PADCEV

Enfortumab vedotin is an antibody-drug conjugate used in the treatment of patients with advanced, treatment-resistant urothelial cancers.

It is comprised of a fully human monoclonal antibody targeted against Nectin-4 and a microtubule-disrupting chemotherapeutic agent, monomethyl auristatin E (MMAE), joined by a protease-cleavable link.

It is similar to brentuximab vedotin, another antibody conjugated with MMAE that targets CD-30 instead of Nectin-4.

The clinical development of enfortumab vedotin was the result of a collaboration between Astellas Pharma and Seattle Genetics and it was first approved for use in the United States in December 2019 under the brand name Padcev TM.

Enfortumab vedotin was later approved by the European Commission on April 13, 2022.

Enfortumab vedotin is indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer who have previously received a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor, and platinum-containing chemotherapy in the neoadjuvant/adjuvant, locally advanced, or metastatic setting. 3, 4 Enfortumab vedotin can also be indicated in combination with pembrolizumab in adult patients with locally advanced or metastatic urothelial cancer who are not eligible for cisplatin-containing chemotherapy under accelerated approval from the FDA.

Enfortumab vedotin is an anti-cancer agent that destroys tumor cells by inhibiting their ability to replicate.

Patients with moderate to severe hepatic impairment should not use enfortumab vedotin.

• although it has not been studied in this population, other MMAE-containing antibody-drug conjugates have demonstrated increased rates of adverse effects in patients with moderate-severe hepatic impairment.

Enfortumab vedotin may also cause significant hyperglycemia leading, in some cases, to diabetic ketoacidosis, and should not be administered to patients with a blood glucose level >250 mg/dl.

Following the first treatment cycle, C max and AUC 0-28d for enfortumab vedotin were 28 µg/mL and 111 µg.d/mL, respectively.

The C max and

AUC 0-28d of unconjugated MMAE following the same cycle were 4.8 ng/mL and 69 ng.d/mL, respectively.

The T max of

MMAE is 1-3 days following the end of the infusion.

The estimated steady-state volume of distribution is 11 L.

The catabolism of enfortumab vedotin has not been studied in humans.

Given its structure, it is expected to be catabolized to smaller peptides, amino acids, unconjugated MMAE, and MMAE metabolites.

MMAE is released from enfortumab vedotin via proteolytic cleavage by intracellular proteases and is metabolized primarily by CYP3A4 in vitro.

Excretion kinetics have not been fully characterized, but may be extrapolated from data available from another MMAE-containing antibody-drug conjugate.

• kinetic studies of this drug demonstrated that 17% of the total MMAE administered was recovered in feces, and 6% was recovered in urine, primarily as unchanged drug, over a 1-week period.

The elimination half-lives of enfortumab vedotin and MMAE are 3.4 days and 2.4 days, respectively.

The mean clearance of enfortumab vedotin and free MMAE was 0.10 L/h and 2.7 L/h, respectively.

The clearance of

MMAE appears to be limited by its rate of release from enfortumab vedotin.

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information regarding enfortumab vedotin is not readily available.

Patients experiencing an overdose are likely at an increased risk of severe adverse effects such as significant nausea, vomiting, neuropathy, or rash.

Symptomatic and supportive measures are recommended.

• 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.

PADCEV is administered as neoadjuvant treatment on Days 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 and 8 of each 21-day cycle for 6 cycles or until disease recurrence or unacceptable toxicity.

• 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 and 8 of a 21-day cycle until disease progression or unacceptable toxicity.

• 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 of a 28-day cycle until disease progression or unacceptable toxicity.

• Avoid use in patients with moderate or severe hepatic impairment. 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 and Table 2.

PADCEV as an intravenous infusion over 30 minutes as recommended.

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 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 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 Duration of Therapy 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, 8, and of a 28-day cycle.

Until disease progression or unacceptable toxicity. 2.2 Dose Modifications Table 3.

Grade is mild, Grade is moderate, Grade is severe, Grade is life-threatening.

Dose Modification Skin Reactions For persistent or recurrent Grade 2 skin reactions Consider withholding until Grade ≤1, then resume treatment at the same dose level or dose reduce by one dose level.

Grade 3 skin reactions Withhold until Grade ≤1, then resume treatment at the same dose level or dose reduce by one dose level.

Immediately withhold, consult a specialist to confirm the diagnosis.

If not

SJS/TEN, see Grade 2-4 skin reactions.

Confirmed SJS or

TEN; Grade 4 or recurrent Grade 3 skin reactions Permanently discontinue.

Blood glucose >250 mg/dL Withhold until elevated blood glucose has improved to ≤250 mg/dL, then resume treatment at the same dose level.

Pneumonitis/Interstitial Lung Disease (ILD) Grade 2 Withhold until Grade ≤1, then resume treatment at the same dose level or consider dose reduction by one dose level.

Grade ≥3 Permanently discontinue.

Grade 2 Withhold until Grade ≤1, then resume treatment at the same dose level (if first occurrence).

For a recurrence, withhold until Grade ≤1, then resume treatment reduced by one dose level.

Grade 3 Withhold until Grade ≤1, then resume treatment at the same dose level or consider dose reduction by one dose level.

Grade 4 Permanently discontinue.

Grade 3, or Grade 2 thrombocytopenia Withhold until Grade ≤1, then resume treatment at the same dose level or consider dose reduction by one dose level.

Grade 4 Withhold until Grade ≤1, then reduce dose by one dose level or discontinue treatment.

Table 4.

Recommended Dose Reduction Schedule Dose Reduction Schedule Dose Level Starting dose 1.25 mg/kg up to 125 mg First dose reduction 1 mg/kg up to 100 mg Second dose reduction 0.75 mg/kg up to 75 mg Third dose reduction 0.5 mg/kg up to 50 mg 2.3 Instructions for Preparation and Administration.

• Administer PADCEV as an intravenous infusion only.

• PADCEV is a hazardous drug.

Follow applicable special handling and disposal procedures.

Prior to administration, the PADCEV vial is reconstituted with Sterile Water for Injection (SWFI).

The reconstituted solution is subsequently diluted in an intravenous infusion bag containing either 5% Dextrose Injection, USP, 0.9% Sodium Chloride Injection, USP, or Lactated Ringer’s Injection, USP.

Vial 1.

Follow procedures for proper handling and disposal of anticancer drugs. 2.

Use appropriate aseptic technique for reconstitution and preparation of dosing solutions. 3.

Calculate the recommended dose based on the patient’s weight to determine the number and strength (20 mg or 30 mg) of vials needed. 4.

Reconstitute each vial as follows and, if possible, direct the stream of SWFI along the walls of the vial and not directly onto the lyophilized powder: a. 20 mg vial: Add 2.3 mL of SWFI, resulting in 10 mg/mL PADCEV. b. 30 mg vial: Add 3.3 mL of SWFI, resulting in 10 mg/mL PADCEV. 5.

Slowly swirl each vial until the contents are completely dissolved.

Allow the reconstituted vial(s) to settle for at least 1 minute until the bubbles are gone.

Do not expose to direct sunlight. 6.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

The reconstituted solution should be clear to slightly opalescent, colorless to light yellow, and free of visible particles.

Discard any vial with visible particles or discoloration. 7.

Based upon the calculated dose amount, the reconstituted solution from the vial(s) should be added to the infusion bag immediately.

This product does not contain a preservative.

If not used immediately, reconstituted vials may be stored for up to 24 hours in refrigeration at 2°C to 8°C (36°F to 46°F).

Discard unused vials with reconstituted solution beyond the recommended storage time.

Bag 1.

Withdraw the calculated dose amount of reconstituted solution from the vial(s) and transfer into an infusion bag. 2.

PADCEV with either 5% Dextrose Injection, 0.9% Sodium Chloride Injection, or Lactated Ringer's Injection.

The infusion bag size should allow enough diluent to achieve a final concentration of 0.3 mg/mL to 4 mg/mL PADCEV. 3.

Mix diluted solution by gentle inversion.

Do not expose to direct sunlight. 4.

Visually inspect the infusion bag for any particulate matter or discoloration prior to use.

USE the infusion bag if particulate matter or discoloration is observed. 5.

Discard any unused portion left in the single-dose vials.

Administration 1.

Immediately administer the infusion over 30 minutes through an intravenous line. 2.

If the infusion is not administered immediately, the prepared infusion bag should not be stored longer than 8 hours at 2°C to 8°C (36°F to 46°F).

DO NOT administer

DO NOT mix

PADCEV with, or administer as an infusion with, other medicinal products.

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.

• 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.

PADCEV is a hazardous drug.

Follow applicable special handling and disposal procedures.

Based on the mechanism of action and findings in animals, PADCEV can cause fetal harm when administered to a pregnant woman.

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.

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.

In a rat pilot embryo-fetal development study, administration of enfortumab vedotin-ejfv on gestation day 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.

Safety and effectiveness of

PADCEV in pediatric patients have not been established.

Of the 167 patients treated with PADCEV in combination with intravenous pembrolizumab for the treatment of MIBC, 37% (n=61) were 65-74 years and 46% (n=77) were 75 years or older.

Of the 564 patients treated with PADCEV in combination with intravenous pembrolizumab for the treatment of locally advanced or mUC, 44% (n=247) were 65‑74 years and 26% (n=144) were 75 years or older.

Of the 720 patients treated with PADCEV as a single agent in clinical trials, 39% (n=282) were 65‑74 years and 24% (n=170) were 75 years or older.

No overall differences in effectiveness were observed between patients 65 years of age or older and younger patients.

Patients 75 years of age or older treated with PADCEV in combination with intravenous pembrolizumab for the treatment of MIBC experienced a higher incidence of fatal adverse reactions than younger patients.

The incidence of fatal adverse reactions was 4% in patients younger than and 12% in patients 75 years or older.

Patients 75 years of age or older treated with PADCEV in combination with intravenous pembrolizumab for the treatment of locally advanced or mUC experienced a higher incidence of fatal adverse reactions than younger patients.

The incidence of fatal adverse reactions was 4% in patients younger than and 7% in patients 75 years or older.

Patients 75 years of age or older treated with PADCEV as a single agent experienced a higher incidence of fatal adverse reactions than younger patients.

The incidence of fatal adverse reactions was 6% in patients younger than 75 years, and 11% in patients 75 years or older.

No significant difference was observed in the pharmacokinetics of PADCEV between patients 65 years and older and younger patients.