Enfortumab vedotin

PADCEV ®, in combination with pembrolizumab or pembrolizumab and berahyaluronidase alfa-pmph, as neoadjuvant treatment and then continued after cystectomy as adjuvant treatment, is indicated for the treatment of adult patients with muscle invasive bladder cancer (MIBC). PADCEV ®, in combination with pembrolizumab or pembrolizumab and berahyaluronidase alfa-pmph, is indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer (la/mUC). PADCEV, as a single agent, is indicated for the treatment of adult patients with la/mUC who: • have previously received a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor and platinum-containing chemotherapy, or • are ineligible for cisplatin-containing chemotherapy and have previously received one or more prior lines of therapy.

Enfortumab vedotin-ejfv is an ADC. The antibody is a human IgG1 kappa directed against Nectin-4, an adhesion protein located on the surface of cells. The small molecule, MMAE, is a microtubule-disrupting agent, attached to the antibody via a protease-cleavable linker. Nonclinical data suggest that the anticancer activity of enfortumab vedotin-ejfv is due to the binding of the ADC to Nectin-4-expressing cells, followed by internalization of the ADC-Nectin-4 complex, and the release of MMAE via proteolytic cleavage. Release of MMAE disrupts the microtubule network within the cell, subsequently inducing cell cycle arrest and apoptosis. The combination of enfortumab vedotin-ejfv with a PD-1 blocking antibody resulted in up-regulation of immune function and increased anti-tumor activity in syngeneic mouse tumor models expressing Nectin-4.

• For intravenous infusion only. Do not administer PADCEV as an intravenous push or bolus. Do not mix with, or administer as an infusion with, other medicinal products. • MIBC: The recommended dose of PADCEV in combination with pembrolizumab or pembrolizumab and berahyaluronidase alfa-pmph is 1.25 mg/kg (up to a maximum dose of 125 mg) given as an intravenous infusion over 30 minutes.

None. None.

Boxed warning (serious skin reactions • padcev): 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 PADCEV and consider referral for specialized care for suspected SJS or TEN or severe skin reactions. • Hyperglycemia: Diabetic ketoacidosis may occur in patients with and without preexisting diabetes mellitus, which may be fatal. Closely monitor blood glucose levels in patients with, or at risk for, diabetes mellitus or hyperglycemia. Withhold PADCEV if blood glucose is >250 mg/dL. • Pneumonitis/Interstitial Lung Disease (ILD): Severe, life-threatening or fatal pneumonitis/ILD may occur.

The following serious adverse reactions are described elsewhere in the labeling: • Skin Reactions • Hyperglycemia • Pneumonitis/Interstitial Lung Disease (ILD) • Peripheral Neuropathy • Ocular Disorders • Infusion Site Extravasation The most common adverse reactions, including laboratory abnormalities, (≥20%) were: • PADCEV in combination with intravenous pembrolizumab for the treatment of MIBC: decreased hemoglobin, increased aspartate aminotransferase, increased alanine aminotransferase, rash, increased creatinine, decreased lymphocytes, fatigue, pruritus, decreased sodium, peripheral neuropathy, increased potassium, diarrhea, alopecia, dysgeusia, decreased appetite, nausea, constipation, urinary tract infection, dry eye, increased glucose, decreased weight, decreased potassium, hyperglycemia, decreased phosphate, and decreased neutrophils.

Concomitant use of dual P-gp and strong CYP3A4 inhibitors with PADCEV may increase the exposure to monomethyl auristatin E (MMAE). Effects of Other Drugs on PADCEV Dual P-gp and Strong CYP3A4 Inhibitors Concomitant use with dual P-gp and strong CYP3A4 inhibitors may increase unconjugated MMAE exposure, which may increase the incidence or severity of PADCEV toxicities. Closely monitor patients for signs of toxicity when PADCEV is given concomitantly with dual P-gp and strong CYP3A4 inhibitors.

Storage Store PADCEV vials refrigerated at 2ºC to 8ºC (36ºF to 46ºF) in the original carton. Do not freeze. Do not shake.