PADCEV Dosage & Rx Info | Uses, Side Effects

Padcev Generic Name & Formulations

Legal Class

General Description

Enfortumab vedotin-ejfv 20mg, 30mg; per vial; lyophilized pwd for IV infusion after reconstitution and dilution; preservative-free.

Pharmacological Class

Nectin-4 directed antibody-drug conjugate.

How Supplied

Single-dose vial—1

Manufacturer

Astellas Pharma US, Inc.

Generic Availability

Mechanism of Action

Enfortumab vedotin-ejfv is an antibody-drug conjugate (ADC). The antibody is a human IgG1 directed against Nectin-4, an adhesion protein located on the surface of cells. The small molecule, monomethyl auristatin E (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 apoptotic cell death.

Padcev Indications

Indications

As a single agent to treat 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 are ineligible for cisplatin-containing chemotherapy and have previously received ≥1 prior lines of therapy. In combination with pembrolizumab to treat locally advanced or metastatic urothelial cancer in adults.

Padcev Dosage and Administration

Adult

Give by IV infusion over 30min. As a single agent: 1.25mg/kg (max 125mg for patients ≥100kg) on Days 1, 8 and 15 of a 28-day cycle; continue until disease progression or unacceptable toxicity. In combination with pembrolizumab: 1.25mg/kg (max 125mg for patients ≥100kg) on Days 1 and 8 of a 21-day cycle; continue until disease progression or unacceptable toxicity. Dose modifications: see full labeling.

Children

Not established.

Padcev Contraindications

Not Applicable

Padcev Boxed Warnings

Boxed Warning

Serious skin reactions.

Padcev Warnings/Precautions

Warnings/Precautions

Severe cutaneous reactions (including SJS, TEN); monitor closely. Consider withholding for persistent or recurrent Grade 2 skin reactions until Grade ≤1. Withhold, consult a specialist to confirm for suspected SJS, TEN or for Grade 3 reactions; permanently discontinue if confirmed SJS or TEN, Grade 4 or recurrent Grade 3 reactions occur. Monitor blood glucose levels in patients with, or at risk of, diabetes or hyperglycemia; withhold dose if blood glucose >250mg/dL. Monitor for pneumonitis/ILD; withhold if Grade 2 reaction occurs and consider dose reduction; permanently discontinue if Grade 3 or 4 reaction. Monitor for new or worsening symptoms of peripheral neuropathy; consider dose interruption/reduction if occurs; permanently discontinue if Grade ≥3 reaction. Monitor for ocular disorders; if symptoms occur, consider ophthalmologic exam; interrupt/reduce dose if needed. Monitor for infusion site extravasation. Moderate or severe hepatic impairment (total bilirubin >1.5×ULN and any AST): avoid. Embryo-fetal toxicity. Advise to use effective contraception during and for 2 months (females) and for 4 months (males w. female partners) after the last dose. Pregnancy: exclude status prior to initiation. Nursing mothers: not recommended (during and for ≥3 weeks after the last dose).

Padcev Pharmacokinetics

Absorption

Peak ADC concentrations were observed near the end of intravenous infusion while peak unconjugated MMAE concentrations were observed approximately 2 days after enfortumab vedotin-ejfv dosing.

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

Exposure parameters of ADC and unconjugated MMAE after first treatment cycle of 1.25 mg/kg of enfortumab vedotin-ejfv dose of Days 1, 8 and 15:

Mean C_max (± SD): 28 (6.1) μg/mL (for ADC); 5.5 (3.0) ng/mL (for unconjugated MMAE)
Mean AUC_0-28d: 110 (26) μg∙d/mL (for ADC); 85 (50) ng∙d/mL (for unconjugated MMAE)
Mean C_trough,0-28d: 0.31 (0.18) μg/mL (for ADC); 0.81 (0.88) ng/mL (for unconjugated MMAE)

Distribution

Estimated mean steady-state volume of distribution (for ADC): 12.8 L.

Plasma protein bound (for unconjugated MMAE): 68–82%, in vitro.

Metabolism

Not studied in humans.

Expected to undergo catabolism to small peptides, amino acids, unconjugated MMAE, and unconjugated MMAE-related catabolites.

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

Elimination

Half-life: 3.6 days (for ADC); 2.6 days (for unconjugated MMAE).

Mean clearance: 0.11 L/h (for enfortumab vedotin-ejfv); 2.11 L/h (for unconjugated MMAE).

Fecal (17%), renal (6%).

Padcev Interactions

Interactions

May be potentiated by dual P-gp and strong CYP3A4 inhibitors (eg, ketoconazole); monitor closely. May be antagonized by dual P-gp and strong CYP3A4 inducers (eg, rifampin).

Padcev Adverse Reactions

Adverse Reactions

Fatigue, peripheral neuropathy, decreased appetite, rash, alopecia, nausea, dysgeusia, diarrhea, dry eye, pruritus, decreased weight, dry skin, anemia, lab abnormalities (increased AST/ALT, increased glucose, increased creatinine, decreased lymphocytes, decreased hemoglobin, decreased neutrophils, decreased platelets, decreased phosphate, decreased albumin, decreased sodium, increased urate, increased lipase). In combination with pembrolizumab: also constipation, peripheral edema, dry eye, dizziness, arthralgia, urinary tract infection, lab abnormalities (decreased/increased potassium, increased calcium).

Padcev Clinical Trials

See Literature

Padcev Note