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Brand Name
Padcev Ejfv
Generic Name
Enfortumab Vedotin
View Brand Information FDA approval date: December 18, 2019
Form: Injection
What is Padcev Ejfv (Enfortumab Vedotin)?
PADCEV ®, in combination with pembrolizumab, is indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer . 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 or programmed death-ligand 1 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 for the treatment of adult patients with locally advanced or metastatic urothelial cancer. , as a single agent for the treatment of adult patients with locally advanced or metastatic urothelial cancer who: o have previously received a programmed death receptor-1 or programmed death-ligand 1 inhibitor and platinum-containing chemotherapy, or o are ineligible for cisplatin-containing chemotherapy and have previously received one or more prior lines of therapy.
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Brand Information
PADCEV (ENFORTUMAB VEDOTIN)
WARNING: SERIOUS SKIN REACTIONS
- 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
1INDICATIONS AND USAGE
PADCEV
PADCEV
PADCEV, as a single agent, is indicated for the treatment of adult patients with la/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.
2DOSAGE FORMS AND STRENGTHS
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.
3CONTRAINDICATIONS
None.
4ADVERSE REACTIONS
The following serious adverse reactions are described elsewhere in the labeling:
- Skin Reactions
- Hyperglycemia
- Pneumonitis/Interstitial Lung Disease (ILD)
- Peripheral Neuropathy
- Ocular Disorders
- Infusion Site Extravasation
4.1Clinical 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 570 patients in EV-303 (NCT03924895) and EV-304 (NCT04700124) and for the treatment of la/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 570 patients receiving PADCEV in combination with intravenous pembrolizumab for the treatment of MIBC, the most common (≥20%) adverse reactions, including laboratory abnormalities, were decreased hemoglobin, increased aspartate aminotransferase, increased alanine aminotransferase, rash, increased creatinine, decreased lymphocytes, fatigue, pruritus, decreased sodium, peripheral neuropathy, increased potassium, diarrhea, alopecia, dysgeusia, decreased appetite, nausea, constipation, urinary tract infection, dry eye, increased glucose, decreased weight, decreased potassium, hyperglycemia, decreased phosphate, and decreased neutrophils.
Among 564 patients receiving PADCEV in combination with intravenous pembrolizumab for the treatment of la/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, EV-303, and EV-304. Patients from EV-302 and EV-103 received PADCEV 1.25 mg/kg in combination with intravenous pembrolizumab until disease progression or unacceptable toxicity. Patients from EV-303 and EV-304 received PADCEV 1.25 mg/kg in combination with intravenous pembrolizumab for 9 cycles or 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 Patients with MIBC Who Are Cisplatin-Eligible
EV-304
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, active-controlled, multicenter trial (EV-304) in patients with previously untreated MIBC who were eligible for cisplatin-based chemotherapy. Patients received either PADCEV 1.25 mg/kg in combination with intravenous pembrolizumab (n=403) before and after RC with pelvic lymph node dissection (PLND) or chemotherapy (gemcitabine with cisplatin) before RC with PLND (n=396)
For the 403 patients who received PADCEV in the neoadjuvant phase, the median duration of exposure to PADCEV was 2.3 months (range: 0.03 to 4 months) and the median number of cycles of PADCEV was 4 (range: 1, 4) in the neoadjuvant phase. Out of 262 patients who received adjuvant treatment in the PADCEV in combination with pembrolizumab arm, 225 patients received PADCEV. The median duration of exposure to PADCEV was 3 months (range: 0.03 to 18.3 months) and the median number of cycles of PADCEV was 5 (range: 1, 5) for patients who received PADCEV in the adjuvant phase. Across the combined neoadjuvant and adjuvant phases (n=403), the median number of cycles of PADCEV was 6 (range: 1, 9) out of a planned 9 cycles.
Table 5 summarizes the most common (≥20%) adverse reactions in EV-304.
Clinically relevant adverse reactions (<20%) include dry skin (16%), vomiting (13%), hypothyroidism (12%), pneumonitis/ILD (8%), skin hyperpigmentation (3.5%), myositis (0.7%), infusion site extravasation (0.5%), and myasthenia gravis (0.2%).
Neoadjuvant Phase of EV-304
A total of 403 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 common serious adverse reactions (≥1.5%) were rash (3.2%), pneumonitis/ILD (2.2%), and diarrhea (1.7%). Fatal adverse reactions occurred in 1.7% of patients, including multiple organ dysfunction syndrome (0.5%) and COVID-19 pneumonia, cardiac arrest, pneumonia, septic shock, and urosepsis (0.2% each). Additional fatal adverse reactions were reported in 2 patients in the post-surgery phase before adjuvant treatment started, including pneumonia and sepsis (1 patient each).
Adverse reactions leading to discontinuation of PADCEV in the neoadjuvant phase occurred in 21% of patients. The most common adverse reactions (≥1%) leading to discontinuation of PADCEV were peripheral neuropathy (5%) and rash (3.5%).
Adverse reactions leading to dose interruption of PADCEV in the neoadjuvant phase occurred in 35% of patients. The most common adverse reactions (≥2%) leading to dose interruption of PADCEV were rash (10%), increased alanine aminotransferase (4%), neutropenia (3.7%), and hyperglycemia (3%).
Adverse reactions leading to dose reduction of PADCEV in the neoadjuvant phase occurred in 15% of patients. The most common adverse reactions (≥1%) leading to dose reduction of PADCEV were rash (9%) and pruritus (2%).
Of the 403 patients in the PADCEV in combination with intravenous pembrolizumab arm who received neoadjuvant treatment, 13 (3.2%) patients did not receive surgery due to adverse reactions. The adverse reactions that led to cancellation of surgery were multiple organ dysfunction syndrome (0.5%) and adenocarcinoma of colon, COVID-19 pneumonia, cardiac arrest, chronic obstructive pulmonary disease, coronary artery disease, glomerulonephritis, immune-mediated lung disease, myocarditis, pneumonia, pneumonitis, and urosepsis (0.2% each).
Of the 351 patients who received neoadjuvant treatment with PADCEV in combination with intravenous pembrolizumab and underwent RC, 26 (7%) 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-304
Patients who did not proceed to surgery were ineligible for adjuvant treatment. Of the 351 patients who underwent surgery, 225 patients received adjuvant treatment with PADCEV with or without intravenous pembrolizumab. Of the 126 patients who did not receive adjuvant PADCEV, discontinuation of PADCEV prior to the adjuvant phase was due to an adverse event in 65 patients.
In the adjuvant phase, serious adverse reactions occurred in 36% of patients receiving PADCEV. The most common serious adverse reactions (≥1.5%) in the adjuvant phase in patients who received adjuvant PADCEV included urinary tract infection (8%), sepsis (2.2%), and diarrhea, hyperglycemia, pneumonitis/ILD, and urosepsis (1.8% each). Fatal adverse reactions in the adjuvant phase in patients who received adjuvant PADCEV occurred in 3.1% of patients and included cardiac arrest, death, duodenal ulcer perforation, acute pancreatitis, renal failure, small cell lung cancer, and toxic shock syndrome (0.4% each).
Adverse reactions leading to discontinuation of PADCEV in the adjuvant phase occurred in 16% of patients who received PADCEV in the adjuvant phase. The most common adverse reactions (≥1%) leading to discontinuation of PADCEV were rash (3.6%), peripheral neuropathy (1.8%), and urinary tract infection (1.3%).
Adverse reactions leading to dose interruption of PADCEV in the adjuvant phase occurred in 34% of patients who received PADCEV in the adjuvant phase. The most common adverse reactions (≥2%) leading to dose interruption of PADCEV were diarrhea and urinary tract infection (5% each), rash (4%), and COVID-19 (2.7%).
Adverse reactions leading to dose reduction of PADCEV in the adjuvant phase occurred in 5% of patients who received PADCEV in the adjuvant phase. The most common adverse reaction (>1%) resulting in dose reduction of PADCEV in the adjuvant phase included rash (1.3%).
Neoadjuvant and Adjuvant Treatment of Patients with MIBC Who Are Cisplatin-Ineligible
EV-303
The safety of PADCEV in combination with intravenous pembrolizumab as neoadjuvant treatment and continued after 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 PLND or RC with PLND alone (n=159)
For the 167 patients who received PADCEV in the neoadjuvant phase, the median duration of exposure to PADCEV was 1.6 months (range: 0.03 to 2.8 months) and the median number of cycles of PADCEV was 3 (range: 1, 3) in the neoadjuvant phase. Out of 100 patients who received adjuvant treatment in the PADCEV in combination arm, 92 patients received PADCEV. 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) for patients who received PADCEV 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 7 summarizes the most common (≥20%) adverse reactions in EV-303.
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).
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 TEN (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 TEN (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 most common 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 TEN (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 146 patients who underwent surgery, 92 patients received adjuvant treatment with PADCEV with or without intravenous pembrolizumab. Of the 54 patients who did not receive adjuvant PADCEV, discontinuation of PADCEV prior to the adjuvant phase was due to an adverse event in 27 patients.
In the adjuvant phase, serious adverse reactions occurred in 43% of patients receiving PADCEV. The most frequent (≥2%) serious adverse reactions were urinary tract infection (8%), acute kidney injury, pyelonephritis, and urosepsis (4.3% each), and hypokalemia, intestinal obstruction, and sepsis (2.2% each). Fatal adverse reactions occurred in 8% of patients who received PADCEV in the adjuvant phase, including urosepsis, hemorrhage intracranial, death, myocardial infarction, multiple organ dysfunction syndrome, and pneumonia pseudomonal (1.1% each).
Adverse reactions leading to discontinuation of PADCEV in the adjuvant phase occurred in 28% of patients who received PADCEV in the adjuvant phase. The most common adverse reactions (≥2%) leading to discontinuation of PADCEV were peripheral neuropathy (5%) and rash (4.3%).
Adverse reactions leading to dose interruption of PADCEV in the adjuvant phase occurred in 39% of patients who received PADCEV in the adjuvant phase. The most common adverse reactions (≥2%) leading to dose interruption of PADCEV were rash (7%), diarrhea and urinary tract infection (5% each), fatigue (4.3%), pruritus (3.3%), and peripheral neuropathy and pyelonephritis (2.2% each).
Adverse reactions leading to dose reduction of PADCEV in the adjuvant phase occurred in 8% of patients who received PADCEV in the adjuvant phase. The most common adverse reaction (≥2%) leading to dose reduction of PADCEV was weight decreased (2.2%).
Previously Untreated LA/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 la/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 9 summarizes the most common (≥15%) adverse reactions in EV-302.
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%).
Previously Untreated Patients with LA/mUC Who Are Cisplatin-Ineligible
EV-103
The safety of PADCEV was evaluated in combination with intravenous pembrolizumab in a multi cohort trial (EV-103) in 121 patients with la/mUC who were not eligible for cisplatin-containing chemotherapy and received at least one dose of PADCEV 1.25 mg/kg and pembrolizumab
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 11 summarizes the most common (≥20%) adverse reactions in EV-103.
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%).
Previously Treated LA/mUC
EV-301
The safety of PADCEV was evaluated as a single agent in EV-301 in patients with la/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
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 13 summarizes the most common (≥15%) adverse reactions in EV-301.
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%).
EV-201, Cohort 1
The safety of PADCEV was evaluated as a single agent in EV-201, Cohort 1 in patients (n=125) with la/mUC who had received prior treatment with a PD-1 or PD-L1 inhibitor and platinum-based chemotherapy
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 15 summarizes the All Grades and Grades 3-4 adverse reactions reported in patients in EV-201, Cohort 1.
Clinically relevant adverse reactions (<15%) include skin hyperpigmentation (14%), herpes zoster (3%), pneumonitis/ILD (2%), and infusion site extravasation (2%).
EV-201, Cohort 2
The safety of PADCEV was evaluated as a single agent in EV-201, Cohort 2 in patients with la/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 17 summarizes the All Grades and Grades 3-4 adverse reactions reported in patients in EV-201, Cohort 2.
Clinically relevant adverse reactions (<15%) include vomiting (13%), increased aspartate aminotransferase (12%), increased lipase (11%), increased alanine aminotransferase (10%), skin hyperpigmentation (4%), pneumonitis/ILD (4%), and infusion site extravasation (1%).
4.2Post 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, SJS, and TEN
5DESCRIPTION
Enfortumab vedotin-ejfv is a Nectin-4 directed antibody-drug conjugate (ADC) comprised of a fully human anti-Nectin-4 IgG1 kappa monoclonal antibody (AGS-22C3) conjugated to the small molecule microtubule disrupting agent, monomethyl auristatin E (MMAE) via a protease-cleavable maleimidocaproyl valine-citrulline (vc) linker (SGD-1006). Conjugation takes place on cysteine residues that comprise the interchain disulfide bonds of the antibody to yield a product with a drug-to-antibody ratio of approximately 3.8:1. The molecular weight is approximately 152 kDa.
Figure 1. Structural Formula
Approximately 4 molecules of MMAE are attached to each antibody molecule. Enfortumab vedotin-ejfv is produced by chemical conjugation of the antibody and small molecule components. The antibody is produced by mammalian (Chinese hamster ovary) cells and the small molecule components are produced by chemical synthesis.
PADCEV (enfortumab vedotin-ejfv) for injection is provided as a sterile, preservative-free, white to off-white lyophilized powder in single-dose vials for intravenous use. PADCEV is supplied as a 20 mg per vial and a 30 mg per vial and requires reconstitution with Sterile Water for Injection, USP, (2.3 mL and 3.3 mL, respectively) resulting in a clear to slightly opalescent, colorless to slightly yellow solution with a final concentration of 10 mg/mL
6REFERENCES
- "OSHA Hazardous Drugs." OSHA.
7HOW SUPPLIED/STORAGE AND HANDLING
How Supplied
PADCEV (enfortumab vedotin-ejfv) 20 mg and 30 mg are supplied as a sterile, preservative-free, white to off-white lyophilized powder in single-dose vials. PADCEV vials are available in the following packages:
- Carton of one 20 mg single-dose vial (NDC 51144-020-01)
- Carton of one 30 mg single-dose vial (NDC 51144-030-01)
Storage
Store PADCEV vials refrigerated at 2ºC to 8ºC (36ºF to 46ºF) in the original carton. Do not freeze. Do not shake.
Special Handling
PADCEV is a hazardous drug. Follow applicable special handling and disposal procedures.
8PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Patient Information).
Skin Reactions
Inform patients that severe skin reactions including SJS and TEN with fatal outcomes have occurred after administration of PADCEV, predominantly during the first cycle of treatment but may occur later.
Advise patients to contact their healthcare provider immediately if they develop new target lesions, progressively worsening skin reactions, severe blistering, or peeling of the skin
Hyperglycemia
Inform patients about the risk of hyperglycemia and how to recognize associated symptoms
Pneumonitis/ILD
Advise patients to immediately report new or worsening respiratory symptoms
Peripheral Neuropathy
Inform patients to report to their healthcare provider any numbness and tingling of the hands or feet or muscle weakness
Ocular disorders
Advise patients to contact their healthcare provider if they experience any visual changes
Infusion Site Extravasation
Inform patients that infusion site reactions have occurred after administration of PADCEV. These reactions generally occurred immediately after administration but, in some instances, had a delayed onset (e.g., 24 hours). Instruct patients to contact their healthcare provider immediately if they experience an infusion site reaction
Embryo-Fetal Toxicity
Advise pregnant women and females of reproductive potential of the potential risk to the fetus. Advise females to inform their healthcare providers of a known or suspected pregnancy
Females and Males of Reproductive Potential
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
Lactation
Advise women not to breastfeed during treatment with PADCEV and for 3 weeks after the last dose
Infertility
Advise females and males of reproductive potential that PADCEV may impair fertility
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Distributed and Marketed by:
U.S. License 2124
9PACKAGE/LABEL PRINCIPAL DISPLAY PANEL
NDC 51144-020-01
PADCEV
enfortumab vedotin-ejfv
FOR INJECTION
20 mg/vial
CAUTION: Cytotoxic Agent
For intravenous infusion use only
Must reconstitute and dilute before use
Single-dose vial. Discard unused portion
Rx Only
10PACKAGE/LABEL PRINCIPAL DISPLAY PANEL
NDC 51144-030-01
PADCEV
enfortumab vedotin-ejfv
FOR INJECTION
30 mg/vial
CAUTION: Cytotoxic Agent
For intravenous infusion use only
Must reconstitute and dilute before use
Single-dose vial. Discard unused portion
Rx Only