Version July 2025
Enfortumab vedotin can cause severe and fatal cutaneous adverse reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), which occurred predominantly during the first cycle of treatment, but may occur later. Closely monitor patients for skin reactions. Immediately withhold enfortumab vedotin and consider referral for specialized care for suspected SJS or TEN, or severe skin reactions. Permanently discontinue enfortumab vedotin in patients with confirmed SJS or TEN, or grade 4 or recurrent grade 3 skin reactions.
Dosage guidance:
Dosing: Actual body weight (up to the maximum dose of 125 mg for patients ≥100 kg) was used to calculate the dose in the clinical trials (Ref).
Urothelial cancer, locally advanced or metastatic, combination therapy: IV: 1.25 mg/kg (maximum dose: 125 mg) on days 1 and 8 of a 21-day cycle (in combination with pembrolizumab); continue until disease progression or unacceptable toxicity (Ref).
Urothelial cancer, locally advanced or metastatic, single-agent treatment: IV: 1.25 mg/kg (maximum dose: 125 mg) on days 1, 8, and 15 of a 28-day cycle; continue until disease progression or unacceptable toxicity (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer’s labeling; however, kidney impairment had no clinically significant difference in enfortumab vedotin (antibody drug conjugate or monomethyl auristatin E) pharmacokinetics. The effect of end-stage kidney disease (with or without dialysis) is unknown.
Mild impairment (total bilirubin 1 to 1.5 times ULN and any AST, or total bilirubin ≤ ULN and AST > ULN): There are no dosage adjustments provided in the manufacturer’s labeling; however, mild impairment had no clinically significant difference in enfortumab vedotin (antibody drug conjugate or monomethyl auristatin E) pharmacokinetics.
Moderate to severe impairment (total bilirubin >1.5 times ULN and any AST): Avoid enfortumab vedotin use.
Note : Per the manufacturer's labeling, the maximum dose for patients ≥100 kg is 125 mg. Actual body weight (up to the maximum dose of 125 mg) was used to calculate the dose in the clinical trials (Ref).
American Society of Clinical Oncology guidelines for appropriate systemic therapy dosing in adults with cancer with a BMI ≥30 kg/m2: Utilize patient's actual body weight for calculation of BSA- or weight-based dosing ; manage regimen-related toxicities in the same manner as for patients with a BMI <30 kg/m2; if a dose reduction is utilized due to toxicity, may consider resumption of full, weight-based dosing (or previously tolerated dose level) with subsequent cycles only if dose escalations are allowed in the prescribing information, if contributing underlying factors (eg, hepatic or kidney impairment) are sufficiently resolved, AND if performance status has markedly improved or is considered adequate (Ref).
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Initial (usual) dose |
1.25 mg/kg up to a maximum of 125 mg |
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First dose reduction level |
1 mg/kg up to a maximum of 100 mg |
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Second dose reduction level |
0.75 mg/kg up to a maximum of 75 mg |
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Third dosage reduction level |
0.5 mg/kg up to a maximum of 50 mg |
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Adverse reaction |
Severitya |
Enfortumab Vedotin Dose Modification |
|---|---|---|
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a Grade 1 is mild, grade 2 is moderate, grade 3 is severe, and grade 4 is life-threatening. | ||
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Hematologic toxicities |
Grade 3, or grade 2 thrombocytopenia |
Withhold enfortumab vedotin until ≤ grade 1, then resume treatment at the same dose level or consider dose reduction by 1 dose level. |
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Grade 4 |
Withhold enfortumab vedotin until ≤ grade 1, then reduce dose by 1 dose level or discontinue treatment. | |
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Hyperglycemia |
Blood glucose >250 mg/dL |
Withhold enfortumab vedotin until elevated blood glucose has improved to ≤250 mg/dL, then resume treatment at the same dose level. May require insulin. |
|
Peripheral neuropathy |
Grade 2 |
Withhold enfortumab vedotin until ≤ grade 1, then resume treatment at the same dose level (if first occurrence). For a recurrence, withhold until ≤ grade 1, then resume treatment with the dose reduced by 1 dose level. |
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Grade 3 or higher |
Permanently discontinue enfortumab vedotin. | |
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Dermatologic toxicity (skin reactions) |
Consider topical corticosteroids and antihistamines as clinically indicated. | |
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Suspected Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) |
Immediately withhold enfortumab vedotin; consult specialist to confirm the diagnosis. If not SJS/TEN, refer to grade 2 to 4 skin reactions. | |
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Persistent or recurrent grade 2 skin reactions |
Consider withholding enfortumab vedotin until ≤ grade 1, then resume treatment at the same dose level or reduce dose by 1 dose level. | |
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Grade 3 skin reactions |
Withhold enfortumab vedotin until ≤ grade 1, then resume treatment at the same dose level or reduce dose by 1 dose level. | |
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Confirmed SJS or TEN; grade 4 or recurrent grade 3 skin reactions |
Permanently discontinue enfortumab vedotin. | |
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Pulmonary toxicity: Pneumonitis/Interstitial lung disease |
Signs/symptoms indicative of pneumonitis/interstitial lung disease |
Evaluate and exclude infectious, neoplastic, and other causes. |
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Grade 2 |
Withhold enfortumab vedotin until ≤ grade 1, then resume at the same dose level or consider dose reduction by 1 dose level. | |
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Grade 3 or higher |
Permanently discontinue enfortumab vedotin. | |
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Ocular toxicity |
Any |
Consider artificial tears for dry eye prophylaxis and ophthalmologic evaluation if ocular symptoms occur or do not resolve. Ophthalmic topical steroids may be considered (after ophthalmic exam) if clinically indicated. Consider enfortumab vedotin dose interruption or dose reduction for symptomatic ocular disorders. |
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Other nonhematologic toxicity |
Grade 3 |
Withhold enfortumab vedotin until ≤ grade 1, then resume treatment at the same dose level or consider dose reduction by 1 dose level. |
|
Grade 4 |
Permanently discontinue enfortumab vedotin. | |
Refer to adult dosing.
Skin reactions and skin rash may occur with therapy, particularly maculopapular rash and pruritus. Other reactions include dyschromia, exfoliation of skin, skin hyperpigmentation, skin necrosis, and xeroderma. Severe skin reactions (grade 3 to 4) have occurred in up to 10% of treated patients (Ref), including symmetrical drug-related intertriginous and flexural exanthema, bullous dermatitis, erythematous rash, exfoliative dermatitis, and palmar-plantar erythrodysesthesia. Fatal cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported (Ref). Dermatologic toxicities frequently require therapy interruption, dose reduction, and/or discontinuation. Of patients who experienced rash, nearly two-thirds experienced complete resolution and approximately one-fifth experienced partial improvement (Ref). Events occurred at a higher rate when enfortumab vedotin was given concurrently with pembrolizumab.
Mechanism: Not clearly established; Nectin-4 (targeted by enfortumab vedotin and expressed in skin) disturbance may impair cell-cell adhesion leading to epidermal detachment (Ref). Alternatively, delivery of monomethyl auristatin E (MMAE), a microtubule disruption agent conjugated to enfortumab vedotin, may be the sole attributable factor for dermatologic toxicities (Ref).
Onset: Varied; median time to onset of severe skin reactions was 0.6 months (range: 0.1 to 8 months). Median time to onset for SJS and TEN was 11 days (range: 9 to 21 days) (Ref).
Hyperglycemia occurred in patients treated with enfortumab vedotin, including severe (grade 3 or 4) and fatal events; therapy interruption is warranted for blood glucose >250 mg/dL. Diabetic ketoacidosis (DKA) was also observed, including DKA in patients without preexisting diabetes mellitus (Ref).
Onset: Varied; median time to onset of hyperglycemia was 0.5 months (range: 0 to 20 months).
Risk factors:
• Higher BMI
• Higher baseline HbA1c (patients with HbA1c ≥8% were excluded from initial trials)
Ocular effects may occur in patients treated with enfortumab vedotin. Most ocular effects involve the cornea and include keratitis, blurred vision, limbal stem cell deficiency, and other effects associated with dry eye syndrome.
Onset: Varied; median time to onset of symptomatic ocular disorder was 1.7 months (range: 0 to 30.6 months).
Peripheral neuropathy, predominantly peripheral sensory neuropathy and peripheral motor neuropathy, occurred in nearly half of patients treated with enfortumab vedotin in clinical trials. Peripheral neuropathy was usually low grade and manageable, although grade 3 toxicity was reported in a small percentage of patients (Ref). Therapy interruption, dosage reduction, and/or permanent discontinuation may be warranted, depending on the severity. Complete resolution occurred in 11% of patients, and 89% of patients had residual neuropathy (at the time of their last evaluation). Events occurred at a higher rate when enfortumab vedotin was given concurrently with pembrolizumab.
Onset: Varied; median time to onset of grade ≥2 peripheral neuropathy was 4.9 months (range: 0.1 to 20 months).
Pneumonitis/interstitial lung disease (ILD) occurred in patients treated with enfortumab vedotin, including severe (grade 3 or 4) and fatal events. Events occurred at a higher rate when enfortumab vedotin was given concurrently with pembrolizumab.
Onset: Varied; median time to onset of pneumonitis/ILD was 2.9 months (range: 0.6 to 6 months).
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported in adults.
>10%:
Dermatologic: Alopecia (47% to 53%), dermatologic disorder (58%; including maculopapular rash [23%], palmar-plantar erythrodysesthesia, pruritus [26% to 35%]), skin hyperpigmentation (4% to 14%), skin rash (52% to 66%; including symmetrical drug-related intertriginous, flexural exanthema), xeroderma (17% to 26%)
Endocrine & metabolic: Decreased serum albumin (≥20%), decreased serum phosphate (25% to 39%), decreased serum potassium (16% to 19%), hyperglycemia (10% to 17%), weight loss (16% to 35%)
Gastrointestinal: Abdominal pain (20%), constipation (28%), decreased appetite (40% to 52%), diarrhea (35% to 42%; grades 3/4: 4% to 8%), dysgeusia (26% to 42%), increased serum lipase (11% to 18%), nausea (30% to 45%; grades 3/4: 1% to 3%), vomiting (13% to 18%; grades 3/4: 2%)
Genitourinary: Urinary tract infection (17%)
Hematologic & oncologic: Decreased hemoglobin (28% to 34%; grades 3/4: 4% to 10%), decreased neutrophils (14% to 27%; grades 3/4: 5% to 12%), decreased platelet count (≥20%), hemorrhage (17%; grades 3/4: 3%), lymphocytopenia (32% to 43%; grades 3/4: 10% to 15%)
Hepatic: Increased serum aspartate aminotransferase (12%)
Nervous system: Fatigue (48% to 56%), peripheral neuropathy (50% to 58%; grades 3/4: 4% to 8%), peripheral sensory neuropathy (38%)
Neuromuscular & skeletal: Musculoskeletal pain (25%)
Ophthalmic: Dry eye syndrome (24% to 40%), ocular toxicity (40%; including conjunctivitis, increased lacrimation, keratitis, limbal stem cell deficiency)
Renal: Increased serum creatinine (18% to 23%)
Miscellaneous: Fever (22%)
1% to 10%:
Dermatologic: Cellulitis (serious: 5%)
Endocrine & metabolic: Decreased serum sodium (7% to 8%), increased serum potassium (8%), increased uric acid (7% to 9%)
Hematologic & oncologic: Febrile neutropenia (4%)
Hepatic: Increased serum alanine aminotransferase (9% to 10%)
Immunologic: Antibody development (4%)
Infection: Herpes zoster infection (3%), sepsis (3% to 5%)
Nervous system: Myasthenia (8%), peripheral motor neuropathy (7%)
Ophthalmic: Blurred vision (10%)
Renal: Acute kidney injury (3% to 7%)
Respiratory: Dyspnea (serious: 3%), pneumonia (5%), pneumonitis (2% to 4%; including interstitial lung disease)
Postmarketing:
Dermatologic: Bullous dermatitis (Ref), dermatitis (vacuolar interface dermatitis with maturation disarray of keratinocytes) (Ref), dyschromia, erythematous rash (Ref), exfoliation of skin (Ref), exfoliative dermatitis (Ref), indurated plaques of the skin (Ref), pruritic rash (Ref), skin necrosis, Stevens-Johnson syndrome (Ref), toxic epidermal necrolysis (Ref)
Endocrine & metabolic: Diabetic ketoacidosis (Ref)
Hematologic & oncologic: Myelodysplastic syndrome (Ref)
Ophthalmic: Cataract (bilateral anterior subcapsular) (Ref)
Respiratory: Exacerbation of asthma (Ref)
There are no contraindications listed in the manufacturer's US labeling.
Canadian labeling: Hypersensitivity to enfortumab vedotin or any component of the formulation.
Concerns related to adverse effects:
• Extravasation: May be an irritant. Skin and soft tissue reactions secondary to extravasation have been observed after enfortumab vedotin administration, including grade 3 or 4 reactions. A small percentage of patients experienced skin and soft tissue reactions. Extravasation reactions may be delayed. Erythema, swelling, increased temperature, and pain worsened until 2 to 7 days after extravasation and resolved within 1 to 4 weeks of peak. A small percentage of patients also developed extravasation reactions with secondary cellulitis, bullae, or exfoliation.
Special populations:
• Older adults: Patients ≥75 years of age experienced higher incidences of fatal adverse reactions with enfortumab vedotin (either as a single agent or in combination with pembrolizumab), compared to patients <75 years of age.
Disease-related concerns:
• Hepatic impairment: In another antibody drug conjugate also containing monomethyl auristatin E, the incidence of ≥ grade 3 adverse events and fatalities was increased in patients with moderate or severe hepatic impairment (compared to normal hepatic function).
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution Reconstituted, Intravenous [preservative free]:
Padcev: enfortumab vedotin-ejfv 20 mg (1 ea); enfortumab vedotin-ejfv 30 mg (1 ea)
No
Solution (reconstituted) (Padcev Intravenous)
20 mg (per each): $3,370.80
30 mg (per each): $5,056.20
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Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution Reconstituted, Intravenous:
Padcev: 20 mg (1 ea); 30 mg (1 ea)
IV: Infuse over 30 minutes. Do not administer as an IV push or bolus. Do not mix with or administer with other medications.
May be an irritant. Ensure adequate venous access prior to infusion. Monitor infusion site during administration for possible extravasation. If extravasation occurs, stop infusion and monitor for adverse reactions.
When used in combination with pembrolizumab, on the days that both enfortumab vedotin and pembrolizumab are administered, in the clinical trial, enfortumab vedotin was administered first, followed by pembrolizumab ~30 minutes after completion of enfortumab vedotin on the same day (Ref).
Hazardous agent (NIOSH 2024 [table 1]).
Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2023; NIOSH 2024; USP-NF 2020).
Urothelial cancer, locally advanced or metastatic:
Treatment (as a single agent) of locally advanced or metastatic urothelial cancer in adults who have previously received a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor and platinum-containing chemotherapy, or who are ineligible for cisplatin-containing chemotherapy and have previously received 1 or more prior lines of therapy.
Treatment (in combination with pembrolizumab) of locally advanced or metastatic urothelial cancer in adults.
Enfortumab vedotin may be confused with brentuximab vedotin, elotuzumab, encorafenib, polatuzumab vedotin, tisotumab vedotin.
The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drug classes (chemotherapeutic agent, parenteral and oral) which have a heightened risk of causing significant patient harm when used in error (High-Alert Medications in Acute Care, Community/Ambulatory Care, and Long-Term Care Settings).
Substrate of CYP3A4 (Minor), P-glycoprotein (Minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential;
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.
Antidiabetic Agents: Hyperglycemia-Associated Agents may decrease therapeutic effects of Antidiabetic Agents. Risk C: Monitor
CYP3A4 Inducers (Strong): May decrease serum concentration of Enfortumab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be decreased. Risk C: Monitor
Efgartigimod Alfa: May decrease therapeutic effects of Fc Receptor-Binding Agents. Risk C: Monitor
Inhibitors of CYP3A4 (Strong) and P-glycoprotein: May increase serum concentration of Enfortumab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be increased. Risk C: Monitor
Nipocalimab: May decrease therapeutic effects of Fc Receptor-Binding Agents. Risk C: Monitor
Rozanolixizumab: May decrease therapeutic effects of Fc Receptor-Binding Agents. Risk C: Monitor
Evaluate pregnancy status prior to use in patients who could become pregnant. Patients who could become pregnant should use effective contraception during therapy and for 2 months after the last enfortumab vedotin dose. Patients with partners who can become pregnant should use effective contraception during therapy and for 4 months after the last dose of enfortumab vedotin.
Based on data from animal studies, enfortumab vedotin may impair male fertility.
Based on the mechanism of action and data from animal reproduction studies, in utero exposure to enfortumab vedotin may cause fetal harm.
It is not known if enfortumab vedotin is present in breast milk.
Due to the potential for serious adverse reactions in the breastfed infant, breastfeeding is not recommended by the manufacturer during therapy and for 3 weeks after the last enfortumab vedotin dose.
Monitor CBC with differential, blood glucose (monitor closely in patients with, or at risk for, diabetes mellitus or hyperglycemia), and LFTs. Evaluate pregnancy status prior to use in patients who could become pregnant. Monitor for symptoms of new or worsening peripheral neuropathy, ocular disorders, and/or dermatologic toxicity. Monitor for signs/symptoms of pneumonitis or interstitial lung disease (eg, hypoxia, cough, dyspnea, or interstitial infiltrates); evaluate and exclude infectious, neoplastic, or other causes. Consider ophthalmologic evaluation for ocular symptoms that do not resolve. Monitor infusion site during infusion for possible extravasation; if extravasation occurs, monitor extravasation site for adverse reactions.
The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.
Enfortumab vedotin is an antibody drug conjugate (ADC) directed at Nectin-4 (an adhesion protein located on cell surfaces). Nectin-4 is highly expressed in urothelial carcinoma as well as breast, gastric, and lung cancers (Rosenberg 2019). It contains an IgG1 anti-Nectin-4 antibody conjugated to a microtubule-disrupting agent, monomethyl auristatin E (MMAE). MMAE is attached to the antibody via a protease cleavable linker. The ADC binds to Nectin-4 expressing cells to form a complex which is internalized within the cell. Released MMAE binds to the tubules and disrupts the cellular microtubule network, inducing cell cycle arrest and apoptosis of Nectin-4 expressing cells (Rosenberg 2019). In animal models, the combination of enfortumab vedotin with an anti-PD-1 monoclonal antibody resulted in immune function upregulation and increased antitumor activity.
Distribution: Vdss: Antibody drug conjugate (ADC): 12.8 L.
Protein binding: Unconjugated monomethyl auristatin E (MMAE): 68% to 82%.
Metabolism: Enfortumab vedotin is expected to undergo catabolism to small peptides, amino acids, unconjugated MMAE, and unconjugated MMAE-related catabolites. Unconjugated MMAE is released from the ADC via proteolytic cleavage and is primarily metabolized by CYP3A4.
Half-life elimination: ADC: 3.6 days; MMAE: 2.6 days.
Time to peak: ADC: at the end of the infusion; unconjugated MMAE: At ~2 days after a dose.
Excretion: Unconjugated MMAE: Feces: 17%; urine: 6%; primarily as unchanged form (data extrapolated from another ADC product).
Clearance: ADC: 0.11 L/hour; Unconjugated MMAE: 2.11 L/hour.
