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Enfortumab Vedotin

FDA Drug Information • Also known as: Padcev Ejfv

Brand Names
Padcev Ejfv
Route
INTRAVENOUS
Dosage Form
INJECTION, POWDER, LYOPHILIZED, FOR SOLUTION
Product Type
HUMAN PRESCRIPTION DRUG

⚠ Boxed Warning (Black Box)

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.
  • Permanently discontinue PADCEV in patients with confirmed SJS or TEN; or Grade 4 or recurrent Grade 3 skin reactions [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.1 ), and Adverse Reactions ( 6.1 )]. WARNING: SERIOUS SKIN REACTIONS See full prescribing information for complete boxed warning.
  • PADCEV can cause severe and fatal cutaneous adverse reactions, including Stevens-Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN).
  • Immediately withhold PADCEV and consider referral for specialized care for suspected SJS or TEN or severe skin reactions.
  • Permanently discontinue PADCEV in patients with confirmed SJS or TEN; or Grade 4 or recurrent Grade 3 skin reactions. ( 2.2 ), ( 5.1 ), ( 6.1 )

    • Description

    11 DESCRIPTION Enfortumab vedotin-ejfv is a Nectin-4 directed antibody-drug conjugate (ADC) comprised of a fully human anti-Nectin-4 IgG1 kappa monoclonal antibody (AGS-22C3) conjugated to the small molecule microtubule disrupting agent, monomethyl auristatin E (MMAE) via a protease-cleavable maleimidocaproyl valine-citrulline (vc) linker (SGD-1006). Conjugation takes place on cysteine residues that comprise the interchain disulfide bonds of the antibody to yield a product with a drug-to-antibody ratio of approximately 3.8:1. The molecular weight is approximately 152 kDa. Figure 1. Structural Formula Approximately 4 molecules of MMAE are attached to each antibody molecule. Enfortumab vedotin-ejfv is produced by chemical conjugation of the antibody and small molecule components. The antibody is produced by mammalian (Chinese hamster ovary) cells and the small molecule components are produced by chemical synthesis. PADCEV (enfortumab vedotin-ejfv) for injection is provided as a sterile, preservative-free, white to off-white lyophilized powder in single-dose vials for intravenous use. PADCEV is supplied as a 20 mg per vial and a 30 mg per vial and requires reconstitution with Sterile Water for Injection, USP, (2.3 mL and 3.3 mL, respectively) resulting in a clear to slightly opalescent, colorless to slightly yellow solution with a final concentration of 10 mg/mL [see Dosage and Administration ( 2.3 )]. After reconstitution, each vial allows the withdrawal of 2 mL (20 mg) and 3 mL (30 mg). Each mL of reconstituted solution contains 10 mg of enfortumab vedotin-ejfv, histidine (1.4 mg), histidine hydrochloride monohydrate (2.31 mg), polysorbate 20 (0.2 mg), and trehalose dihydrate (55 mg) with a pH of 6.0. Enfortumab vedotin structural formula

    What Is Enfortumab Vedotin Used For?

    1 INDICATIONS AND USAGE 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) who are ineligible for cisplatin-containing chemotherapy. 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 (mUC). PADCEV, as a single agent, is indicated for the treatment of adult patients with locally advanced or 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. PADCEV is a Nectin-4-directed antibody and microtubule inhibitor conjugate indicated:
  • in combination with pembrolizumab or pembrolizumab and berahyaluronidase alfa-pmph, as neoadjuvant treatment and then continued after cystectomy as adjuvant treatment, for the treatment of adult patients with muscle invasive bladder cancer (MIBC) who are ineligible for cisplatin-containing chemotherapy. ( 1 )
  • in combination with pembrolizumab or pembrolizumab and berahyaluronidase alfa-pmph, for the treatment of adult patients with locally advanced or metastatic urothelial cancer (mUC). ( 1 )
  • as a single agent for the treatment of adult patients with locally advanced or mUC who: o have previously received a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor and platinum-containing chemotherapy, or o are ineligible for cisplatin-containing chemotherapy and have previously received one or more prior lines of therapy. ( 1 )

    • Dosage and Administration

    2 DOSAGE AND ADMINISTRATION

  • 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. ( 2.3 )
  • 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. PADCEV is administered as neoadjuvant treatment on Days 1 and 8 of each 21-day cycle for 3 cycles or until disease progression that precludes curative intent cystectomy or unacceptable toxicity, followed by adjuvant treatment on Days 1 and 8 of each 21-day cycle for 6 cycles or until disease recurrence or unacceptable toxicity. ( 2.1 )
  • Locally Advanced or mUC: 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 on Days 1 and 8 of a 21-day cycle until disease progression or unacceptable toxicity. ( 2.1 )
  • The recommended dose of PADCEV as a single agent is 1.25 mg/kg (up to a maximum dose of 125 mg) given as an intravenous infusion over 30 minutes on Days 1, 8, and 15 of a 28-day cycle until disease progression or unacceptable toxicity. ( 2.1 )
  • Avoid use in patients with moderate or severe hepatic impairment. ( 8.6 ) 2.1 Recommended Dosage The recommended dosages for PADCEV in combination with pembrolizumab or pembrolizumab and berahyaluronidase alfa-pmph, and PADCEV as a single agent are presented in Table 1 and Table 2 . Administer PADCEV as an intravenous infusion over 30 minutes as recommended [see Instructions for Preparation and Administration ( 2.3 ) ]. Administer PADCEV prior to pembrolizumab or pembrolizumab and berahyaluronidase alfa-pmph if administering on the same day. Table 1. Recommended Dosages for PADCEV in combination with pembrolizumab or pembrolizumab and berahyaluronidase alfa-pmph Administer PADCEV prior to pembrolizumab or pembrolizumab and berahyaluronidase alfa-pmph if administering on the same day. For the recommended dosage of pembrolizumab or pembrolizumab and berahyaluronidase alfa-pmph, refer to the respective Prescribing Information. Indication Recommended PADCEV Dosage Duration of Therapy Neoadjuvant and Adjuvant Muscle Invasive Bladder Cancer (MIBC) PADCEV 1.25 mg/kg (up to a maximum of 125 mg for patients ≥100 kg) on Days 1 and 8 of a 21-day cycle. Neoadjuvant: 3 cycles or until disease progression that precludes curative intent cystectomy or unacceptable toxicity. Adjuvant: 6 cycles or until disease recurrence or unacceptable toxicity. Locally advanced or metastatic Urothelial Cancer (mUC) PADCEV 1.25 mg/kg (up to a maximum of 125 mg for patients ≥100 kg) on Days 1 and 8 of a 21-day cycle. Until disease progression or unacceptable toxicity. Table 2. Recommended Dosages for PADCEV as a single agent Indication Recommended PADCEV Dosage...

    • Side Effects (Adverse Reactions)

    6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling:

  • Skin Reactions [see Boxed Warning , Warnings and Precautions ( 5.1 )]
  • Hyperglycemia [see Warnings and Precautions ( 5.2 )]
  • Pneumonitis/Interstitial Lung Disease (ILD) [see Warnings and Precautions ( 5.3 )]
  • Peripheral Neuropathy [see Warnings and Precautions ( 5.4 )]
  • Ocular Disorders [see Warnings and Precautions ( 5.5 )]
  • Infusion Site Extravasation [see Warnings and Precautions ( 5.6 )] The most common adverse reactions, including laboratory abnormalities, (≥20%) were:
  • PADCEV in combination with intravenous pembrolizumab for the treatment of MIBC: increased glucose, decreased hemoglobin, increased aspartate aminotransferase, rash, increased alanine aminotransferase, fatigue, pruritus, increased creatinine, decreased sodium, decreased lymphocytes, peripheral neuropathy, increased potassium, alopecia, dysgeusia, diarrhea, decreased appetite, constipation, nausea, decreased phosphate, urinary tract infection, dry eye, and decreased weight. ( 6.1 )
  • PADCEV in combination with intravenous pembrolizumab for the treatment of locally advanced or mUC: increased aspartate aminotransferase, increased creatinine, rash, increased glucose, peripheral neuropathy, increased lipase, decreased lymphocytes, increased alanine aminotransferase, decreased hemoglobin, fatigue, decreased sodium, decreased phosphate, decreased albumin, pruritus, diarrhea, alopecia, decreased weight, decreased appetite, increased urate, decreased neutrophils, decreased potassium, dry eye, nausea, constipation, increased potassium, dysgeusia, urinary tract infection, and decreased platelets. ( 6.1 )
  • PADCEV as a single agent: increased glucose, increased aspartate aminotransferase, decreased lymphocytes, increased creatinine, rash, fatigue, peripheral neuropathy, decreased albumin, decreased hemoglobin, alopecia, decreased appetite, decreased neutrophils, decreased sodium, increased alanine aminotransferase, decreased phosphate, diarrhea, nausea, pruritus, increased urate, dry eye, dysgeusia, constipation, increased lipase, decreased weight, decreased platelets, abdominal pain, and dry skin. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Astellas Pharma US, Inc. at 1-800-727-7003 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety population described in the WARNINGS AND PRECAUTIONS reflect exposure to PADCEV 1.25 mg/kg in combination with intravenous pembrolizumab for the treatment of MIBC in 167 patients in EV-303 (NCT03924895) and for the treatment of locally advanced or mUC in 564 patients in EV-302 (NCT04223856) and EV-103 (NCT03288545); PADCEV as a single agent at 1.25 mg/kg in 720 patients in EV-301 (NCT03474107), EV-201 (NCT03219333), EV-203 (NCT04995419), EV-101 (NCT02091999), and EV-102 (NCT03070990). Ocular disorders reflect 384 patients in EV‑201, EV-101, and EV-102. Among 167 patients receiving PADCEV in combination with intravenous pembrolizumab for the treatment of MIBC, the most common (≥20%) adverse reactions, including laboratory abnormalities, were increased glucose, decreased hemoglobin, increased aspartate aminotransferase, rash, increased alanine aminotransferase, fatigue, pruritus, increased creatinine, decreased sodium, decreased lymphocytes, peripheral neuropathy, increased potassium, alopecia, dysgeusia, diarrhea, decreased appetite, constipation, nausea, decreased phosphate, urinary tract infection, dry eye, and decreased weight. Among 564 patients receiving PADCEV in combination with intravenous pembrolizumab for the treatment of locally advanced or mUC, 59% were exposed to PADCEV for ≥6 months, and 24% were exposed for...

    • Drug Interactions

    7 DRUG INTERACTIONS Concomitant use of dual P-gp and strong CYP3A4 inhibitors with PADCEV may increase the exposure to monomethyl auristatin E (MMAE). ( 7.1 ) 7.1 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 [see Clinical Pharmacology ( 12.3 )] , 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.

    Contraindications

    4 CONTRAINDICATIONS None. None. ( 4 )

    Pregnancy and Breastfeeding

    8.1 Pregnancy Risk Summary Based on the mechanism of action and findings in animals, PADCEV can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology ( 12.1 )] . There are no available human data on PADCEV use in pregnant women to inform a drug-associated risk. In an animal reproduction study, administration of enfortumab vedotin-ejfv to pregnant rats during organogenesis caused maternal toxicity, embryo-fetal lethality, structural malformations, and skeletal anomalies at maternal exposures similar to the exposures at the recommended human dose of 1.25 mg/kg (see Data ) . Advise patients of the potential risk to the fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively. Data Animal Data In a rat pilot embryo-fetal development study, administration of enfortumab vedotin-ejfv on gestation day 6 and 13 during the period of organogenesis resulted in a complete litter loss in all pregnant rats at the maternally toxic dose of 5 mg/kg (approximately 3 times the exposure at the recommended human dose). A dose of 2 mg/kg (similar to the exposure at the recommended human dose) resulted in maternal toxicity, embryo-fetal lethality, and structural malformations that included gastroschisis, malrotated hindlimb, absent forepaw, malpositioned internal organs, and fused cervical arch. Additionally, skeletal anomalies (asymmetric, fused, incompletely ossified, and misshapen sternebrae, misshapen cervical arch, and unilateral ossification of the thoracic centra) and decreased fetal weight were observed.

    How Supplied

    16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied PADCEV (enfortumab vedotin-ejfv) 20 mg and 30 mg are supplied as a sterile, preservative-free, white to off-white lyophilized powder in single-dose vials. PADCEV vials are available in the following packages:

  • Carton of one 20 mg single-dose vial (NDC 51144-020-01)
  • Carton of one 30 mg single-dose vial (NDC 51144-030-01) Storage Store PADCEV vials refrigerated at 2ºC to 8ºC (36ºF to 46ºF) in the original carton. Do not freeze. Do not shake. Special Handling PADCEV is a hazardous drug. Follow applicable special handling and disposal procedures. 1

    • About This Information

    This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

    What are side effects?

    Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

    What are drug interactions?

    Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.