2.1 Recommended Dosage

The recommended dose of PADCEV as a single agent is 1.25 mg/kg (up to a maximum of 125 mg for patients ≥100 kg) administered as an intravenous infusion over 30 minutes on Days 1, 8 and 15 of a 28-day cycle until disease progression or unacceptable toxicity.

When given in combination with pembrolizumab, the recommended dose of PADCEV is 1.25 mg/kg (up to a maximum of 125 mg for patients ≥100 kg) administered as an intravenous infusion over 30 minutes on Days 1 and 8 of a 21-day cycle until disease progression or unacceptable toxicity. Refer to the pembrolizumab Prescribing Information for the recommended dosing information of pembrolizumab.

2.2 Dose Modifications

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.1

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.

Reconstitution in Single-dose 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 SHAKE THE VIAL. 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). DO NOT FREEZE. Discard unused vials with reconstituted solution beyond the recommended storage time.

Dilution in Infusion Bag

8.

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

9.

Dilute 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.

10.

Mix diluted solution by gentle inversion. DO NOT SHAKE THE BAG. Do not expose to direct sunlight.

11.

Visually inspect the infusion bag for any particulate matter or discoloration prior to use. The reconstituted solution should be clear to slightly opalescent, colorless to light yellow and free of visible particles. DO NOT USE the infusion bag if particulate matter or discoloration is observed.

12.

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

Administration

13.

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

14.

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 FREEZE.

DO NOT administer PADCEV as an intravenous push or bolus.

DO NOT mix PADCEV with, or administer as an infusion with, other medicinal products.

5.1 Skin Reactions

Severe cutaneous adverse reactions, including fatal cases of SJS or TEN occurred in patients treated with PADCEV. SJS and TEN occurred predominantly during the first cycle of treatment but may occur later.

Skin reactions occurred in 56% (all grades) of the 753 patients treated with PADCEV as a single agent in clinical trials. Twenty-four percent (24%) of patients had maculo-papular rash and 33% had pruritus. Grade 3-4 skin reactions occurred in 12% of patients, including maculo-papular rash, erythematous rash, rash or drug eruption, symmetrical drug-related intertriginous and flexural exanthema (SDRIFE), bullous dermatitis, exfoliative dermatitis, and palmar-plantar erythrodysesthesia. The median time to onset of severe skin reactions was 0.7 months (range: 0.1 to 6 months). Among patients experiencing a skin reaction leading to dose interruption who then restarted PADCEV (n=59), 24% of patients restarting at the same dose and 16% of patients restarting at a reduced dose experienced recurrent severe skin reactions. Skin reactions led to discontinuation of PADCEV in 2.6% of patients [see Adverse Reactions (6.1)].

When PADCEV was given in combination with pembrolizumab, the incidence of skin reactions, including severe events, occurred at a higher rate. Skin reactions occurred in 72% (all grades) of the 121 patients treated with PADCEV in combination with pembrolizumab in clinical trials. The majority of the skin reactions that occurred with combination therapy included maculo-papular rash, macular rash and papular rash. Grade 3-4 skin reactions occurred in 20% of patients (Grade 3: 19%, Grade 4: 0.8%), including maculo-papular rash, bullous dermatitis, dermatitis, exfoliative dermatitis, pemphigoid, rash, erythematous rash, macular rash, and papular rash. A fatal reaction of bullous dermatitis occurred in one patient (0.8%). The median time to onset of severe skin reactions was 2.6 months (range: 0.3 to 16 months). Skin reactions led to discontinuation of PADCEV in 6% of patients [see Adverse Reactions (6.1)].

Monitor patients closely throughout treatment for skin reactions. Consider topical corticosteroids and antihistamines, as clinically indicated.

For persistent or recurrent Grade 2 skin reactions, consider withholding PADCEV until Grade ≤1. Withhold PADCEV and refer for specialized care for suspected SJS, TEN or for Grade 3 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)].

5.2 Hyperglycemia

Hyperglycemia and diabetic ketoacidosis (DKA), including fatal events, occurred in patients with and without pre-existing diabetes mellitus, treated with PADCEV.

Patients with baseline hemoglobin A1C ≥8% were excluded from clinical trials.

In clinical trials of PADCEV as a single agent, 14% of the 753 patients treated with PADCEV developed hyperglycemia; 7% of patients developed Grade 3-4 hyperglycemia. Fatal events of hyperglycemia and diabetic ketoacidosis occurred in one patient each (0.1%). The incidence of Grade 3-4 hyperglycemia increased consistently in patients with higher body mass index and in patients with higher baseline A1C. Five percent (5%) of patients required initiation of insulin therapy for treatment of hyperglycemia. The median time to onset of hyperglycemia was 0.6 months (range: 0.1 to 20 months). Hyperglycemia led to discontinuation of PADCEV in 0.4% of patients [see Adverse Reactions (6.1)].

Closely monitor blood glucose levels in patients with, or at risk for, diabetes mellitus or hyperglycemia.

If blood glucose is elevated (>250 mg/dL), withhold PADCEV [see Dosage and Administration (2.2)].

5.3 Pneumonitis/Interstitial Lung Disease (ILD)

Severe, life-threatening or fatal pneumonitis/ILD occurred in patients treated with PADCEV.

In clinical trials of PADCEV as a single agent, 2.9% of the 753 patients treated with PADCEV had pneumonitis/ILD of any grade and 0.8% had Grade 3-4. The median time to onset of pneumonitis/ILD was 2.7 months (range: 0.6 to 6 months).

The incidence of pneumonitis/ILD, including severe events occurred at a higher rate when PADCEV was given in combination with pembrolizumab. When PADCEV was given in combination with pembrolizumab, 9% of the 121 patients treated with combination therapy had pneumonitis/ILD of any grade and 3.3% had Grade 3. A fatal event of pneumonitis occurred in one patient (0.8%). The median time to onset of pneumonitis/ILD was 6 months (range: 0.6 to 26 months).

Monitor patients for signs and symptoms indicative of pneumonitis/ILD such as hypoxia, cough, dyspnea or interstitial infiltrates on radiologic exams. Evaluate and exclude infectious, neoplastic and other causes for such signs and symptoms through appropriate investigations.

Withhold PADCEV for patients who develop Grade 2 pneumonitis/ILD and consider dose reduction. Permanently discontinue PADCEV in all patients with Grade 3 or 4 pneumonitis/ILD [see Dosage and Administration (2.2)].

5.4 Peripheral Neuropathy

Peripheral neuropathy occurred in 53% of the 753 patients treated with PADCEV as a single agent in clinical trials including 40% with sensory neuropathy, 7% with muscular weakness and 7% with motor neuropathy. Thirty percent of patients experienced Grade 2 reactions and 5% experienced Grade 3-4 reactions. Peripheral neuropathy occurred in patients treated with PADCEV with or without preexisting peripheral neuropathy. The median time to onset of Grade ≥2 peripheral neuropathy was 4.9 months (range: 0.1 to 20 months). Neuropathy led to treatment discontinuation in 7% of patients [see Adverse Reactions (6.1)]. Of the patients who experienced neuropathy who had data regarding resolution (N = 319) 14% had complete resolution, 46% had partial improvement, and 40% had no improvement at the time of their last evaluation. Of the 86% of patients with residual neuropathy at last evaluation, 51% had Grade 2 or greater neuropathy at the time of their last evaluation.

The incidence of peripheral neuropathy occurred at a higher rate when PADCEV was given in combination with pembrolizumab. When PADCEV was given in combination with pembrolizumab, 65% of the 121 patients treated with combination therapy had peripheral neuropathy of any grade, 45% had Grade 2 neuropathy, and 3.3% had Grade 3 neuropathy. The median time to onset of Grade ≥2 peripheral neuropathy was 6 months (range: 0.3 to 25 months).

Monitor patients for symptoms of new or worsening peripheral neuropathy and consider dose interruption or dose reduction of PADCEV when peripheral neuropathy occurs.

Permanently discontinue PADCEV in patients who develop Grade >3 peripheral neuropathy [see Dosage and Administration (2.2)].

5.5 Ocular Disorders

Ocular disorders were reported in 40% of the 384 patients treated with PADCEV as a single agent in clinical trials in which ophthalmologic exams were scheduled. The majority of these events involved the cornea and included events associated with dry eye such as keratitis, blurred vision, increased lacrimation, conjunctivitis, limbal stem cell deficiency, and keratopathy.

Dry eye symptoms occurred in 34% of patients, and blurred vision occurred in 13% of patients, during treatment with PADCEV. The median time to onset to symptomatic ocular disorder was 1.6 months (range: 0 to 19 months). Monitor patients for ocular disorders. Consider artificial tears for prophylaxis of dry eyes and ophthalmologic evaluation if ocular symptoms occur or do not resolve. Consider treatment with ophthalmic topical steroids, if indicated after an ophthalmic exam. Consider dose interruption or dose reduction of PADCEV for symptomatic ocular disorders.

5.6 Infusion Site Extravasation

Skin and soft tissue reactions secondary to extravasation have been observed after administration of PADCEV. Of the 753 patients treated with PADCEV as a single agent in clinical trials, 1.5% of patients experienced skin and soft tissue reactions, including 0.3% who experienced Grade 3-4 reactions. Reactions may be delayed. Erythema, swelling, increased temperature, and pain worsened until 2-7 days after extravasation and resolved within 1-4 weeks of peak. Two patients (0.3%) developed extravasation reactions with secondary cellulitis, bullae, or exfoliation. Ensure adequate venous access prior to starting PADCEV and monitor for possible extravasation during administration. If extravasation occurs, stop the infusion and monitor for adverse reactions.

5.7 Embryo-Fetal Toxicity

Based on the mechanism of action and findings in animals, PADCEV can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of enfortumab vedotin-ejfv to pregnant rats during the period of organogenesis caused maternal toxicity, embryo-fetal lethality, structural malformations and skeletal anomalies at maternal exposures similar to the clinical exposures at the recommended human dose of 1.25 mg/kg.

Advise patients of the potential risk to the fetus. Advise female patients of reproductive potential to use effective contraception during treatment with PADCEV and for 2 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with PADCEV and for 4 months after the last dose [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.1)].

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 pooled safety population described in the WARNINGS AND PRECAUTIONS reflect exposure to PADCEV as a single agent at 1.25 mg/kg in 753 patients in EV-301, EV-201, EV-103, EV-101 (NCT02091999), and EV-102 (NCT03070990). In addition, certain subsections in the WARNINGS AND PRECAUTIONS describe adverse reactions observed with exposure to PADCEV in combination with pembrolizumab at 1.25 mg/kg in 121 patients in EV-103. Ocular disorders reflect 384 patients in EV-201, EV-101, and EV-102. Among 753 patients receiving PADCEV as a single agent, 25% were exposed for >6 months, and 13% were exposed for ≥12 months. In this pooled population, the most common (>20%) adverse reactions, including laboratory abnormalities, were rash, aspartate aminotransferase increased, glucose increased, creatinine increased, fatigue, peripheral neuropathy, lymphocytes decreased, alopecia, decreased appetite, hemoglobin decreased, diarrhea, sodium decreased, nausea, pruritus, phosphate decreased, dysgeusia, alanine aminotransferase increased, anemia, albumin decreased, neutrophils decreased, urate increased, lipase increased, platelets decreased, decreased weight and dry skin.

The data described in the following sections reflect exposure to PADCEV as a single agent from an open-label, randomized, study (EV‑301); Cohort 1 and Cohort 2 of an open-label, single arm, two cohort study (EV-201); and Cohort K of an open-label, multi-cohort study (EV-103). Patients received PADCEV 1.25 mg/kg until disease progression or unacceptable toxicity.

The data described in the following section also reflects exposure to PADCEV in combination with pembrolizumab from the dose escalation cohort, Cohort A and Cohort K of EV-103. Patients received PADCEV 1.25 mg/kg in combination with pembrolizumab until disease progression or unacceptable toxicity.

Previously Treated Locally Advanced or Metastatic Urothelial Cancer

EV-301

The safety of PADCEV was evaluated as a single agent in EV-301 in patients with locally advanced or metastatic urothelial cancer (n=296) who received at least one dose of PADCEV 1.25 mg/kg and who were previously treated with a PD-1 or PD-L1 inhibitor and a platinum-based chemotherapy [see Clinical Studies (14)]. Routine ophthalmologic exams were not conducted in EV-301. The median duration of exposure to PADCEV was 5 months (range: 0.5 to 19 months).

Serious adverse reactions occurred in 47% of patients treated with PADCEV. The most common serious adverse reactions (≥2%) were urinary tract infection, acute kidney injury (7% each) and pneumonia (5%). Fatal adverse reactions occurred in 3% of patients, including multiorgan dysfunction (1.0%), hepatic dysfunction, septic shock, hyperglycemia, pneumonitis and pelvic abscess (0.3% each).

Adverse reactions leading to discontinuation occurred in 17% of patients; the most common adverse reactions (≥2%) leading to discontinuation were peripheral neuropathy (5%) and rash (4%).

Adverse reactions leading to dose interruption occurred in 61% of patients; the most common adverse reactions (≥4%) leading to dose interruption were peripheral neuropathy (23%), rash (11%) and fatigue (9%).

Adverse reactions leading to dose reduction occurred in 34% of patients; the most common adverse reactions (≥2%) leading to dose reduction were peripheral neuropathy (10%), rash (8%), decreased appetite (3%) and fatigue (3%).

Table 3 summarizes the most common (≥15%) adverse reactions in EV-301.

Clinically relevant adverse reactions (<15%) include vomiting (14%), aspartate aminotransferase increased (12%), hyperglycemia (10%), alanine aminotransferase increased (9%), pneumonitis (3%) and infusion site extravasation (0.7%).

EV-201, Cohort 1

The safety of PADCEV was evaluated as a single agent in EV-201, Cohort 1 in patients (n=125) with locally advanced or metastatic urothelial cancer who had received prior treatment with a PD-1 or PD-L1 inhibitor and platinum-based chemotherapy [see Clinical Studies (14)]. Patients received PADCEV 1.25 mg/kg on Days 1, 8 and 15 of a 28-day cycle until disease progression or unacceptable toxicity. The median duration of exposure to PADCEV was 4.6 months (range: 0.5-15.6).

Serious adverse reactions occurred in 46% of patients treated with PADCEV. The most common serious adverse reactions (≥3%) were urinary tract infection (6%), cellulitis (5%), febrile neutropenia (4%), diarrhea (4%), sepsis (3%), acute kidney injury (3%), dyspnea (3%), and rash (3%). Fatal adverse reactions occurred in 3.2% of patients, including acute respiratory failure, aspiration pneumonia, cardiac disorder, sepsis and pneumonitis (each 0.8%).

Adverse reactions leading to discontinuation occurred in 16% of patients; the most common adverse reaction leading to discontinuation was peripheral neuropathy (6%).

Adverse reactions leading to dose interruption occurred in 64% of patients; the most common adverse reactions leading to dose interruption were peripheral neuropathy (18%), rash (9%) and fatigue (6%).

Adverse reactions leading to dose reduction occurred in 34% of patients; the most common adverse reactions leading to dose reduction were peripheral neuropathy (12%), rash (6%) and fatigue (4%).

Table 5 summarizes the All Grades and Grades 3-4 adverse reactions reported in patients in EV-201, Cohort 1.

Clinically relevant adverse reactions (<15%) include herpes zoster (3%), pneumonitis (2%) and infusion site extravasation (2%).

EV-201, Cohort 2

The safety of PADCEV was evaluated as a single agent in EV-201, Cohort 2 in patients with locally advanced or metastatic urothelial cancer (n=89) who received at least one dose of PADCEV 1.25 mg/kg and had prior treatment with a PD-1 or PD-L1 inhibitor and were not eligible for cisplatin-based chemotherapy. The median duration of exposure was 5.98 months (range: 0.3 to 24.6 months).

Serious adverse reactions occurred in 39% of patients treated with PADCEV. The most common serious adverse reactions (≥3%) were pneumonia, sepsis and diarrhea (5% each). Fatal adverse reactions occurred in 8% of patients, including acute kidney injury (2.2%), metabolic acidosis, sepsis, multiorgan dysfunction, pneumonia and pneumonitis (1.1% each).

Adverse reactions leading to discontinuation occurred in 20% of patients; the most common adverse reaction (≥2%) leading to discontinuation was peripheral neuropathy (7%).

Adverse reactions leading to dose interruption occurred in 60% of patients; the most common adverse reactions (≥3%) leading to dose interruption were peripheral neuropathy (19%), rash (9%), fatigue (8%), diarrhea (5%), aspartate aminotransferase increased (3%) and hyperglycemia (3%).

Adverse reactions leading to dose reduction occurred in 49% of patients; the most common adverse reactions (≥3%) leading to dose reduction were peripheral neuropathy (19%), rash (11%) and fatigue (7%).

Table 7 summarizes the All Grades and Grades 3-4 adverse reactions reported in patients in EV-201, Cohort 2.

Clinically relevant adverse reactions (<15%) include vomiting (13%), aspartate aminotransferase increased (12%), lipase increased (11%), alanine aminotransferase increased (10%), pneumonitis (4%) and infusion site extravasation (1%).

Previously Untreated Cisplatin Ineligible Patients with Locally Advanced or Metastatic Urothelial Carcinoma

EV-103

The safety of PADCEV was evaluated in combination with pembrolizumab in a multi cohort study (EV-103) in 121 patients with locally advanced or metastatic urothelial cancer who were not eligible for cisplatin-containing chemotherapy and received at least one dose of PADCEV 1.25 mg/kg and pembrolizumab [see Clinical Studies (14)]. The median duration of exposure to PADCEV was 7 months (range: 0.6 to 33 months).

Serious adverse reactions occurred in 50% of patients treated with PADCEV in combination with pembrolizumab. The most common serious adverse reactions (≥2%) were acute kidney injury (7%), urinary tract infection (7%), urosepsis (5%), sepsis (3.3%), pneumonia (3.3%), hematuria (3.3%), pneumonitis (3.3%), urinary retention (2.5%), diarrhea (2.5%), myasthenia gravis (2.5%), myositis (2.5%), anemia (2.5%), and hypotension (2.5%).

Fatal adverse reactions occurred in 5% of patients treated with PADCEV in combination with pembrolizumab including sepsis (1.6%), bullous dermatitis (0.8%), myasthenia gravis (0.8%), and pneumonitis/ILD (0.8%).

Adverse reactions leading to discontinuation of PADCEV occurred in 36% of patients. The most common adverse reactions (≥2%) leading to discontinuation of PADCEV were peripheral neuropathy (20%) and rash (6%).

Adverse reactions leading to dose interruption of PADCEV occurred in 69% of patients. The most common adverse reactions (≥2%) leading to dose interruption of PADCEV were peripheral neuropathy (18%), rash (12%), lipase increased (6%), pneumonitis (6%), diarrhea (4.1%), acute kidney injury (3.3%), alanine aminotransferase increased (3.3%), fatigue (3.3%), neutropenia (3.3%), urinary tract infection (3.3%), amylase increased (2.5%), anemia (2.5%), COVID-19 (2.5%), hyperglycemia (2.5%), and hypotension (2.5%).

Adverse reactions leading to dose reduction of PADCEV occurred in 45% of patients. The most common adverse reactions (≥2%) leading to dose reduction of PADCEV were peripheral neuropathy (17%), rash (12%), fatigue (5%), neutropenia (5%), and diarrhea (4.1%).

The most common adverse reactions (>20%), including laboratory abnormalities, of PADCEV in combination with pembrolizumab were glucose increased, aspartate aminotransferase increased, rash, hemoglobin decreased, creatinine increased, peripheral neuropathy, lymphocytes decreased, fatigue, alanine aminotransferase increased, sodium decreased, lipase increased, albumin decreased, alopecia, phosphate decreased, decreased weight, diarrhea, pruritus, decreased appetite, nausea, dysgeusia, potassium decreased, neutrophils decreased, urinary tract infection, constipation, potassium increased, calcium increased, peripheral edema, dry eye, dizziness, arthralgia, and dry skin.

Table 9 summarizes the most common (≥20%) adverse reactions in EV-103.

Clinically relevant adverse reactions (<20%) include vomiting (19.8%), pyrexia (18%), hypothyroidism (11%), pneumonitis (9%), myasthenia gravis (2.5%), myositis (3.3%), and infusion site extravasation (0.8%).

Table 10. Selected Laboratory Abnormalities ≥20% (All Grades) in Patients Treated with PADCEV in Combination with Pembrolizumab in EV-103

6.2 Post Marketing Experience

The following adverse reactions have been identified during post-approval use of PADCEV. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Skin and subcutaneous tissue disorders: Epidermal necrosis, Stevens-Johnson syndrome, toxic epidermal necrolysis [see Warnings and Precautions (5.1)].

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.

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.

8.2 Lactation

Risk Summary

There are no data on the presence of enfortumab vedotin-ejfv in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise lactating women not to breastfeed during treatment with PADCEV and for at least 3 weeks after the last dose.

8.3 Females and Males of Reproductive Potential

Pregnancy Testing

Verify pregnancy status in females of reproductive potential prior to initiating PADCEV treatment [see Use in Specific Populations (8.1)].

Contraception

Females

PADCEV can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with PADCEV and for 2 months after the last dose.

Males

Advise male patients with female partners of reproductive potential to use effective contraception during treatment with PADCEV and for 4 months after the last dose.

Infertility

Females

Based on findings in animal studies with MMAE-containing antibody-drug conjugates (ADCs), PADCEV may impair female fertility. The effect on fertility is reversible [see Nonclinical Toxicology (13.1)].

Males

Based on findings from animal studies, PADCEV may impair male fertility [see Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

Safety and effectiveness of PADCEV in pediatric patients have not been established.

8.5 Geriatric Use

Of the 753 patients treated with PADCEV as a single agent in clinical trials, 40% (n=300) were 65-74 years and 27% (n=202) were 75 years or older. Of the 121 patients treated with PADCEV in combination with pembrolizumab, 43% (n=52) were 65-74 years and 33% (n=40) were 75 years or older. No overall differences in effectiveness were observed between patients 65 years of age or older and younger patients.

Patients 65 years of age or older treated with PADCEV as a single agent experienced a higher incidence of serious and fatal adverse reactions than younger patients. In clinical trials, the incidence of serious adverse reactions was 42% in patients younger than 65 years, 45% in patients ages 65-74 years, and 49% in patients 75 years or older. The incidence of fatal adverse reactions was 4.4% in patients younger than 65 years, 6% in patients ages 65-74 years, and 11% in patients 75 years or older. The incidence of treatment discontinuations of PADCEV due to adverse reactions was 17% in patients younger than 65 years, 20% in patients ages 65-74 years, and 26% in patients 75 years or older.

There were an insufficient number of patients treated with PADCEV in combination with pembrolizumab in clinical trials to accurately characterize safety by age.

No significant difference was observed in the pharmacokinetics of PADCEV between patients 65 years and older and younger patients [see Clinical Pharmacology (12.3)].

8.6 Hepatic Impairment

Avoid the use of PADCEV in patients with moderate or severe hepatic impairment (total bilirubin >1.5 x ULN and AST any). PADCEV has only been studied in a limited number of patients with moderate hepatic impairment (n=3) and has not been evaluated in patients with severe hepatic impairment [see Clinical Pharmacology (12.3)]. In another ADC that contains MMAE, the frequency of ≥ Grade 3 adverse reactions and deaths was greater in patients with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment compared to patients with normal hepatic function. No adjustment in the starting dose is required when administering PADCEV to patients with mild hepatic impairment (total bilirubin 1 to 1.5 × ULN and AST any, or total bilirubin ≤ULN and AST >ULN).

8.7 Renal Impairment

No dose adjustment is required in patients with mild (CrCL >60-90 mL/min), moderate (CrCL 30-60 mL/min) or severe (CrCL <30 mL/min) renal impairment [see Clinical Pharmacology (12.3)].

12.1 Mechanism of Action

Enfortumab vedotin-ejfv is an ADC. The antibody is a human IgG1 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, 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.

Cardiac Electrophysiology

At the recommended dose, PADCEV had no large QTc prolongation (>20 msec).

12.3 Pharmacokinetics

Population pharmacokinetic analysis included data from 748 patients treated with PADCEV as a single agent in clinical trials. Enfortumab vedotin-ejfv pharmacokinetics were characterized after single and multiple doses in patients with locally advanced or metastatic urothelial carcinoma and other solid tumors.

The pharmacokinetics of ADC and unconjugated MMAE were consistent when assessed following PADCEV administration as a single agent and in combination with pembrolizumab.

The exposure parameters of ADC and unconjugated MMAE (the cytotoxic component of enfortumab vedotin-ejfv) are summarized in Table 11 below. 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. Minimal accumulation of the ADC and unconjugated MMAE was observed following repeat administration of enfortumab vedotin-ejfv in patients. Steady-state concentrations of ADC and unconjugated MMAE were reached after 1 treatment cycle.

Distribution

The estimated mean steady-state volume of distribution of ADC was 12.8 liters following administration of enfortumab vedotin-ejfv. Plasma protein binding of unconjugated MMAE ranged from 68% to 82%, in vitro.

Elimination

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 enfortumab vedotin-ejfv and unconjugated MMAE in patients was 0.11 L/h and 2.11 L/h, respectively, in patients. Elimination of unconjugated MMAE appeared to be limited by its rate of release from enfortumab vedotin-ejfv.

Metabolism

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

Excretion

The excretion of enfortumab vedotin-ejfv 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 drug. A similar excretion profile of unconjugated MMAE is expected after enfortumab vedotin-ejfv administration.

Specific Populations

Based on population pharmacokinetic analysis, no clinically significant differences in the pharmacokinetics of enfortumab vedotin-ejfv were observed based on age (24 to 90 years), sex, or race/ethnicity (Caucasian, Asian, Black, or others).

Hepatic Impairment

Based on population pharmacokinetics analysis, there was a 37% AUC0-28d increase in unconjugated MMAE exposure observed in patients with mild hepatic impairment (total bilirubin of 1 to 1.5 × ULN and AST any, or total bilirubin ≤ULN and AST >ULN, n=65) compared to normal hepatic function. Enfortumab vedotin-ejfv has only been studied in limited number of patients with moderate hepatic impairment and has not been evaluated in patients with severe hepatic impairment. The effect of moderate or severe hepatic impairment (total bilirubin >1.5 x ULN and AST any) or liver transplantation on the pharmacokinetics of ADC or unconjugated MMAE is unknown.

Renal Impairment

The pharmacokinetics of enfortumab vedotin-ejfv and unconjugated MMAE were evaluated after the administration of 1.25 mg/kg of enfortumab vedotin-ejfv to patients with mild (creatinine clearance; CrCL >60–90 mL/min; n=272), moderate (CrCL 30–60 mL/min; n=315) and severe (CrCL <30 mL/min; n=25) renal impairment. No significant differences in exposure (AUC) of ADC and unconjugated MMAE were observed in patients with mild, moderate or severe renal impairment compared to patients with normal renal function. The effect of end stage renal disease with or without dialysis on the pharmacokinetics of ADC or unconjugated MMAE is unknown.

Drug Interaction Trials

No clinical trials evaluating the drug-drug interaction potential of enfortumab vedotin-ejfv have been conducted.

Physiologically Based Pharmacokinetic (PBPK) Modeling Predictions:

Dual P-gp and Strong CYP3A4 Inhibitor: Concomitant use of enfortumab vedotin-ejfv with ketoconazole (a dual P-gp and strong CYP3A4 inhibitor) is predicted to increase unconjugated MMAE Cmax by 15% and AUC by 38%.

Dual P-gp and Strong CYP3A4 Inducer: Concomitant use of enfortumab vedotin-ejfv with rifampin (a dual P-gp and strong CYP3A4 inducer) is predicted to decrease unconjugated MMAE Cmax by 28% and AUC by 53%.

Sensitive CYP3A substrates: Concomitant use of enfortumab vedotin-ejfv is predicted not to affect exposure to midazolam (a sensitive CYP3A substrate).

In Vitro Studies

Transporter Systems: MMAE is a substrate of P-glycoprotein (P-gp), but 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.

In the 0.3-to-52.1-month treatment periods with ADA sampling in five clinical studies of PADCEV 1.25 mg/kg as a single agent in patients with locally advanced or metastatic urothelial cancer [see Clinical Studies (14)],the incidence of treatment emergent anti-enfortumab vedotin-ejfv antibody formation was 3.6% [23 of 640 total PADCEV-treated patients who were tested for ADA]. When PADCEV was administered in combination with pembrolizumab, the incidence of treatment emergent ADA against enfortumab vedotin-ejfv was 2.9% [3 of 105 total PADCEV-treated patients who were tested for ADA]. The incidence of treatment-emergent anti-enfortumab-ejfv antibody formation was consistent when assessed following PADCEV administration as a single agent and in combination with pembrolizumab.

Because of the low occurrence of ADA, the effect of these antibodies on the pharmacokinetics, pharmacodynamics, safety and/or effectiveness of PADCEV is unknown.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies with enfortumab vedotin-ejfv or the small molecule cytotoxic agent (MMAE) have not been conducted.

MMAE was genotoxic in the rat bone marrow micronucleus study through an aneugenic mechanism. This effect is consistent with the pharmacological effect of MMAE as a microtubule-disrupting agent. MMAE was not mutagenic in the bacterial reverse mutation assay (Ames test) or the L5178Y mouse lymphoma forward mutation assay.

Fertility studies with enfortumab vedotin-ejfv or MMAE have not been conducted. However, results of repeat-dose toxicity studies indicate the potential for enfortumab vedotin-ejfv to impair female and male reproductive function and fertility.

In repeat-dose toxicology studies conducted in rats for up to 13 weeks, doses ≥2 mg/kg enfortumab vedotin-ejfv (at exposures similar to the exposures at the recommended human dose) resulted in decreases in testes and epididymis weights, seminiferous tubule degeneration, spermatid/spermatocyte depletion in the testes and cell debris, sperm granuloma and hypospermia/abnormal spermatids in the epididymis. Findings in the testes and epididymis did not reverse by the end of the recovery period.

MMAE-containing ADCs have been associated with adverse ovarian effects when administered to sexually immature animals. Adverse effects included decrease in, or absence of, secondary and tertiary ovarian follicles after weekly administration to cynomolgus monkeys in studies of 4-week duration. These effects showed a trend towards recovery 6 weeks after the end of dosing; no changes were observed in primordial follicles.

14.1 Metastatic Urothelial Cancer

Previously Treated Locally Advanced or Metastatic Urothelial Carcinoma

EV-301

The efficacy of PADCEV as a single agent was evaluated in EV-301 (NCT03474107), an open-label, randomized, multicenter trial that enrolled 608 patients with locally advanced or metastatic urothelial cancer who received prior treatment with a PD-1 or PD-L1 inhibitor and platinum-based chemotherapy. Patients were randomized 1:1 to receive either PADCEV 1.25 mg/kg on Days 1, 8 and 15 of a 28-day cycle or investigator’s choice of chemotherapy. Randomization was stratified by ECOG PS (0 vs 1), region of world (Western Europe vs US vs Rest of World), and presence of liver metastasis.

Patients were excluded if they had active central nervous system (CNS) metastases, ongoing sensory or motor neuropathy ≥Grade 2, or uncontrolled diabetes defined as hemoglobin A1C (HbA1c) ≥8% or HbA1c ≥7% with associated diabetes symptoms.

The median age was 68 years (range: 30 to 88 years) and 77% were male. Racial demographics were reported as White (52%), Asian (33%), Black (0.7%), Native Hawaiian or Other Pacific Islander (0.2%) or not reported (15%). Nine percent of patients were Hispanic or Latino. All patients had a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0 (40%) or 1 (60%). Thirty-four percent of patients had tumors located in the upper tract that included the renal pelvis and ureter. Eighty percent of patients had visceral metastases including 31% with liver metastases. Seventy-six percent of patients had pure transitional cell carcinoma (TCC) histology; 14% had TCC with other histologic variants; and 10% had other tumor histologies including adenocarcinoma and squamous cell carcinoma. The median number of prior therapies was 2 (range 1 to ≥3). Sixty-three percent of patients received prior cisplatin-based regimens, 26% received prior carboplatin-based regimens, and an additional 11% received both cisplatin and carboplatin-based regimens. Patients on the control arm received docetaxel (38%), paclitaxel (36%) or vinflunine (25%).

The major efficacy outcome measures were overall survival (OS), progression free survival (PFS), and overall response rate (ORR) assessed by investigator using RECIST v1.1. Efficacy results were consistent across all stratified patient subgroups.

Table 12 and Figures 2-3 summarize the efficacy results for EV-301.

EV-201, Cohort 1

The efficacy of PADCEV as a single agent was also investigated in Cohort 1 of EV-201 (NCT03219333), a single-arm, multi-cohort, multicenter trial that enrolled 125 patients with locally advanced or metastatic urothelial cancer who received prior treatment with a PD-1 or PD-L1 inhibitor and a platinum-based chemotherapy. Patients were excluded if they had active central nervous system (CNS) metastases, ongoing sensory or motor neuropathy ≥Grade 2, heart failure, or uncontrolled diabetes defined as hemoglobin A1C (HbA1c) ≥8% or HbA1c ≥7% with associated diabetes symptoms.

PADCEV was administered at a dose of 1.25 mg/kg, as an intravenous (IV) infusion on days 1, 8, and 15 of each 28-day cycle.

The median age was 69 years (range: 40 to 84 years) and 70% were male. Racial demographics were reported as White (85%), Asian (9%), Black (2%), Other (0.8%) or not reported (4%). Four percent of patients were Hispanic or Latino. All patients had a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0 (32%) or 1 (68%). Ninety percent of patients had visceral metastases including 40% with liver metastases. Approximately two-thirds (67%) of patients had pure transitional cell carcinoma (TCC) histology; 33% had TCC with other histologic variants. The median number of prior systemic therapies was 3 (range: 1 to 6). Sixty-six percent of patients received prior cisplatin-based regimens, 26% received prior carboplatin-based regimens, and an additional 8% received both cisplatin and carboplatin-based regimens.

The major efficacy outcome measures were confirmed objective response rate (ORR) and duration of response (DOR) assessed by blinded independent central review (BICR) using RECIST v1.1.

Efficacy results are presented in Table 13.

Previously Treated Cisplatin Ineligible Patients with Locally Advanced or Metastatic Urothelial Carcinoma

EV-201, Cohort 2

The efficacy of PADCEV as a single agent was also evaluated in Cohort 2 of EV-201, a single-arm, multi-cohort, multicenter trial in 89 patients with locally advanced or metastatic urothelial cancer who received prior treatment with a PD-1 or PD-L1 inhibitor and were cisplatin ineligible and did not receive platinum in the locally advanced or metastatic setting. Patients were excluded if they had active CNS metastases, ongoing sensory or motor neuropathy ≥Grade 2, heart failure, or uncontrolled diabetes defined as hemoglobin A1C (HbA1c) ≥8% or HbA1c ≥7% with associated diabetes symptoms.

PADCEV was administered at a dose of 1.25 mg/kg, as an intravenous (IV) infusion on days 1, 8, and 15 of each 28-day cycle.

The median age was 75 years (range: 49 to 90 years), 74% were male. Racial demographics were reported as White (70%), Asian (22%) or not reported (8%). One percent of patients were Hispanic or Latino. Patients had a baseline ECOG performance status of 0 (42%), 1 (46%) and 2 (12%). Forty-three percent of patients had tumors located in the upper tract that included the renal pelvis and ureter. Seventy-nine percent of patients had visceral metastases and 24% had liver metastases.

Reasons for cisplatin ineligibility included: 66% with baseline creatinine clearance of 30 – 59 mL/min, 7% with ECOG PS of 2, 15% with Grade 2 or greater hearing loss, and 12% with more than one cisplatin-ineligibility criteria. Seventy percent of patients had TCC histology; 13% had TCC with squamous differentiation and 17% had TCC with other histologic variants.

The median number of prior systemic therapies was 1 (range: 1 to 4).

Efficacy results are presented in Table 14 below.

Previously Untreated Cisplatin Ineligible Patients with Locally Advanced or Metastatic Urothelial Carcinoma

EV-103

The efficacy of PADCEV in combination with pembrolizumab was evaluated in EV-103 (NCT03288545), an open-label, multi-cohort (dose escalation cohort, Cohort A, Cohort K) study in patients with locally advanced or metastatic urothelial cancer who were ineligible for cisplatin-containing chemotherapy and received no prior systemic therapy for locally advanced or metastatic disease. Patients with active CNS metastases, ongoing sensory or motor neuropathy Grade ≥2, or uncontrolled diabetes defined as hemoglobin A1C (HbA1c) ≥8% or HbA1c ≥7% with associated diabetes symptoms were excluded from participating in the study.

Patients in the dose escalation cohort (n=5), Cohort A (n=40), and Cohort K (n=76) received PADCEV 1.25 mg/kg as an IV infusion over 30 minutes on Days 1 and 8 of a 21-day cycle followed by pembrolizumab 200 mg as an IV infusion on Day 1 of a 21-day cycle approximately 30 minutes after PADCEV. Patients were treated until disease progression or unacceptable toxicity.

A total of 121 patients received PADCEV in combination with pembrolizumab. The median age was 71 years (range: 51 to 91); 74% were male; 85% were White, 5% were Black, 4% were Asian and 6% were other, unknown or not reported. Ten percent of patients were Hispanic or Latino. Forty-five percent of patients had an ECOG performance status of 1 and 15% had an ECOG performance status of 2. Forty-seven percent of patients had a documented baseline HbA1c of <5.7%. Reasons for cisplatin ineligibility included: 60% with baseline creatinine clearance of 30 ̶ 59 mL/min, 10% with ECOG PS of 2, 13% with Grade 2 or greater hearing loss, and 16% with more than one cisplatin-ineligibility criteria.

At baseline, 97.5% of patients had metastatic urothelial cancer and 2.5% of patients had locally advanced urothelial cancer. Thirty-seven percent of patients had upper tract disease. Eighty-four percent of patients had visceral metastasis at baseline including 22% with liver metastases. Thirty-nine percent of patients had TCC histology; 13% had TCC with squamous differentiation and 48% had TCC with other histologic variants.

The major efficacy outcome measures were ORR and DoR as assessed by BICR according to RECIST v1.1.

The median follow-up time for the dose escalation cohort + Cohort A was 44.7 months (range: 0.7 to 52.4) and for Cohort K was 14.8 months (range: 0.6 to 26.2).

Efficacy results are presented in Table 15 below.

The median duration of response for the dose escalation cohort + Cohort A was 22.1 months (range: 1.0+ to 46.3+) and for Cohort K was not reached (range: 1.2 to 24.1+).