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.
Urothelial cancer, locally advanced or metastatic: IV: 1.25 mg/kg (maximum dose: 125 mg) on days 1, 8, and 15 every 28 days until disease progression or unacceptable toxicity (Powles 2021; Rosenberg 2019).
Note: Actual body weight (up to the maximum dose of 125 mg) was used to calculate the dose in the clinical trials (Powles 2021; Rosenberg 2019).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
No dosage adjustment necessary.
Mild impairment (total bilirubin 1 to 1.5 times ULN and any AST, or total bilirubin ≤ ULN and AST > ULN): No dosage adjustment necessary.
Moderate to severe impairment (total bilirubin >1.5 times ULN and any AST): Avoid enfortumab vedotin use.
Refer to adult dosing.
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 (Powles 2021; Rosenberg 2019).
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 (ASCO [Griggs 2021]).
|
Initial (usual) dose |
1.25 mg/kg up to a maximum of 125 mg |
|
First dose reduction level |
1 mg/kg up to a maximum of 100 mg |
|
Second dose reduction level |
0.75 mg/kg up to a maximum of 75 mg |
|
Third dosage reduction level |
0.5 mg/kg up to a maximum of 50 mg |
|
Adverse reaction |
Severitya |
Enfortumab Vedotin Dose Modification |
|---|---|---|
|
a Grade 1 is mild, grade 2 is moderate, grade 3 is severe, and grade 4 is life-threatening. | ||
|
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. |
|
Grade 4 |
Withhold enfortumab vedotin until ≤ grade 1, then reduce dose by 1 dose level or discontinue treatment. | |
|
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. |
|
Grade 3 or higher |
Permanently discontinue enfortumab vedotin. | |
|
Dermatologic toxicity (skin reactions) |
Consider topical corticosteroids and antihistamines as clinically indicated. | |
|
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. | |
|
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. | |
|
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. | |
|
Confirmed SJS or TEN; grade 4 or recurrent grade 3 skin reactions |
Permanently discontinue enfortumab vedotin. | |
|
Pulmonary toxicity: Pneumonitis |
Grade 2 |
Withhold enfortumab vedotin until ≤ grade 1 for persistent or recurrent grade 2 pneumonitis; consider dose reduction by 1 dose level. |
|
Grade 3 or higher |
Permanently discontinue enfortumab vedotin. | |
|
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. |
|
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. | |
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
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution Reconstituted, Intravenous:
Padcev: 20 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.
Hazardous agent (NIOSH [group 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 2016; USP-NF 2020).
Urothelial cancer, locally advanced or metastatic: Treatment 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.
Enfortumab vedotin may be confused with belantamab mafodotin, brentuximab vedotin, elotuzumab, encorafenib, polatuzumab vedotin.
This medication is in a class the Institute for Safe Medication Practices includes among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.
Bone marrow suppression, including anemia, decreased neutrophils, leukopenia, and lymphocytopenia, may commonly occur; febrile neutropenia has also been reported. Therapy interruption, dosage reduction, and/or permanent discontinuation may be warranted, depending on the severity and type of hematologic toxicity.
Skin reactions and skin rash are very common with therapy, particularly maculopapular rash and pruritus. Other reactions include exfoliation of skin, skin photosensitivity, urticaria, vesicular eruption, 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, 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).
Mechanism: Skin toxicity is believed to occur because enfortumab vedotin targets Nectin-4, which is also expressed in skin (Ref). Nectin-4 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 6.4 months). Median time to onset for SJS and TEN was 11 days (range: 9 to 21 days) (Ref).
Enfortumab vedotin is associated with a moderate emetic potential. Nausea, vomiting, diarrhea, dysgeusia, and decreased appetite commonly occur and are generally mild; antiemetics may be recommended to prevent nausea and vomiting.
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.
Onset: Varied; median time to onset of hyperglycemia was 0.6 months (range: 0.1 to 20.3 months).
Risk factors:
• Higher BMI
• Higher baseline HbA1c (patients with HbA1c >8% were excluded from initial trials)
Ocular disorders are common in patients treated with enfortumab vedotin. The majority of ocular events involve the cornea and include keratitis, blepharitis, blurred vision, limbal stem cell deficiency, and other events associated with dry eye syndrome.
Onset: Varied; median time to onset of symptomatic ocular disorder was 1.6 months (range: 0 to 19.1 months).
Peripheral neuropathy, predominantly peripheral sensory neuropathy, peripheral motor neuropathy, and asthenia, 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. Nearly one-fifth of patients experiencing peripheral neuropathy had complete resolution, and approximately one-fourth had partial improvement (at the time of their last evaluation).
Onset: Varied; median time to onset of grade ≥2 peripheral neuropathy was 4.6 months (range: 0.1 to 15.8 months).
Pneumonitis occurred in patients treated with enfortumab vedotin, including severe (grade 3 or 4) and fatal events.
Onset: Varied; median time to onset of pneumonitis 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%), maculopapular rash (23%), pruritus (26% to 35%), skin rash (52% to 66%; including symmetrical drug-related intertriginous and flexural exanthema [Keerty 2020]), xeroderma (17% to 26%)
Endocrine & metabolic: Decreased serum phosphate (25% to 39%), decreased serum potassium (16% to 19%), hyperglycemia (10% to 16%), 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 6%), 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: Anemia (20% to 38%; grade 3/4: 6% to 11%), decreased neutrophils (14% to 27%; grade 3/4: 5% to 12%), hemorrhage (17%; grade 3/4: 3%), lymphocytopenia (32% to 43%; grade 3/4: 10% to 15%)
Hepatic: Increased serum aspartate aminotransferase (12%)
Nervous system: Fatigue (48% to 56%), peripheral neuropathy (50% to 58%; grade 3/4: 4% to 8%; including abnormal gait and hypoesthesia), peripheral sensory neuropathy (39%)
Neuromuscular & skeletal: Musculoskeletal pain (25%)
Ophthalmic: Blurred vision (13%), dry eye syndrome (24% to 40%; including limbal stem cell deficiency), ocular toxicity (40%)
Renal: Increased serum creatinine (18% to 23%)
Miscellaneous: Fever (22%)
1% to 10%:
Dermatologic: Cellulitis (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 (3%)
Infection: Herpes zoster infection (3%), sepsis (3% to 5%)
Nervous system: Peripheral motor neuropathy (6%)
Neuromuscular & skeletal: Asthenia (7%)
Renal: Acute renal injury (3% to 7%)
Respiratory: Dyspnea (3%), pneumonia (5%), pneumonitis (2% to 4%)
Frequency not defined:
Dermatologic: Acneiform eruption, bullous dermatitis, contact dermatitis, erythema multiforme, erythematous rash (Dobry 2021), exfoliation of skin, exfoliative dermatitis, palmar-plantar erythrodysesthesia, pustular rash, skin photosensitivity, stasis dermatitis, urticaria, vesicular eruption
Endocrine & metabolic: Diabetic ketoacidosis
Ophthalmic: Blepharitis, conjunctivitis, eye irritation, increased lacrimation, keratitis, punctate keratitis
Postmarketing: Dermatologic: Dermatitis (vacuolar interface dermatitis with maturation disarray of keratinocytes) (Wu 2019), indurated plaques of the skin (Dobry 2021), pruritic rash (Dobry 2021), Stevens-Johnson syndrome (Francis 2020; Viscuse 2021), toxic epidermal necrolysis (Francis 2020; Viscuse 2021)
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.
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).
Substrate of CYP3A4 (minor), P-glycoprotein/ABCB1 (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 Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
CYP3A4 Inducers (Strong): May decrease the serum concentration of Enfortumab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be decreased. Risk C: Monitor therapy
Efgartigimod Alfa: May diminish the therapeutic effect of Fc Receptor-Binding Agents. Risk C: Monitor therapy
Inhibitors of CYP3A4 (Strong) and P-glycoprotein: May increase the serum concentration of Enfortumab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be increased. Risk C: Monitor therapy
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 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 at least 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 pulmonary toxicity (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).
Distribution: Vdss: Antibody drug conjugate (ADC): 12.8 L.
Protein binding: 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. MMAE is released 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; MMAE: At ~2 days after a dose.
Excretion: MMAE: Feces: 17%; urine: 6%; primarily as unchanged drug (data extrapolated from another ADC product).
Clearance: Enfortumab vedotin: 0.11 L/hour; MMAE (unconjugated): 2.11 L/hour.
Hepatic function impairment: Unconjugated monomethyl auristatin E (MMAE) AUC0-28d exposure increased 37% in patients with mild impairment (total bilirubin 1 to 1.5 times ULN and any AST, or total bilirubin ≤ ULN and AST > ULN) compared to normal hepatic function.
Solution (reconstituted) (Padcev Intravenous)
20 mg (per each): $3,062.40
30 mg (per each): $4,593.60
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