PADCEV

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.

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.

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.

® , 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).

• 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.

• 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.

• in combination with pembrolizumab or pembrolizumab and berahyaluronidase alfa-pmph, for the treatment of adult patients with locally advanced or metastatic urothelial cancer (mUC).

• 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.

Mechanism of Action 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. 12.2 Pharmacodynamics In an exposure-response analysis for safety, higher enfortumab vedotin-ejfv exposure was associated with higher incidence of some adverse reactions (e.g., Grade ≥2 peripheral neuropathy, Grade ≥3 hyperglycemia).

The exposure‑response relationship for efficacy has not been fully characterized.

At the recommended dose, PADCEV had no large QTc prolongation (>20 msec). 12.3 Pharmacokinetics Enfortumab vedotin-ejfv (ADC) pharmacokinetics were characterized after single and multiple doses in patients with solid tumors.

The pharmacokinetics of the ADC and unconjugated MMAE were consistent when assessed following PADCEV administration as a single agent and in combination with intravenous pembrolizumab after 1 treatment cycle.

The exposure parameters of the ADC and unconjugated MMAE (the cytotoxic component of enfortumab vedotin-ejfv) are summarized in Table 17 below.

ADC concentrations were observed near the end of intravenous infusion while peak unconjugated MMAE concentrations were observed approximately 2 days after PADCEV dosing.

Minimal accumulation of the ADC and unconjugated MMAE was observed following repeat administration of PADCEV in patients.

Steady-state concentrations of the

ADC were reached after 1 treatment cycle for the ADC as a single agent and in combination with intravenous pembrolizumab.

Table 17.

Exposure Parameters of the ADC and Unconjugated MMAE after First Treatment Cycle of 1.25 mg/kg of PADCEV Dose of Days 1, 8, and 15 C max = maximum concentration, AUC 0-28d = area under the concentration-time curve from time zero to 28 days, C trough,0-28d = pre-dose concentration on day 28.

Mean (± SD) Unconjugated MMAE Mean (± SD) C max 28 µg/mL 5.5 ng/mL AUC 0-28d 110 µg∙d/mL 85 ng∙d/mL C trough,0-28d 0.31 µg/mL 0.81 ng/mL Distribution The estimated mean steady-state volume of distribution of the ADC was 12.8 L following administration of PADCEV.

In vitro, plasma protein binding of unconjugated MMAE ranged from 68% to 82%.

Elimination The ADC and unconjugated

MMAE exhibited multi-exponential declines with an elimination half-life of 3.6 days and 2.6 days, respectively.

The mean clearance (CL) of the ADC and unconjugated MMAE was 0.11 L/h and 2.11 L/h, respectively.

Elimination of unconjugated

MMAE appeared to be limited by its rate of release from the ADC.

Metabolism Catabolism of the

ADC has not been studied in humans; however, it is expected to undergo catabolism to small peptides, amino acids, unconjugated MMAE, and unconjugated MMAE-related catabolites.

The ADC releases

MMAE via proteolytic cleavage, and unconjugated MMAE is primarily metabolized by CYP3A4 in vitro.

Excretion The excretion of the

ADC is not fully characterized.

Following a single-dose of another ADC that contains unconjugated MMAE, 17% of the total unconjugated MMAE administered was recovered in feces and 6% in urine over a 1-week period, primarily as unchanged form.

A similar excretion profile of unconjugated MMAE is expected after PADCEV administration.

No clinically significant differences in the pharmacokinetics of the ADC or unconjugated MMAE were identified based on age (24 to 90 years), sex, race (White, Asian, or Black), renal impairment, and mild hepatic impairment (total bilirubin of to 1.5 × ULN and any AST, or total bilirubin ≤ULN and AST >ULN).

The effect of end-stage renal disease with or without dialysis and moderate or severe hepatic impairment (total bilirubin >1.5 × ULN and any AST) on the pharmacokinetics of the ADC or unconjugated MMAE is unknown.

No clinical trials evaluating the drug-drug interaction potential of the ADC have been conducted.

Pharmacokinetic (PBPK) Modeling Predictions: Dual P-gp and Strong CYP3A4 Inhibitor: Concomitant use of PADCEV with ketoconazole (a dual P-gp and strong CYP3A4 inhibitor) is predicted to increase unconjugated MMAE C max by 15% and AUC by 38%.

CYP3A4 Inducer: Concomitant use of PADCEV with rifampin (a dual P-gp and strong CYP3A4 inducer) is predicted to decrease unconjugated MMAE C max by 28% and AUC by 53%.

CYP3A Substrates: Concomitant use of PADCEV is predicted not to affect exposure to midazolam (a sensitive CYP3A substrate).

MMAE is a substrate of P-glycoprotein (P-gp) and is not an inhibitor of P-gp. 12.6 Immunogenicity The observed incidence of anti-drug antibody (ADA) is highly dependent on the sensitivity and specificity of the assay.

Differences in assay methods preclude meaningful comparisons of the incidence of ADA in the studies described below with the incidence of ADA in other studies, including those of PADCEV or of other enfortumab vedotin products.

ADA was evaluated during the treatment periods (up to 5.5 years) in nine clinical studies of PADCEV as a single agent or in combination with intravenous pembrolizumab at the approved recommended dosages.

• 3.7% (25/684) of patients who received PADCEV as a single agent.

• 1.3% (2/156) of patients who received PADCEV in combination with intravenous pembrolizumab for the treatment of MIBC.

• 7% (34/485) of patients who received PADCEV in combination with intravenous pembrolizumab for the treatment of locally advanced or mUC.

Because of the low occurrence of

ADA, the effect of the ADA on the pharmacokinetics, pharmacodynamics, safety, and/or effectiveness of PADCEV is unknown.

• Pneumonitis/Interstitial Lung Disease (ILD).

• 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.

• 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.

• 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.

To report SUSPECTED ADVERSE

REACTIONS, contact Astellas Pharma US, Inc.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 ≥12 months.

In this pooled population, the most common (≥20%) adverse reactions, including laboratory abnormalities, were 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.

Among 720 patients receiving PADCEV as a single agent, 37% were exposed for ≥6 months, and 14% were exposed for ≥12 months.

In this pooled population, the most common (≥20%) adverse reactions, including laboratory abnormalities, were 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.

The data described in the following section reflects exposure to PADCEV in combination with intravenous pembrolizumab from EV‑302, the dose escalation cohort, Cohort A and Cohort K of EV-103, and EV-303.

Patients received

PADCEV 1.25 mg/kg in combination with intravenous pembrolizumab until disease progression or unacceptable toxicity.

The data described in the following section also reflects exposure to PADCEV as a single agent from an open-label, randomized, trial (EV‑301) and Cohort and Cohort of an open-label, single arm, two cohort trial (EV-201).

PADCEV 1.25 mg/kg until disease progression or unacceptable toxicity.

Neoadjuvant and Adjuvant Treatment of Cisplatin-Ineligible

Patients with MIBC EV-303 The safety of PADCEV in combination with intravenous pembrolizumab as neoadjuvant treatment and continued after radical cystectomy (RC) as adjuvant treatment was evaluated in an open-label, randomized, multicenter trial (EV-303) in patients with previously untreated MIBC who were ineligible for or declined cisplatin-based chemotherapy.

PADCEV 1.25 mg/kg in combination with intravenous pembrolizumab (n=167) before and after RC with pelvic lymph node dissection (PLND) or RC with PLND alone (n=159) .

For the 167 patients who received PADCEV in the neoadjuvant phase, the median duration of exposure to PADCEV was 1.6 months (range: 0.03 to 2.8 months) and the median number of cycles of PADCEV was 3 (range: 1, 3) in the neoadjuvant phase.

For the 92 patients who received PADCEV in the adjuvant phase, the median duration of exposure to PADCEV was 3.7 months (range: 0.03 to 7.6 months) and the median number of cycles of PADCEV was 6 (range: 1, 6) in the adjuvant phase.

Across the combined neoadjuvant and adjuvant phases (n=167), the median number of cycles of PADCEV was 5 (range: 1, 9) out of a planned 9 cycles.

Table 5 summarizes the most common (≥20%) adverse reactions in EV-303.

Table 5.

Reactions ≥20% (All Grades) in Patients Treated with PADCEV in Combination with Intravenous Pembrolizumab in EV-303 Adverse Reaction PADCEV in combination with intravenous pembrolizumab before and after RC with PLND n=167 RC with PLND alone n=159 All Grades % Grade 3-4 % All Grades % Grade 3-4 % Skin and subcutaneous tissue disorders Rash Includes: multiple terms. 54 7 1.3 0 Pruritus 47 3 0 0 Alopecia 35 0.6 0 0 General disorders and administration site conditions Fatigue 47 4.2 6 0.6 Nervous system disorders Peripheral neuropathy 39 3 1.9 0 Dysgeusia 35 0 0 0 Gastrointestinal disorders Diarrhea 34 5 3.1 1.3 Constipation 28 1.8 8 0 Nausea 26 1.2 8 0.6 Metabolism and nutrition disorders Decreased appetite 28 0.6 1.9 0.

Infections and infestations Urinary tract infection 24 12 13 11 Eye disorders Dry eye 21 0 0 0.

Investigations Decreased weight 20 0 3.1 0 Clinically relevant adverse reactions (<20%) include dry skin (15%), hypothyroidism (14%), vomiting (9%), pneumonitis/ILD (4.2%), skin hyperpigmentation (3%), infusion site extravasation (1.2%), and myasthenia gravis and myositis (0.6% each).

Table 6.

Reported in ≥20% (All Grades) of Patients Treated with PADCEV in Combination with Intravenous Pembrolizumab in EV-303 Laboratory Abnormality PADCEV in combination with intravenous pembrolizumab before and after RC with PLND RC with PLND alone All Grades The denominator used to calculate the rate of PADCEV in combination with intravenous pembrolizumab was and the denominator used to calculate the rate for RC and PLND alone varied from to 121 based on the number of patients with a baseline value and at least one post-treatment value. % Grade 3-4 % All Grades % Grade 3-4 % Chemistry Increased glucose 72 12 24 1.7 Increased aspartate aminotransferase 55 6 11 1.8 Increased alanine aminotransferase 53 4.8 13 0.9 Increased creatinine 47 8 31 2.5 Decreased sodium 44 13 18 7 Increased potassium 39 7 20 6 Decreased phosphate 26 6 1.8 0 Hematology Decreased hemoglobin 60 13 48 8 Decreased lymphocytes 40 8 17 1.7 Neoadjuvant Phase of EV-303 A total of 167 patients received at least one dose of PADCEV in combination with intravenous pembrolizumab as neoadjuvant treatment before receiving RC.

In the neoadjuvant phase, serious adverse reactions occurred in 27% of patients receiving PADCEV in combination with intravenous pembrolizumab.

The most frequent (≥2%) serious adverse reactions were urinary tract infection (3.6%) and hematuria (2.4%).

Fatal adverse reactions occurred in 1.2% of patients including myasthenia gravis and toxic epidermal necrolysis (0.6% each).

Additional fatal adverse reactions were reported in 2.7% of patients in the post-surgery phase before adjuvant treatment started, including sepsis and intestinal obstruction (1.4% each).

Adverse reactions leading to discontinuation of

PADCEV in the neoadjuvant phase occurred in 22% of patients.

The most common adverse reactions (≥1%) leading to discontinuation of PADCEV were rash (4.8%), peripheral neuropathy (2.4%), and diarrhea, dysgeusia, fatigue, pruritus, and toxic epidermal necrolysis (1.2% each).

Adverse reactions leading to dose interruption of PADCEV in the neoadjuvant phase occurred in 29% of patients.

The most common adverse reactions (≥2%) leading to dose interruption of PADCEV were rash (8%), neutropenia (3.6%), hyperglycemia (3%), and fatigue and peripheral neuropathy (2.4% each).

Adverse reactions leading to dose reduction of PADCEV in the neoadjuvant phase occurred in 13% of patients.

The most common adverse reactions (≥1%) leading to dose reduction of PADCEV were rash (4.8%), pruritus (1.8%), and peripheral neuropathy, increase alanine aminotransferase, increased aspartate aminotransferase, decreased appetite, fatigue, neutropenia, and decreased weight (1.2% each).

Of the 167 patients in the PADCEV in combination with intravenous pembrolizumab arm who received neoadjuvant treatment, 7 (4.2%) patients did not receive surgery due to adverse reactions.

The adverse reactions that led to cancellation of surgery were acute myocardial infarction, bile duct cancer, colon cancer, respiratory distress, urinary tract infection and the deaths due to myasthenia gravis and toxic epidermal necrolysis (0.6% each).

Of the 146 patients who received neoadjuvant treatment with PADCEV in combination with intravenous pembrolizumab and underwent RC, 6 (4.1%) patients experienced delay of surgery (defined as time from last neoadjuvant treatment to surgery exceeding 8 weeks) due to adverse reactions.

Adjuvant Phase of

EV-303 Patients who did not proceed to surgery were ineligible for adjuvant treatme.

• 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.