PADCEV EJFV

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

2 DOSAGE AND ADMINISTRATION • For intravenous infusion only. Do not administer PADCEV as an intravenous push or bolus. Do not mix with, or administer as an infusion with, other medicinal products. ( 2.3 ) • MIBC: The recommended dose of PADCEV in combination with pembrolizumab or pembrolizumab and berahyaluronidase alfa-pmph is 1.25 mg/kg (up to a maximum dose of 125 mg) given as an intravenous infusion over 30 minutes. PADCEV is administered as neoadjuvant treatment on Days 1 and 8 of each 21-day cycle for 3 cycles or until disease progression that precludes curative intent cystectomy or unacceptable toxicity, followed by adjuvant treatment on Days 1 and 8 of each 21-day cycle for 6 cycles or until disease recurrence or unacceptable toxicity. ( 2.1 ) • Locally Advanced or mUC: The recommended dose of PADCEV in combination with pembrolizumab or pembrolizumab and berahyaluronidase alfa-pmph is 1.25 mg/kg (up to a maximum dose of 125 mg) given as an intravenous infusion over 30 minutes on Days 1 and 8 of a 21-day cycle until disease progression or unacceptable toxicity. ( 2.1 ) • The recommended dose of PADCEV as a single agent is 1.25 mg/kg (up to a maximum dose of 125 mg) given as an intravenous infusion over 30 minutes on Days 1, 8, and 15 of a 28-day cycle until disease progression or unacceptable toxicity. ( 2.1 ) • Avoid use in patients with moderate or severe hepatic impairment. ( 8.6 ) 2.1 Recommended Dosage The recommended dosages for PADCEV in combination with pembrolizumab or pembrolizumab and berahyaluronidase alfa-pmph, and PADCEV as a single agent are presented in Table 1 and Table 2 . Administer PADCEV as an intravenous infusion over 30 minutes as recommended [see Instructions for Preparation and Administration ( 2.3 ) ]. Administer PADCEV prior to pembrolizumab or pembrolizumab and berahyaluronidase alfa-pmph if administering on the same day. Table 1. Recommended Dosages for PADCEV in combination with pembrolizumab or pembrolizumab and berahyaluronidase alfa-pmph Administer PADCEV prior to pembrolizumab or pembrolizumab and berahyaluronidase alfa-pmph if administering on the same day. For the recommended dosage of pembrolizumab or pembrolizumab and berahyaluronidase alfa-pmph, refer to the respective Prescribing Information. Indication Recommended PADCEV Dosage Duration of Therapy Neoadjuvant and Adjuvant Muscle Invasive Bladder Cancer (MIBC) PADCEV 1.25 mg/kg (up to a maximum of 125 mg for patients ≥100 kg) on Days 1 and 8 of a 21-day cycle. Neoadjuvant: 3 cycles or until disease progression that precludes curative intent cystectomy or unacceptable toxicity. Adjuvant: 6 cycles or until disease recurrence or unacceptable toxicity. Locally advanced or metastatic Urothelial Cancer (mUC) PADCEV 1.25 mg/kg (up to a maximum of 125 mg for patients ≥100 kg) on Days 1 and 8 of a 21-day cycle. Until disease progression or unacceptable toxicity. Table 2. Recommended Dosages for PADCEV as a single agent Indication Recommended PADCEV Dosage 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 15 of a 28-day cycle. Until disease progression or unacceptable toxicity. 2.2 Dose Modifications Table 3. Dose Modifications Adverse Reaction Severity Grade 1 is mild, Grade 2 is moderate, Grade 3 is severe, Grade 4 is life-threatening. Dose Modification Skin Reactions [see Boxed Warning , Warnings and Precautions ( 5.1 )] 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. Suspected SJS or TEN 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. Hyperglycemia [see Warnings and Precautions ( 5.2 )] 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) [see Warnings and Precautions ( 5.3 )] 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. Peripheral Neuropathy [see Warnings and Precautions ( 5.4 )] 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 Permanently discontinue. Other Nonhematologic Toxicity [see Adverse Reactions ( 6 )] 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. Hematologic Toxicity [see Adverse Reactions ( 6 )] 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. 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 1. Withdraw the calculated dose amount of reconstituted solution from the vial(s) and transfer into an infusion bag. 2. 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. 3. Mix diluted solution by gentle inversion. DO NOT SHAKE THE BAG. Do not expose to direct sunlight. 4. 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. 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 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.

4 CONTRAINDICATIONS None. None. ( 4 )

5 WARNINGS AND PRECAUTIONS • Hyperglycemia: Diabetic ketoacidosis may occur in patients with and without preexisting diabetes mellitus, which may be fatal. Closely monitor blood glucose levels in patients with, or at risk for, diabetes mellitus or hyperglycemia. Withhold PADCEV if blood glucose is >250 mg/dL. ( 2.2 , 5.2 ) • Pneumonitis/Interstitial Lung Disease (ILD): Severe, life-threatening or fatal pneumonitis/ILD may occur. Withhold PADCEV for Grade 2 pneumonitis/ILD and consider dose reduction. Permanently discontinue PADCEV for Grade 3 or 4 pneumonitis/ILD. ( 2.2 , 5.3 ) • Peripheral Neuropathy: Monitor patients for new or worsening peripheral neuropathy and consider dose interruption, dose reduction, or discontinuation of PADCEV. ( 2.2 , 5.4 ) • Ocular Disorders: Ocular disorders, including vision changes, may occur. Monitor patients for signs or symptoms of ocular disorders. Consider prophylactic artificial tears for dry eyes and treatment with ophthalmic topical steroids after an ophthalmic exam. Consider dose interruption or dose reduction of PADCEV when symptomatic ocular disorders occur. ( 5.5 ) • Infusion Site Extravasation: Ensure adequate venous access prior to administration. Monitor the infusion site during PADCEV administration and stop the infusion immediately for suspected extravasation. ( 5.6 ) • Embryo-Fetal Toxicity: PADCEV can cause fetal harm. Advise of the potential risk to a fetus and to use effective contraception. ( 5.7 , 8.1 , 8.3 ) 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 61% (all grades) of the 167 patients treated with PADCEV in combination with intravenous pembrolizumab for the treatment of MIBC in clinical trials. The majority of the skin reactions that occurred with combination therapy included rash and maculo-papular rash. Grade 3-4 skin reactions occurred in 10% of patients (Grade 3: 9%, Grade 4: 1.2%), including rash, maculo-papular rash, toxic skin eruption, dermatitis exfoliative generalized, erythema, exfoliative rash, skin toxicity, toxic epidermal necrolysis, and toxic erythema of chemotherapy. A fatal reaction of toxic epidermal necrolysis occurred in one patient (0.6%). The median time to onset of severe skin reactions was 0.6 months (range: 0.2 to 8.8 months). Skin reactions led to discontinuation of PADCEV in 10% of patients [see Adverse Reactions ( 6.1 )] . Of the patients who experienced a skin reaction and had data regarding resolution (n=102), 83% had complete resolution and 17% had residual skin reactions at their last evaluation. Of the patients with residual skin reactions at last evaluation, 29% (5/17) had Grade ≥2 skin reactions. Skin reactions occurred in 70% (all grades) of the 564 patients treated with PADCEV in combination with intravenous pembrolizumab for the treatment of locally advanced or mUC in clinical trials. When PADCEV was given in combination with intravenous pembrolizumab, the incidence of skin reactions, including severe events, occurred at a higher rate compared to PADCEV as a single agent. 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 17% of patients (Grade 3: 16%, Grade 4: 1%), 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 (0.2%). The median time to onset of severe skin reactions was 1.7 months (range: 0.1 to 17.2 months). Skin reactions led to discontinuation of PADCEV in 6% of patients [see Adverse Reactions ( 6.1 )] . Of the patients who experienced a skin reaction and had data regarding resolution (n=391), 59% had complete resolution and 41% had residual skin reactions at their last evaluation. Of the patients with residual skin reactions at last evaluation, 27% (43/159) had Grade ≥2 skin reactions. Skin reactions occurred in 58% (all grades) of the 720 patients treated with PADCEV as a single agent in clinical trials. Twenty-three percent (23%) of patients had maculo-papular rash and 34% had pruritus. Grade 3-4 skin reactions occurred in 14% 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 0.6 months (range: 0.1 to 8 months). Among patients experiencing a skin reaction leading to dose interruption who then restarted PADCEV (n=75), 24% of patients restarting at the same dose and 24% of patients restarting at a reduced dose experienced recurrent severe skin reactions. Skin reactions led to discontinuation of PADCEV in 3.1% of patients [see Adverse Reactions ( 6.1 )] . Of the patients who experienced a skin reaction and had data regarding resolution (n=328), 58% had complete resolution and 42% had residual skin reactions at their last evaluation. Of the patients with residual skin reactions at last evaluation, 39% (53/137) had Grade ≥2 skin reactions. 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, 17% of the 720 patients treated with PADCEV developed hyperglycemia of any grade; 7% of patients developed Grade 3-4 hyperglycemia (Grade 3: 6.5%, Grade 4: 0.6%). 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. The median time to onset of hyperglycemia was 0.5 months (range: 0 to 20 months). Hyperglycemia led to discontinuation of PADCEV in 0.7% of patients [see Adverse Reactions ( 6.1 )] . Five percent (5%) of patients required initiation of insulin therapy for treatment of hyperglycemia. Of the patients who initiated insulin therapy for treatment of hyperglycemia, 66% (23/35) discontinued insulin by the time of last evaluation. 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. When PADCEV was given in combination with intravenous pembrolizumab for the treatment of MIBC, 4.2% of the 167 patients treated with combination therapy had pneumonitis/ILD of any grade. All events were Grade 1-2. The median time to onset of any grade pneumonitis/ILD was 2.5 months (range: 1.9 to 9.7 months). When PADCEV was given in combination with intravenous pembrolizumab for the treatment of locally advanced or mUC, 10% of the 564 patients treated with combination therapy had pneumonitis/ILD of any grade and 4% had Grade 3-4. A fatal event of pneumonitis/ILD occurred in two patients (0.4%). The incidence of pneumonitis/ILD, including severe events, occurred at a higher rate when PADCEV was given in combination with intravenous pembrolizumab compared to PADCEV as a single agent. The median time to onset of any grade pneumonitis/ILD was 4 months (range: 0.3 to 26 months). In clinical trials of PADCEV as a single agent, 3% of the 720 patients treated with PADCEV had pneumonitis/ILD of any grade and 0.8% had Grade 3-4. The median time to onset of any grade pneumonitis/ILD was 2.9 months (range: 0.6 to 6 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 When PADCEV was given in combination with intravenous pembrolizumab for the treatment of MIBC, 39% of the 167 patients treated with combination therapy had peripheral neuropathy of any grade, 12% had Grade 2 neuropathy, and 3% had Grade 3 neuropathy. The median time to onset of Grade ≥2 peripheral neuropathy was 4.7 months (range: 0.2 to 11 months) [see Adverse Reactions ( 6.1 )] . Of the patients who experienced neuropathy and had data regarding resolution (n=65), 32% had complete resolution, and 68% of patients had residual neuropathy at last evaluation. Of the patients with residual neuropathy at last evaluation, 27% (12/44) had Grade ≥2 neuropathy. When PADCEV was given in combination with intravenous pembrolizumab for the treatment of locally advanced or mUC, 67% of the 564 patients treated with combination therapy had peripheral neuropathy of any grade, 36% had Grade 2 neuropathy, and 7% had Grade 3 neuropathy. The incidence of peripheral neuropathy occurred at a higher rate when PADCEV was given in combination with intravenous pembrolizumab compared to PADCEV as a single agent. The median time to onset of Grade ≥2 peripheral neuropathy was 6 months (range: 0.3 to 25 months) [see Adverse Reactions ( 6.1 )] . Of the patients who experienced neuropathy and had data regarding resolution (n=373), 13% had complete resolution, and 87% of patients had residual neuropathy at last evaluation. Of the patients with residual neuropathy at last evaluation, 45% (146/326) had Grade ≥2 neuropathy. Peripheral neuropathy occurred in 53% of the 720 patients treated with PADCEV as a single agent in clinical trials including 38% with sensory neuropathy, 8% 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 6% of patients [see Adverse Reactions ( 6.1 )] . Of the patients who experienced neuropathy who had data regarding resolution (n=296), 11% had complete resolution, and 89% had residual neuropathy at the time of their last evaluation. Of the patients with residual neuropathy at last evaluation, 50% (132/262) had Grade ≥2 neuropathy. 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 30% of patients, and blurred vision occurred in 10% of patients, during treatment with PADCEV. The median time to onset to symptomatic ocular disorder was 1.7 months (range: 0 to 30.6 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 720 patients treated with PADCEV as a single agent in clinical trials, 1% 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 )] .

7 DRUG INTERACTIONS Concomitant use of dual P-gp and strong CYP3A4 inhibitors with PADCEV may increase the exposure to monomethyl auristatin E (MMAE). ( 7.1 ) 7.1 Effects of Other Drugs on PADCEV Dual P-gp and Strong CYP3A4 Inhibitors Concomitant use with dual P-gp and strong CYP3A4 inhibitors may increase unconjugated MMAE exposure [see Clinical Pharmacology ( 12.3 )] , which may increase the incidence or severity of PADCEV toxicities. Closely monitor patients for signs of toxicity when PADCEV is given concomitantly with dual P-gp and strong CYP3A4 inhibitors.

6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: • Skin Reactions [see Boxed Warning , Warnings and Precautions ( 5.1 )] • Hyperglycemia [see Warnings and Precautions ( 5.2 )] • Pneumonitis/Interstitial Lung Disease (ILD) [see Warnings and Precautions ( 5.3 )] • Peripheral Neuropathy [see Warnings and Precautions ( 5.4 )] • Ocular Disorders [see Warnings and Precautions ( 5.5 )] • Infusion Site Extravasation [see Warnings and Precautions ( 5.6 )] The most common adverse reactions, including laboratory abnormalities, (≥20%) were: • PADCEV in combination with intravenous pembrolizumab for the treatment of MIBC: increased glucose, decreased hemoglobin, increased aspartate aminotransferase, rash, increased alanine aminotransferase, fatigue, pruritus, increased creatinine, decreased sodium, decreased lymphocytes, peripheral neuropathy, increased potassium, alopecia, dysgeusia, diarrhea, decreased appetite, constipation, nausea, decreased phosphate, urinary tract infection, dry eye, and decreased weight. ( 6.1 ) • PADCEV in combination with intravenous pembrolizumab for the treatment of locally advanced or mUC: increased aspartate aminotransferase, increased creatinine, rash, increased glucose, peripheral neuropathy, increased lipase, decreased lymphocytes, increased alanine aminotransferase, decreased hemoglobin, fatigue, decreased sodium, decreased phosphate, decreased albumin, pruritus, diarrhea, alopecia, decreased weight, decreased appetite, increased urate, decreased neutrophils, decreased potassium, dry eye, nausea, constipation, increased potassium, dysgeusia, urinary tract infection, and decreased platelets. ( 6.1 ) • PADCEV as a single agent: increased glucose, increased aspartate aminotransferase, decreased lymphocytes, increased creatinine, rash, fatigue, peripheral neuropathy, decreased albumin, decreased hemoglobin, alopecia, decreased appetite, decreased neutrophils, decreased sodium, increased alanine aminotransferase, decreased phosphate, diarrhea, nausea, pruritus, increased urate, dry eye, dysgeusia, constipation, increased lipase, decreased weight, decreased platelets, abdominal pain, and dry skin. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Astellas Pharma US, Inc. at 1-800-727-7003 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety population described in the WARNINGS AND PRECAUTIONS reflect exposure to PADCEV 1.25 mg/kg in combination with intravenous pembrolizumab for the treatment of MIBC in 167 patients in EV-303 (NCT03924895) and for the treatment of locally advanced or mUC in 564 patients in EV-302 (NCT04223856) and EV-103 (NCT03288545); PADCEV as a single agent at 1.25 mg/kg in 720 patients in EV-301 (NCT03474107), EV-201 (NCT03219333), EV-203 (NCT04995419), EV-101 (NCT02091999), and EV-102 (NCT03070990). Ocular disorders reflect 384 patients in EV‑201, EV-101, and EV-102. Among 167 patients receiving PADCEV in combination with intravenous pembrolizumab for the treatment of MIBC, the most common (≥20%) adverse reactions, including laboratory abnormalities, were increased glucose, decreased hemoglobin, increased aspartate aminotransferase, rash, increased alanine aminotransferase, fatigue, pruritus, increased creatinine, decreased sodium, decreased lymphocytes, peripheral neuropathy, increased potassium, alopecia, dysgeusia, diarrhea, decreased appetite, constipation, nausea, decreased phosphate, urinary tract infection, dry eye, and decreased weight. Among 564 patients receiving PADCEV in combination with intravenous pembrolizumab for the treatment of locally advanced or mUC, 59% were exposed to PADCEV for ≥6 months, and 24% were exposed for ≥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 1 and Cohort 2 of an open-label, single arm, two cohort trial (EV-201). Patients received 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. Patients received 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) [see Clinical Studies ( 14 )] . 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. Adverse 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. Selected Laboratory Abnormalities 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 167 and the denominator used to calculate the rate for RC and PLND alone varied from 110 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 treatment. Of the 149 patients who underwent surgery, 100 patients received adjuvant treatment with PADCEV in combination with intravenous pembrolizumab. Of the 49 patients who did not receive adjuvant treatment, discontinuation of treatment with PADCEV in combination with intravenous pembrolizumab prior to the adjuvant phase was due to an adverse event in 21 patients. In the adjuvant phase, serious adverse reactions occurred in 43% of patients receiving PADCEV in combination with intravenous pembrolizumab. The most frequent (≥2%) serious adverse reactions were urinary tract infection (8%), acute kidney injury and pyelonephritis (5% each), urosepsis (4%), and hypokalemia, intestinal obstruction, and sepsis (2% each). Fatal adverse reactions occurred in 7% of patients, including urosepsis, hemorrhage intracranial, death, myocardial infarction, multiple organ dysfunction syndrome, and pneumonia pseudomonal (1% each). Adverse reactions leading to discontinuation of PADCEV in the adjuvant phase occurred in 26% of patients. The most common adverse reactions (≥2%) leading to discontinuation of PADCEV were peripheral neuropathy (5%) and rash (4%). Adverse reactions leading to dose interruption of PADCEV in the adjuvant phase occurred in 36% of patients. The most common adverse reactions (≥2%) leading to dose interruption of PADCEV were rash (6%), diarrhea and urinary tract infection (5% each), fatigue (4%), pruritus (3%), and peripheral neuropathy and pyelonephritis (2% each). Adverse reactions leading to dose reduction of PADCEV in the adjuvant phase occurred in 7% of patients. The most common adverse reaction (≥2%) leading to dose reduction of PADCEV was weight decreased (2%). Previously Untreated Locally Advanced or mUC EV-302 The safety of PADCEV in combination with intravenous pembrolizumab was evaluated in an open-label, randomized, multicenter trial (EV-302) in patients with locally advanced or mUC. Patients received either PADCEV 1.25 mg/kg and pembrolizumab (n=440) or gemcitabine and platinum chemotherapy (either cisplatin or carboplatin) (n=433). Among patients who received PADCEV and pembrolizumab, the median duration of exposure for PADCEV was 7 months (range: 0.3 to 31.9 months). Serious adverse reactions occurred in 50% of patients treated with PADCEV in combination with intravenous pembrolizumab. The most common serious adverse reactions (≥2%) were rash (6%), acute kidney injury (5%), pneumonitis/ILD (4.5%), urinary tract infection (3.6%), diarrhea (3.2%), pneumonia (2.3%), pyrexia (2%), and hyperglycemia (2%). Fatal adverse reactions occurred in 3.9% of patients treated with PADCEV in combination with intravenous pembrolizumab including acute respiratory failure (0.7%), pneumonia (0.5%), and pneumonitis/ILD (0.2%). Adverse reactions leading to discontinuation of PADCEV occurred in 35% of patients. The most common adverse reactions (≥2%) leading to discontinuation of PADCEV were peripheral neuropathy (15%), rash (4.1%), and pneumonitis/ILD (2.3%). Adverse reactions leading to dose interruption of PADCEV occurred in 73% of patients. The most common adverse reactions (≥2%) leading to dose interruption of PADCEV were peripheral neuropathy (22%), rash (16%), COVID-19 (10%), diarrhea (5%), pneumonitis/ILD (4.8%), fatigue (3.9%), hyperglycemia (3.6%), increased alanine aminotransferase (3%), and pruritus (2.5%). Adverse reactions leading to dose reduction of PADCEV occurred in 42% of patients. The most common adverse reactions (≥2%) leading to dose reduction of PADCEV were rash (16%), peripheral neuropathy (13%), and fatigue (2.7%). Table 7 summarizes the most common (≥15%) adverse reactions in EV-302. Table 7. Adverse Reactions ≥15% (All Grades) in Patients Treated with PADCEV in Combination with Intravenous Pembrolizumab in EV-302 Adverse Reaction PADCEV in combination with intravenous pembrolizumab n=440 Chemotherapy n=433 All Grades % Grade 3-4 % All Grades % Grade 3-4 % Skin and subcutaneous tissue disorders Rash Includes: multiple terms. 68 15 15 0 Pruritus 41 1.1 7 0 Alopecia 35 0.5 8 0.2 Dry skin 17 0.2 1 0 General disorders and administration site conditions Fatigue 51 6 57 7 Pyrexia 18 0.7 16 1.2 Nervous system disorders Peripheral neuropathy 67 8 14 0 Dysgeusia 21 0 9 0 Metabolism and nutrition disorders Decreased appetite 33 1.8 26 1.8 Gastrointestinal disorders Diarrhea 38 4.5 16 1.4 Nausea 26 1.6 41 2.8 Constipation 26 0 34 0.7 Investigations Decreased weight 33 3.6 9 0.2 Eye disorders Dry eye 24 0 2.1 0 Infections and infestations Urinary tract infection 21 5 19 8 Clinically relevant adverse reactions (<15%) include vomiting (12%), pneumonitis/ILD and hypothyroidism (10% each), blurred vision and skin hyperpigmentation (6% each), infusion site extravasation (1.8%), and myositis (0.5%). Table 8. Selected Laboratory Abnormalities Reported in ≥15% (All Grades) of Patients Treated with PADCEV in Combination with Intravenous Pembrolizumab in EV-302 Laboratory Abnormality PADCEV in combination with intravenous pembrolizumab Chemotherapy All Grades The denominator used to calculate the rate varied from 407 to 439 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 aspartate aminotransferase 75 5 39 3 Increased creatinine 71 3 68 3 Increased glucose 66 14 54 5 Increased alanine aminotransferase 59 5 49 3 Decreased sodium 46 13 47 13 Decreased phosphate 44 9 36 9 Decreased albumin 39 2 35 0.5 Decreased potassium 26 5 16 3 Increased potassium 24 1 36 4 Increased calcium 21 1 14 0.2 Hematology Decreased lymphocytes 58 15 59 17 Decreased hemoglobin 53 7 89 33 Decreased neutrophils 30 9 80 50 Previously Untreated Cisplatin-Ineligible Patients with Locally Advanced or mUC EV-103 The safety of PADCEV was evaluated in combination with intravenous pembrolizumab in a multi cohort trial (EV-103) in 121 patients with locally advanced or mUC 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 intravenous 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/ILD (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 intravenous 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%), increased lipase (6%), pneumonitis/ILD (6%), diarrhea (4.1%), acute kidney injury (3.3%), increased alanine aminotransferase (3.3%), fatigue (3.3%), neutropenia (3.3%), urinary tract infection (3.3%), increased amylase (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%). Table 9 summarizes the most common (≥20%) adverse reactions in EV-103. Table 9. Adverse Reactions ≥20% (All Grades) in Patients Treated with PADCEV in Combination with Intravenous Pembrolizumab in EV-103 Adverse Reaction PADCEV in combination with intravenous pembrolizumab n=121 All Grades % Grade 3-4 % Skin and subcutaneous tissue disorders Rash Includes: multiple terms. 71 21 Alopecia 52 0 Pruritus 40 3.3 Dry skin 21 0.8 Nervous system disorders Peripheral neuropathy 65 3.3 Dysgeusia 35 0 Dizziness 23 0 General disorders and administration site conditions Fatigue 60 11 Peripheral edema 26 0 Investigations Decreased weight 48 5 Gastrointestinal disorders Diarrhea 45 7 Nausea 36 0.8 Constipation 27 0 Metabolism and nutrition disorders Decreased appetite 38 0.8 Infections and infestations Urinary tract infection 30 12 Eye disorders Dry eye 25 0 Musculoskeletal and connective tissue disorders Arthralgia 23 1.7 Clinically relevant adverse reactions (<20%) include vomiting (20%), pyrexia (18%), hypothyroidism (11%), pneumonitis/ILD (10%), skin hyperpigmentation (8%), 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 Intravenous Pembrolizumab in EV-103 Laboratory Abnormality PADCEV in combination with intravenous pembrolizumab All Grades The denominator used to calculate the rate varied from 114 to 121 based on the number of patients with a baseline value and at least one post-treatment value. % Grade 3-4 % Chemistry Increased glucose 74 13 Increased aspartate aminotransferase 73 9 Increased creatinine 69 3.3 Decreased sodium 60 19 Increased alanine aminotransferase 60 7 Increased lipase 59 32 Decreased albumin 59 4.2 Decreased phosphate 51 15 Decreased potassium 35 8 Increased potassium 27 1.7 Increased calcium 27 4.2 Hematology Decreased hemoglobin 69 15 Decreased lymphocytes 64 17 Decreased neutrophils 32 12 Previously Treated Locally Advanced or mUC EV-301 The safety of PADCEV was evaluated as a single agent in EV-301 in patients with locally advanced or mUC (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%), hepatic dysfunction, septic shock, hyperglycemia, pneumonitis/ILD, 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 11 summarizes the most common (≥15%) adverse reactions in EV-301. Table 11. Adverse Reactions (≥15%) in Patients Treated with PADCEV in EV-301 Adverse Reaction PADCEV n=296 Chemotherapy n=291 All Grades % Grade 3-4 % All Grades % Grade 3-4 % Skin and subcutaneous tissue disorders Rash Includes: multiple terms. 54 14 20 0.3 Alopecia 47 0 38 0 Pruritus 34 2 7 0 Dry skin 17 0 4 0 General disorders and administration site conditions Fatigue 50 9 40 7 Pyrexia 22 2 14 0 Nervous system disorders Peripheral neuropathy 50 5 34 3 Dysgeusia 26 0 8 0 Metabolism and nutrition disorders Decreased appetite 41 5 27 2 Gastrointestinal disorders Diarrhea 35 4 23 2 Nausea 30 1 25 2 Constipation 28 1 25 2 Abdominal Pain 20 1 14 3 Musculoskeletal and connective tissue disorders Musculoskeletal Pain 25 2 35 5 Eye Disorders Dry eye 24 0.7 6 0.3 Infections and infestations Urinary Tract Infection 17 6 13 3 Vascular disorders Hemorrhage 17 3 13 2 Investigations Decreased weight 16 0.3 7 0 Clinically relevant adverse reactions (<15%) include vomiting (14%), increased aspartate aminotransferase (12%), hyperglycemia (10%), increased alanine aminotransferase (9%), skin hyperpigmentation (8%), pneumonitis/ILD (3%), and infusion site extravasation (0.7%). Table 12. Selected Laboratory Abnormalities Reported in ≥15% (Grades 2-4) or ≥5% (Grade 3-4) of Patients Treated with PADCEV in EV-301 Laboratory Abnormality PADCEV The denominator used to calculate the rate varied from 262 to 287 based on the number of patients with a baseline value and at least one post-treatment value. Chemotherapy Grades 2-4 % Grade 3-4 % Grades 2-4 % Grade 3-4 % Hematology Decreased lymphocytes 41 14 34 18 Decreased hemoglobin 28 4 42 14 Decreased neutrophils 27 12 25 17 Chemistry Decreased phosphate 39 8 24 6 Increased glucose (non-fasting) 33 9 27 6 Increased creatinine 18 2 13 0 Decreased potassium 16 2 7 3 Increased lipase 13 8 7 4 Decreased sodium 8 8 5 5 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 mUC 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 to 15.6 months). 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/ILD (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 13 summarizes the All Grades and Grades 3-4 adverse reactions reported in patients in EV-201, Cohort 1. Table 13. Adverse Reactions Reported in ≥15% (All Grades) or ≥5% (Grade 3-4) of Patients Treated with PADCEV in EV-201 Cohort 1 Adverse Reaction PADCEV n=125 All Grades % Grade 3-4 % General disorders and administration site conditions Fatigue Includes: multiple terms. 56 6 Nervous system disorders Peripheral neuropathy 56 4 Dysgeusia 42 0 Metabolism and nutrition disorders Decreased appetite 52 2 Skin and subcutaneous tissue disorders Rash 52 13 Alopecia 50 0 Dry skin 26 0 Pruritus 26 2 Gastrointestinal disorders Nausea 45 3 Diarrhea 42 6 Vomiting 18 2 Eye disorders Dry eye 40 0 Clinically relevant adverse reactions (<15%) include skin hyperpigmentation (14%), herpes zoster (3%), pneumonitis/ILD (2%), and infusion site extravasation (2%). Table 14. Selected Laboratory Abnormalities Reported in ≥15% (Grades 2-4) or ≥5% (Grade 3-4) of Patients Treated with PADCEV in EV-201, Cohort 1 Laboratory Abnormality PADCEV Grades 2-4 Denominator for each laboratory parameter is based on the number of patients with a baseline and post-treatment laboratory value available for 121 or 122 patients. % Grade 3-4 % Hematology Decreased hemoglobin 34 10 Decreased lymphocytes 32 10 Decreased neutrophils 14 5 Chemistry Decreased phosphate 34 10 Increased glucose (non-fasting) 27 8 Increased creatinine 20 2 Decreased potassium 19 Includes Grade 1 (potassium 3.0-3.5 mmol/L) – Grade 4. 1 Increased lipase 14 9 Decreased sodium 8 8 Increased urate 7 7 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 mUC (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/ILD (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%), increased aspartate aminotransferase (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 15 summarizes the All Grades and Grades 3-4 adverse reactions reported in patients in EV-201, Cohort 2. Table 15. Adverse Reactions ≥15% (All Grades) or ≥5% (Grades 3-4) in Patients Treated with PADCEV in EV‑201, Cohort 2 Adverse Reaction PADCEV n=89 All Grades (%) Grades 3-4 (%) Skin and subcutaneous tissue disorders Rash Includes: multiple terms. 66 17 Alopecia 53 0 Pruritus 35 3 Dry skin 19 1 Nervous system disorders Peripheral neuropathy 58 8 Dysgeusia 29 0 General disorders and administration site conditions Fatigue 48 11 Metabolism and nutrition disorders Decreased appetite 40 6 Hyperglycemia 16 9 Gastrointestinal disorders Diarrhea 36 8 Nausea 30 1 Investigations Decreased weight 35 1 Eye disorders Dry eye 30 0 Clinically relevant adverse reactions (<15%) include vomiting (13%), increased aspartate aminotransferase (12%), increased lipase (11%), increased alanine aminotransferase (10%), skin hyperpigmentation (4%), pneumonitis/ILD (4%), and infusion site extravasation (1%). Table 16. Selected Laboratory Abnormalities Reported in ≥15% (Grades 2-4) or ≥5% (Grades 3-4) of Patients Treated with PADCEV in EV-201, Cohort 2 Laboratory Abnormality PADCEV n=88 Based on the number of patients with a baseline value and at least one post-treatment value. Grades 2-4 % Grade 3-4 % Hematology Decreased lymphocytes 43 15 Decreased hemoglobin 34 5 Decreased neutrophils 20 9 Chemistry Increased glucose (non-fasting) 36 13 Decreased phosphate 25 7 Increased creatinine 23 3 Increased lipase 18 11 Increased urate 9 9 Increased potassium 8 6 Decreased sodium 7 7 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, and toxic epidermal necrolysis [see Warnings and Precautions ( 5.1 )] .

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.