Enfortumab vedotin

Indications

Enfortumab vedotin is used for: Urothelial Carcinoma

Adult Dose

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

Child Dose

Renal Dose

Renal impairment Mild, moderate, or severe (CrCl ?90 mL/min): No dose adjustment required

Administration

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

Contra Indications

Precautions

Peripheral neuropathy, predominantly sensory, occurred in nearly half of patients treated; consider dose interruption or reduction if symptom occur/worsen; permanently discontinue if severe Ocular disorders in nearly half of patients treated; most events involved the cornea, including keratitis, blurred vision, limbal stem cell deficiency, and other conditions associated with drug eyes; monitor for symptoms; consider dose interruption or reduction if symptomatic Hyperglycemia occurred in patients, including death; diabetic ketoacidosis reported in patients with and without preexisting diabetes mellitus; incidence of Grade 3-4 hyperglycemia increased consistently in patients with higher body mass index and with higher baseline A1C; closely monitor blood glucose, and if elevated (>250 mg/dL) withhold dosing Skin reactions (eg, maculopapular rash, pruritus) occurred in over half of treated patients; severe skin reactions also reported (eg, symmetrical drug-related intertriginous and flexural exanthema [SDRIFE], bullous dermatitis, exfoliative dermatitis, and palmar-plantar erythrodysesthesia Skin and soft tissue reactions secondary to extravasation reported; symptoms may be delayed until 4-7 days following extravasation

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

Interactions

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

Adverse Effects

Side effects of Enfortumab vedotin : >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%) 1-10% Grade 3 or more Fatigue (6%) Diarrhea (6%) Peripheral neuropathy (4%) Nausea (3%) Decreased appetite (2%) Pruritus (2%) Vomiting (2%)

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