Padcev (Enfortumab Vedotin)

• •
  PADCEV can cause severe and fatal cutaneous adverse reactions including Stevens-Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN), which occurred predominantly during the first cycle of treatment, but may occur later.
• •
  Closely monitor patients for skin reactions.
• •
  Immediately withhold PADCEV and consider referral for specialized care for suspected SJS or TEN or severe skin reactions.
• •
  Permanently discontinue PADCEV in patients with confirmed SJS or TEN; or Grade 4 or recurrent Grade 3 skin reactions

  [see Dosage and Administration (

  2.2 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 ]	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 ]	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 ]	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 ]	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 ]	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 ]	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

  ), Warnings and Precautions (

  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 ]

  . 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 ]

  . 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 ]

  . 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 ]

  .

  ), and Adverse Reactions (

  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 ]

  .

  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 5summarizes 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
  RashIncludes: 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 7summarizes 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
  RashIncludes: 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 ]

  . 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 9summarizes 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
  RashIncludes: 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 ]

  . 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 11summarizes 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
  RashIncludes: 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 ].

  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 13summarizes 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
  FatigueIncludes: 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	19Includes 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 15summarizes 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
  RashIncludes: 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

  )].

Indications and Usage (

Dosage and Administration (

Warnings and Precautions (

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.

• •
  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 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

  • 1.000000000000000e+00Follow procedures for proper handling and disposal of anticancer drugs.
  • 2.000000000000000e+00Use appropriate aseptic technique for reconstitution and preparation of dosing solutions.
  • 3.000000000000000e+00Calculate the recommended dose based on the patient’s weight to determine the number and strength (20 mg or 30 mg) of vials needed.
  • 4.000000000000000e+00Reconstitute 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.
  • 5.000000000000000e+00Slowly 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.
  • 6.000000000000000e+00Parenteral 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.
  • 7.000000000000000e+00Based 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

  • 1.000000000000000e+00Withdraw the calculated dose amount of reconstituted solution from the vial(s) and transfer into an infusion bag.
  • 2.000000000000000e+00Dilute 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.
  • 3.000000000000000e+00Mix diluted solution by gentle inversion. DO NOT SHAKE THE BAG. Do not expose to direct sunlight.
  • 4.000000000000000e+00Visually 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.
  • 5.000000000000000e+00Discard any unused portion left in the single-dose vials.

  Administration

  • 1.000000000000000e+00Immediately administer the infusion over 30 minutes through an intravenous line.
  • 2.000000000000000e+00If 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.
  )
• •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 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 1and Table 2.

  Administer PADCEV as an intravenous infusion over 30 minutes as recommended [see

  Instructions for Preparation and Administration

  ]. 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.
  )
• •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 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 1and Table 2.

  Administer PADCEV as an intravenous infusion over 30 minutes as recommended [see

  Instructions for Preparation and Administration

  ]. 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.
  )
• •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 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 1and Table 2.

  Administer PADCEV as an intravenous infusion over 30 minutes as recommended [see

  Instructions for Preparation and Administration

  ]. 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.
  )
• •Avoid use in patients with moderate or severe hepatic impairment. (
  8.6 Hepatic Impairment

  Avoid the use of PADCEV in patients with moderate or severe hepatic impairment (total bilirubin >1.5 × ULN and any AST). PADCEV has only been studied in a limited number of patients with moderate or severe hepatic impairment

  [see Clinical Pharmacology ]

  . 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.
  )

For Injection: 20 mg and 30 mg of enfortumab vedotin-ejfv as a white to off-white lyophilized powder in a single-dose vial for reconstitution.

• •Lactation: Advise women not to breastfeed. (
  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 3 weeks after the last dose.
  )