C; closely monitor BG

            Peripheral neuropathy, predominantly sensory, occurred in nearly half of patients treated; monitor for symptoms of new or worsening peripheral neuropathy and consider dose interruption or reduction when peripheral neuropathy occurs

            Ocular disorders occurred in nearly half of patients treated; most events involved the cornea, including keratitis, blurred vision, limbal stem cell deficiency, and other conditions associated with eyes; monitor for symptoms; consider dose interruption or reduction if symptomatic

            Can cause fetal harm, based on the mechanism of action and findings in animals

            Skin reactions

            • Severe cutaneous adverse reactions, including fatal cases of SJS or TEN reported
            • SJS and TEN occurred predominantly during first treatment cycle, but may occur later
            • Other skin reactions (eg, maculopapular rash, pruritis, symmetrical drug-related intertriginous and flexural exanthema, dermatitis bullous, dermatitis exfoliative, and palmoplantar erythrodysesthesia) reported
            • Closely monitor during treatment for skin reactions
            • Consider topical corticosteroids and antihistamines, as needed
            • Consider referral for specialized care for severe (Grade 3) skin reactions

            Infusion site extravasation

            • Skin and soft tissue reactions secondary to extravasation have observed after administration
            • Erythema, swelling, increased temperature, and pain worsened until 2-7 days after extravasation and resolved within 1-4 weeks of peak
            • Ensure adequate venous access before starting therapy and monitor for possible extravasation during administration
            • If extravasation occurs, stop infusion and monitor for adverse reactions

            Drug interaction overview

            • CYP3A4 inhibitors
              • Enfortumab vedotin is an antibody-drug conjugate that releases monomethylauristatin E (MMAE) via proteolytic cleavage
              • MMAE is primarily metabolized by CYP3A4 in vitro
              • Coadministration with strong CYP3A4 inhibitors may increase free MMAE exposure, which may increase the incidence or severity of toxicities; monitor
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            Pregnancy & Lactation

            Pregnancy

            Based on the mechanism of action and findings in animals, can cause fetal harm

            There are no available human data regarding use in pregnancy

            Advise patients of potential risk and verify pregnancy status in females of reproductive potential before initiating

            Animal studies

            • In an animal reproduction study, administration to pregnant rats during organogenesis caused maternal toxicity, embryo-fetal lethality, structural malformations, and skeletal anomalies at maternal exposures approximately similar to the exposures at the recommended human dose of 1.25 mg/kg

            Contraception

            • Females of reproductive potential: Use effective contraception during treatment and for 2 months after the last dose
            • Males with female partners of reproductive potential: Use effective contraception during treatment and for 4 months after the last dose

            Infertility

            • Males: Based on findings from animal studies, may impair male fertility

            Lactation

            Data are not available regarding the presence of enfortumab vedotin in human milk, effects on the breastfed child, or effects on milk production

            Because of the potential for serious adverse reactions in a breastfed child, advise lactating women not to breastfeed during treatment and for at least 3 weeks after the last dose

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

            Enfortumab vedotin is an antibody-drug conjugate (ADC) composed of an anti-nectin-4 monoclonal antibody attached to the cell-killing agent, monomethylauristatin E (MMAE)

            Nectin-4 is a cell adhesion molecule that is expressed on many solid tumors; once the antibody attaches to nectin-4, the complex is internalized in the lysosome, which releases MMAE

            Absorption

            Steady-state concentrations of ADC and MMAE were reached after 1 treatment cycle

            Peak plasma concentration

            • ADC: 28 mcg/mL
            • Unconjugated MMAE: 4.8 ng/mL

            AUC (0-28 days)

            • ADC: 111 mcg⋅d/mL
            • Unconjugated MMAE: 69 ng⋅d/mL

            Distribution

            Vd (steady-state): 11 L

            Protein bound: 68-82%

            Metabolism

            Enfortumab vedotin-ejfv catabolism not studied in humans

            However, it is expected to undergo catabolism to small peptides, amino acids, unconjugated MMAE, and unconjugated MMAE-related catabolites

            Enfortumab vedotin-ejfv releases MMAE via proteolytic cleavage, and MMAE is primarily metabolized by CYP3A4

            Elimination

            Half-life

            • ADC: 3.4 days
            • Unconjugated MMAE: 2.4 days

            Clearance

            • ADC: 0.1 L/hr
            • Unconjugated MMAE: 2.7 L/hr

            Excretion

            • Feces: 17% of the total MMAE
            • Urine: 6% in urine
            • Primarily as unchanged drug
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            Administration

            IV Incompatibilities

            Do not mix with or administer as an infusion with other medicinal products

            IV Compatibilities

            Dextrose 5%, 0.9% NaCl, or lactated ringer

            IV Preparation

            Reconstitution

            • Reconstitute each vial with 2.3 mL (20-mg vial) or 3.3 mL (30-mg vial) of sterile water for injection (SWFI), resulting in 10 mg/mL
            • If possible, direct stream of SWFI along walls of vial and not directly onto lyophilized powder
            • Slowly swirl each vial until contents are completely dissolved
            • Allow reconstituted vial(s) to settle for at least 1 min until the bubbles are gone
            • Do not shake vial; do not expose to direct sunlight
            • Visually inspect for particulate matter and discoloration befire administration, whenever solution and container permit
            • Reconstituted solution should be clear to slightly opalescent, colorless to light yellow, and free of visible particles
            • Add reconstituted solution to the infusion bag immediately
            • Discard unused vials with reconstituted solution beyond the recommended storage time

            Dilution

            • Calculate dosage volume (mL) and withdraw dose from vial(s)
            • Patients weighing >100 kg: dose should be calculated for 100 kg
            • Dilute reconstituted solution to allow enough diluent to achieve a final concentration of 0.3-4 mg/mL
            • Gently invert bag to mix solution; do not shake
            • Do not expose to direct sunlight
            • Visually inspect the infusion bag for any particulate matter or discoloration before use; reconstituted solution should be clear to slightly opalescent, colorless to light yellow, and free of visible particles
            • Do not use the infusion bag if particulate matter or discoloration is observed
            • Discard any unused portion left in the single-dose vial

            IV Administration

            Infuse over 30 min

            Do not administer as an IV push or bolus

            Storage

            Do not freeze; do not shake

            Unused vials: Refrigerate at 2-8ºC (36-46ºF) in the original carton

            Reconstituted vials

            • Does not contain a preservative
            • If not used immediately, refrigerate for up to 4 hr at 2-8ºC (36-46ºF)

            Diluted solutions

            • If not administered immediately, refrigerate for up to 8 hr at 2-8ºC (36-46ºF)

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            Formulary

            FormularyPatient Discounts

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            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.