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)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The pooled safety population described in the WARNINGS AND PRECAUTIONS reflect exposure to PADCEV in combination with pembrolizumab at 1.25 mg/kg in 564 patients in EV-302 and EV-103 and PADCEV as a single agent at 1.25 mg/kg in 720 patients in EV-301, EV-201, EV-203 (NCT04995419), EV-101 (NCT02091999), and EV-102 (NCT03070990). Ocular disorders reflect 384 patients in EV-201, EV-101, and EV-102. Among 564 patients receiving PADCEV in combination with pembrolizumab, 59% were exposed 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, dry skin.

The data described in the following section reflects exposure to PADCEV in combination with pembrolizumab from EV‑302 and the dose escalation cohort, Cohort A and Cohort K of EV-103. Patients received PADCEV 1.25 mg/kg in combination with pembrolizumab until disease progression or unacceptable toxicity.

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.

Previously Untreated Locally Advanced or Metastatic Urothelial Cancer

EV-302

The safety of PADCEV in combination with pembrolizumab was evaluated in an open-label, randomized, multicenter trial (EV-302) in patients with locally advanced or metastatic urothelial cancer. 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 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 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 3 summarizes the most common (≥15%) adverse reactions in EV-302.

Table 3. Adverse Reactions ≥15% (All Grades) in Patients Treated with PADCEV in Combination with Pembrolizumab in EV-302
Adverse Reaction	PADCEV in combination with pembrolizumab n=440		Chemotherapy n=433
Adverse Reaction	All Grades %	Grade 3-4 %	All Grades %	Grade 3-4 %
* Includes: multiple terms
Skin and subcutaneous tissue disorders
Rash*	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 (10%), hypothyroidism (10%), blurred vision (6%), skin hyperpigmentation (6%), infusion site extravasation (2%), and myositis (0.5%).

Table 4. Selected Laboratory Abnormalities Reported in ≥15% (All Grades) of Patients Treated with PADCEV in Combination with Pembrolizumab in EV-302
Laboratory Abnormality	PADCEV in combination with pembrolizumab		Chemotherapy
Laboratory Abnormality	All Grades* %	Grade 3-4* %	All Grades* %	Grade 3-4* %
* 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
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 Metastatic Urothelial Cancer

EV-103

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

Serious adverse reactions occurred in 50% of patients treated with PADCEV in combination with pembrolizumab. The most common serious adverse reactions (≥2%) were acute kidney injury (7%), urinary tract infection (7%), urosepsis (5%), sepsis (3.3%), pneumonia (3.3%), hematuria (3.3%), pneumonitis/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 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 5 summarizes the most common (≥20%) adverse reactions in EV-103.

Table 5. Adverse Reactions ≥20% (All Grades) in Patients Treated with PADCEV in Combination with Pembrolizumab in EV-103
Adverse Reaction	PADCEV in combination with pembrolizumab n=121
Adverse Reaction	All Grades %	Grade 3-4 %
* Includes: multiple terms
Skin and subcutaneous tissue disorders
Rash*	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 6. Selected Laboratory Abnormalities ≥20% (All Grades) in Patients Treated with PADCEV in Combination with Pembrolizumab in EV-103
Laboratory Abnormality	PADCEV in combination with pembrolizumab
Laboratory Abnormality	All Grades* %	Grade 3-4* %
* 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.
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 Metastatic Urothelial Cancer

EV-301

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

Serious adverse reactions occurred in 47% of patients treated with PADCEV. The most common serious adverse reactions (≥2%) were urinary tract infection, acute kidney injury (7% each) and pneumonia (5%). Fatal adverse reactions occurred in 3% of patients, including multiorgan dysfunction (1%), 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 7 summarizes the most common (≥15%) adverse reactions in EV-301.

Table 7. Adverse Reactions (≥15%) in Patients Treated with PADCEV in EV-301
Adverse Reaction	PADCEV n=296		Chemotherapy n=291
Adverse Reaction	All Grades %	Grade 3-4 %	All Grades %	Grade 3-4 %
* Includes: multiple terms
Skin and subcutaneous tissue disorders
Rash*	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 8. 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*		Chemotherapy*
Laboratory Abnormality	Grades 2-4 %	Grade 3-4 %	Grades 2-4 %	Grade 3-4 %
* 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.
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 metastatic urothelial cancer who had received prior treatment with a PD-1 or PD-L1 inhibitor and platinum-based chemotherapy [see Clinical Studies (14)]. Patients received PADCEV 1.25 mg/kg on Days 1, 8 and 15 of a 28-day cycle until disease progression or unacceptable toxicity. The median duration of exposure to PADCEV was 4.6 months (range: 0.5-15.6).

Serious adverse reactions occurred in 46% of patients treated with PADCEV. The most common serious adverse reactions (≥3%) were urinary tract infection (6%), cellulitis (5%), febrile neutropenia (4%), diarrhea (4%), sepsis (3%), acute kidney injury (3%), dyspnea (3%), and rash (3%). Fatal adverse reactions occurred in 3.2% of patients, including acute respiratory failure, aspiration pneumonia, cardiac disorder, sepsis and pneumonitis/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 9 summarizes the All Grades and Grades 3-4 adverse reactions reported in patients in EV-201, Cohort 1.

Table 9. 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
Adverse Reaction	All Grades %	Grade 3-4 %
* Includes: multiple terms
General disorders and administration site conditions
Fatigue*	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 10. 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
Laboratory Abnormality	Grades 2-4* %	Grade 3-4* %
* 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 † Includes Grade 1 (potassium 3.0-3.5 mmol/L) – Grade 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†	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 metastatic urothelial cancer (n=89) who received at least one dose of PADCEV 1.25 mg/kg and had prior treatment with a PD-1 or PD-L1 inhibitor and were not eligible for cisplatin-based chemotherapy. The median duration of exposure was 5.98 months (range: 0.3 to 24.6 months).

Serious adverse reactions occurred in 39% of patients treated with PADCEV. The most common serious adverse reactions (≥3%) were pneumonia, sepsis and diarrhea (5% each). Fatal adverse reactions occurred in 8% of patients, including acute kidney injury (2.2%), metabolic acidosis, sepsis, multiorgan dysfunction, pneumonia and pneumonitis/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 11 summarizes the All Grades and Grades 3-4 adverse reactions reported in patients in EV-201, Cohort 2.

Table 11. 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
Adverse Reaction	All Grades (%)	Grades 3-4 (%)
* Includes: multiple terms
Skin and subcutaneous tissue disorders
Rash*	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 12. 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*
Laboratory Abnormality	Grades 2-4* %	Grade 3-4* %
* Based on the number of patients with a baseline value and at least one post-treatment value
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, toxic epidermal necrolysis [see Warnings and Precautions (5.1)].