SPL PATIENT PACKAGE INSERT SECTION.

PATIENT INFORMATIONPADCEV(R) (PAD-sev)(enfortumab vedotin-ejfv)for injectionWhat is the most important information should know about PADCEVPADCEV may cause serious side effects, including:Skin reactions. Severe skin reactions have happened in people treated with PADCEV, in some cases severe skin reactions have caused death. Most severe skin reactions occurred during the first cycle (28 days) of treatment but may happen later. Your healthcare provider will monitor you during treatment and may prescribe medicines if you get skin reactions. Tell your healthcare provider right away if you develop any of these signs of new or worsening skin reaction:otarget lesions (skin reactions that look like rings)orash or itching that continues to get worse oblistering or peeling of the skinopainful sores or ulcers in mouth or nose, throat, or genital areaofever or flu-like symptomsoswollen lymph nodesSee What are the possible side effects of PADCEV for more information about side effects.What is PADCEVPADCEV is prescription medicine used to treat adults with bladder cancer and cancers of the urinary tract (renal pelvis, ureter or urethra) that has spread or cannot be removed by surgery. PADCEV may be used if you:ohave received an immunotherapy medicine and chemotherapy that contains platinum, or oyou are not able to receive chemotherapy that contains the medicine cisplatin and you have received one or more prior therapy.It is not known if PADCEV is safe and effective in children.Before receiving PADCEV, tell your healthcare provider about all of your medical conditions, including if you:oare currently experiencing numbness or tingling in your hands or feetohave history of high blood sugar or diabetesohave liver problemsoare pregnant or plan to become pregnant. PADCEV can harm your unborn baby. Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with PADCEV. Females who are able to become pregnant:oYour healthcare provider should do pregnancy test before you start treatment with PADCEV.oYou should use an effective method of birth control during your treatment and for at least months after the last dose of PADCEV. Males with female sexual partner who is able to become pregnant:oIf your female partner is pregnant, PADCEV can harm the unborn baby.oYou should use an effective method of birth control during your treatment and for at least months after the last dose of PADCEV.oare breastfeeding or plan to breastfeed. It is not known if PADCEV passes into your breast milk. Do not breastfeed during treatment and for at least weeks after the last dose of PADCEV.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking PADCEV with certain other medicines may cause side effects.How will receive PADCEVoPADCEV will be given to you by intravenous (IV) infusion into your vein over 30 minutes.oYou will receive your PADCEV over periods of time called cycles. oEach PADCEV cycle is 28 days.oYou will receive PADCEV on days 1, and 15 of every cycle.oYour healthcare provider will decide how many treatment cycles you need.oYour healthcare provider may do blood tests regularly during treatment with PADCEV.What are the possible side effects of PADCEVPADCEV may cause serious side effects, including: oSee What is the most important information should know about PADCEV oHigh blood sugar (hyperglycemia). You can develop high blood sugar during treatment with PADCEV. High blood sugar, serious condition called diabetic ketoacidosis (DKA), and death have happened in people with and without diabetes, treated with PADCEV. Tell your healthcare provider right away if you have any symptoms of high blood sugar, including:ofrequent urinationoincreased thirstoblurred visionoconfusionoit becomes harder to control your blood sugarodrowsinessoloss of appetiteofruity smell on your breathonausea, vomiting, or stomach painoLung problems. PADCEV may cause severe or life-threatening inflammation of the lungs that can lead to death. Tell your healthcare provider right away if you get new or worsening symptoms, including trouble breathing, shortness of breath, or cough.oPeripheral neuropathy. You may develop nerve problems called peripheral neuropathy during treatment with PADCEV. Tell your healthcare provider right away if you get new or worsening numbness or tingling in your hands or feet or muscle weakness.oEye problems. You can develop certain eye problems during treatment with PADCEV. Tell your healthcare provider right away if you have dry eyes, blurred vision, or any vision changes. You may use artificial tear substitutes to help prevent or treat dry eyes.oLeakage of PADCEV out of your vein into the tissues around your infusion site (extravasation). If PADCEV leaks from the injection site or the vein into the nearby skin and tissues, it could cause an infusion site reaction. These reactions can happen right after you receive an infusion, but sometimes may happen days after your infusion. Tell your healthcare provider or get medical help right away if you notice any redness, swelling, itching, or discomfort at the infusion site.The most common side effects of PADCEV include:oskin rashochanges in liver and kidney function testsoincreased sugar (glucose) in the bloodotirednessonumbness or tingling in your hands or feet, or muscle weaknessodecreased white blood cell, red blood cell, and platelet countsohair lossodecreased appetiteodiarrheaodecreased sodium, phosphate and protein (albumin) in the blood onauseaoitchingochange in sense of tasteoincreased uric acid in the bloodoincreased lipase (a blood test done to check your pancreas)odecreased weightodry skinIf you have certain side effects, your healthcare provider may decrease your dose or stop your treatment with PADCEV for period of time (temporarily) or completely.PADCEV may cause fertility problems in males, which may affect the ability to father children. Talk to your healthcare provider if you have concerns about fertility.These are not all of the possible side effects of PADCEV.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.General information about the safe and effective use of PADCEV.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. If you would like more information about PADCEV, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about PADCEV that is written for healthcare professionals.What are the ingredients in PADCEVActive ingredient: enfortumab vedotin-ejfvInactive ingredients: histidine, histidine hydrochloride monohydrate, polysorbate 20, and trehalose dihydrate.Manufactured and Marketed by: Astellas Pharma US, Inc., Northbrook, Illinois 60062 Distributed and Marketed by: Seagen Inc., Bothell, WA 98021U.S. License 2124PADCEV is registered trademark jointly owned by Agensys, Inc. and Seagen Inc.(C)2021 Agensys, Inc. and Seagen Inc.For more information, go to www.padcev.com or call 1-888-4-PADCEV335645-EV-USAThis Patient Information has been approved by the U.S. Food and Drug Administration. Revised: July 2021. otarget lesions (skin reactions that look like rings). orash or itching that continues to get worse oblistering or peeling of the skin. opainful sores or ulcers in mouth or nose, throat, or genital area. ofever or flu-like symptoms. oswollen lymph nodes. ohave received an immunotherapy medicine and chemotherapy that contains platinum, or oyou are not able to receive chemotherapy that contains the medicine cisplatin and you have received one or more prior therapy.. oare currently experiencing numbness or tingling in your hands or feet. ohave history of high blood sugar or diabetes. ohave liver problems. oare pregnant or plan to become pregnant. PADCEV can harm your unborn baby. Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with PADCEV.. Females who are able to become pregnant:oYour healthcare provider should do pregnancy test before you start treatment with PADCEV.oYou should use an effective method of birth control during your treatment and for at least months after the last dose of PADCEV.. oYour healthcare provider should do pregnancy test before you start treatment with PADCEV.. oYou should use an effective method of birth control during your treatment and for at least months after the last dose of PADCEV.. Males with female sexual partner who is able to become pregnant:oIf your female partner is pregnant, PADCEV can harm the unborn baby.oYou should use an effective method of birth control during your treatment and for at least months after the last dose of PADCEV.. oIf your female partner is pregnant, PADCEV can harm the unborn baby.. oYou should use an effective method of birth control during your treatment and for at least months after the last dose of PADCEV.. oare breastfeeding or plan to breastfeed. It is not known if PADCEV passes into your breast milk. Do not breastfeed during treatment and for at least weeks after the last dose of PADCEV.. oPADCEV will be given to you by intravenous (IV) infusion into your vein over 30 minutes.. oYou will receive your PADCEV over periods of time called cycles. oEach PADCEV cycle is 28 days.oYou will receive PADCEV on days 1, and 15 of every cycle.. oEach PADCEV cycle is 28 days.. oYou will receive PADCEV on days 1, and 15 of every cycle.. oYour healthcare provider will decide how many treatment cycles you need.. oYour healthcare provider may do blood tests regularly during treatment with PADCEV.. oSee What is the most important information should know about PADCEV oHigh blood sugar (hyperglycemia). You can develop high blood sugar during treatment with PADCEV. High blood sugar, serious condition called diabetic ketoacidosis (DKA), and death have happened in people with and without diabetes, treated with PADCEV. Tell your healthcare provider right away if you have any symptoms of high blood sugar, including:. ofrequent urination. oincreased thirst. oblurred vision. oconfusion. oit becomes harder to control your blood sugar. odrowsiness. oloss of appetite. ofruity smell on your breath. onausea, vomiting, or stomach pain. oLung problems. PADCEV may cause severe or life-threatening inflammation of the lungs that can lead to death. Tell your healthcare provider right away if you get new or worsening symptoms, including trouble breathing, shortness of breath, or cough.. oPeripheral neuropathy. You may develop nerve problems called peripheral neuropathy during treatment with PADCEV. Tell your healthcare provider right away if you get new or worsening numbness or tingling in your hands or feet or muscle weakness.. oEye problems. You can develop certain eye problems during treatment with PADCEV. Tell your healthcare provider right away if you have dry eyes, blurred vision, or any vision changes. You may use artificial tear substitutes to help prevent or treat dry eyes.. oLeakage of PADCEV out of your vein into the tissues around your infusion site (extravasation). If PADCEV leaks from the injection site or the vein into the nearby skin and tissues, it could cause an infusion site reaction. These reactions can happen right after you receive an infusion, but sometimes may happen days after your infusion. Tell your healthcare provider or get medical help right away if you notice any redness, swelling, itching, or discomfort at the infusion site.. oskin rash. ochanges in liver and kidney function tests. oincreased sugar (glucose) in the blood. otiredness. onumbness or tingling in your hands or feet, or muscle weakness. odecreased white blood cell, red blood cell, and platelet counts. ohair loss. odecreased appetite. odiarrhea. odecreased sodium, phosphate and protein (albumin) in the blood onausea. oitching. ochange in sense of taste. oincreased uric acid in the blood. oincreased lipase (a blood test done to check your pancreas). odecreased weight. odry skin.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS oLactation: Advise women not to breastfeed. (8.2). oLactation: Advise women not to breastfeed. (8.2). 8.1 Pregnancy Risk SummaryBased on the mechanism of action and findings in animals, PADCEV can cause fetal harm when administered to pregnant woman [see Clinical Pharmacology (12.1)]. There are no available human data on PADCEV use in pregnant women to inform drug-associated risk. In an animal reproduction study, administration of enfortumab vedotin-ejfv to pregnant rats during organogenesis caused maternal toxicity, embryo-fetal lethality, structural malformations and skeletal anomalies at maternal exposures similar to the exposures at the recommended human dose of 1.25 mg/kg (see Data). Advise patients of the potential risk to the fetus.The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively.DataAnimal DataIn rat pilot embryo-fetal development study, administration of enfortumab vedotin-ejfv on gestation day and 13 during the period of organogenesis resulted in complete litter loss in all pregnant rats at the maternally toxic dose of mg/kg (approximately times the exposure at the recommended human dose). dose of mg/kg (similar to the exposure at the recommended human dose) resulted in maternal toxicity, embryo-fetal lethality and structural malformations that included gastroschisis, malrotated hindlimb, absent forepaw, malpositioned internal organs and fused cervical arch. Additionally, skeletal anomalies (asymmetric, fused, incompletely ossified, and misshapen sternebrae, misshapen cervical arch, and unilateral ossification of the thoracic centra) and decreased fetal weight were observed. 8.2 Lactation Risk SummaryThere 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 breastfed child, advise lactating women not to breastfeed during treatment with PADCEV and for at least weeks after the last dose.. 8.3 Females and Males of Reproductive Potential Pregnancy testingVerify pregnancy status in females of reproductive potential prior to initiating PADCEV treatment [see Use in Specific Populations (8.1)].ContraceptionFemalesPADCEV can cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with PADCEV and for months after the last dose.MalesAdvise male patients with female partners of reproductive potential to use effective contraception during treatment with PADCEV and for months after the last dose.InfertilityMalesBased on findings from animal studies, PADCEV may impair male fertility [see Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use Safety and effectiveness of PADCEV in pediatric patients have not been established.. 8.5 Geriatric Use Of the 680 patients treated with PADCEV in clinical trials, 440 (65%) were 65 years or older and 168 (25%) were 75 years or older. No overall differences in safety or effectiveness were observed between these patients and younger patients [see Clinical Pharmacology (12.3)].. 8.6 Hepatic Impairment. Avoid the use of PADCEV in patients with moderate or severe hepatic impairment (total bilirubin >1.5 ULN and AST any). PADCEV has only been studied in limited number of patients with moderate hepatic impairment (n=3) and has not been evaluated in patients with severe hepatic impairment [see Clinical Pharmacology (12.3)]. In another ADC that contains MMAE, the frequency of >= Grade adverse reactions and deaths was greater in patients with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment compared to patients with normal hepatic function. No adjustment in the starting dose is required when administering PADCEV to patients with mild hepatic impairment (total bilirubin to 1.5 ULN and AST any, or total bilirubin <=ULN and AST >ULN). 8.7 Renal Impairment No dose adjustment is required in patients with mild (CrCL >60-90 mL/min), moderate (CrCL 30-60 mL/min) or severe (CrCL <30 mL/min) renal impairment [see Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS oHyperglycemia: Diabetic ketoacidosis may occur in patients with and without preexisting diabetes mellitus, which may be fatal. Closely monitor blood glucose levels in patients with, or at risk for, diabetes mellitus or hyperglycemia. Withhold PADCEV if blood glucose is >250 mg/dL. (2.2, 5.2)oPneumonitis: Severe, life-threatening or fatal pneumonitis may occur. Withhold PADCEV for persistent or recurrent Grade pneumonitis and consider dose reduction. Permanently discontinue PADCEV for Grade or pneumonitis. (2.2, 5.3)oPeripheral neuropathy: Monitor patients for new or worsening peripheral neuropathy and consider dose interruption, dose reduction or discontinuation of PADCEV. (2.2, 5.4)oOcular disorders: Ocular disorders, including vision changes, may occur. Monitor patients for signs or symptoms of ocular disorders. Consider prophylactic artificial tears for dry eyes and treatment with ophthalmic topical steroids after an ophthalmic exam. Consider dose interruption or dose reduction of PADCEV when symptomatic ocular disorders occur. (5.5)oInfusion Site Extravasation: Ensure adequate venous access prior to administration. Monitor the infusion site during PADCEV administration and stop the infusion immediately for suspected extravasation. (5.6)oEmbryo-fetal toxicity: PADCEV can cause fetal harm. Advise of the potential risk to fetus and to use effective contraception. (5.7, 8.1, 8.3). oHyperglycemia: Diabetic ketoacidosis may occur in patients with and without preexisting diabetes mellitus, which may be fatal. Closely monitor blood glucose levels in patients with, or at risk for, diabetes mellitus or hyperglycemia. Withhold PADCEV if blood glucose is >250 mg/dL. (2.2, 5.2). oPneumonitis: Severe, life-threatening or fatal pneumonitis may occur. Withhold PADCEV for persistent or recurrent Grade pneumonitis and consider dose reduction. Permanently discontinue PADCEV for Grade or pneumonitis. (2.2, 5.3). oPeripheral neuropathy: Monitor patients for new or worsening peripheral neuropathy and consider dose interruption, dose reduction or discontinuation of PADCEV. (2.2, 5.4). oOcular disorders: Ocular disorders, including vision changes, may occur. Monitor patients for signs or symptoms of ocular disorders. Consider prophylactic artificial tears for dry eyes and treatment with ophthalmic topical steroids after an ophthalmic exam. Consider dose interruption or dose reduction of PADCEV when symptomatic ocular disorders occur. (5.5). oInfusion Site Extravasation: Ensure adequate venous access prior to administration. Monitor the infusion site during PADCEV administration and stop the infusion immediately for suspected extravasation. (5.6). oEmbryo-fetal toxicity: PADCEV can cause fetal harm. Advise of the potential risk to fetus and to use effective contraception. (5.7, 8.1, 8.3). 5.1 Skin Reactions. Severe cutaneous adverse reactions, including fatal cases of SJS or TEN occurred in patients treated with PADCEV. SJS and TEN occurred predominantly during the first cycle of treatment but may occur later. Skin reactions occurred in 55% of the 680 patients treated with PADCEV in clinical trials. Twenty-three percent (23%) of patients had maculopapular rash and 33% had pruritus. Grade 3-4 skin reactions occurred in 13% of patients, including maculo-papular rash, rash erythematous, rash or drug eruption, symmetrical drug-related intertriginous and flexural exanthema (SDRIFE), dermatitis bullous, dermatitis exfoliative, and palmar-plantar erythrodysesthesia. In clinical trials, the median time to onset of severe skin reactions was 0.6 months (range: 0.1 to 6.4 months). Among patients experiencing skin reaction leading to dose interruption who then restarted PADCEV (n=59), 24% of patients restarting at the same dose and 16% of patients restarting at reduced dose experienced recurrent severe skin reactions. Skin reactions led to discontinuation of PADCEV in 2.6% of patients [see Adverse Reactions (6.1)]. Monitor patients closely throughout treatment for skin reactions. Consider topical corticosteroids and antihistamines, as clinically indicated. Withhold PADCEV and refer for specialized care for suspected SJS, TEN or for severe (Grade 3) skin reactions. Permanently discontinue PADCEV in patients with confirmed SJS or TEN; or Grade or recurrent Grade skin reactions [see Dosage and Administration (2.2)]. 5.2 Hyperglycemia. Hyperglycemia and diabetic ketoacidosis (DKA), including fatal events, occurred in patients with and without pre-existing diabetes mellitus, treated with PADCEV. Patients with baseline hemoglobin A1C >=8% were excluded from clinical trials. In clinical trials, 14% of the 680 patients treated with PADCEV developed hyperglycemia; 7% of patients developed Grade 3-4 hyperglycemia. The incidence of Grade 3-4 hyperglycemia increased consistently in patients with higher body mass index and in patients with higher baseline A1C. Five percent (5%) of patients required initiation of insulin therapy for treatment of hyperglycemia. The median time to onset of hyperglycemia was 0.6 months (range: 0.1 to 20.3 months). Hyperglycemia led to discontinuation of PADCEV in 0.6% of patients. [see Adverse Reactions (6.1)]. Closely monitor blood glucose levels in patients with, or at risk for, diabetes mellitus or hyperglycemia. If blood glucose is elevated (>250 mg/dL), withhold PADCEV [see Dosage and Administration (2.2)].. 5.3 Pneumonitis. Severe, life-threatening or fatal pneumonitis occurred in patients treated with PADCEV. In clinical trials, 3.1% of the 680 patients treated with PADCEV had pneumonitis of any grade and 0.7% had Grade 3-4. In clinical trials, the median time to onset of pneumonitis was 2.9 months (range: 0.6 to months).Monitor patients for signs and symptoms indicative of pneumonitis such as hypoxia, cough, dyspnea or interstitial infiltrates on radiologic exams. Evaluate and exclude infectious, neoplastic and other causes for such signs and symptoms through appropriate investigations. Withhold PADCEV for patients who develop persistent or recurrent Grade pneumonitis and consider dose reduction. Permanently discontinue PADCEV in all patients with Grade or pneumonitis [see Dosage and Administration (2.2)].. 5.4 Peripheral Neuropathy. Peripheral neuropathy occurred in 52% of the 680 patients treated with PADCEV in clinical trials including 39% with sensory neuropathy, 7% with muscular weakness and 6% with motor neuropathy; 4% experienced Grade 3-4 reactions. Peripheral neuropathy occurred in patients treated with PADCEV with or without preexisting peripheral neuropathy. The median time to onset of Grade >=2 peripheral neuropathy was 4.6 months (range: 0.1 to 15.8 months). Neuropathy led to treatment discontinuation in 5% of patients. [see Adverse Reactions (6.1)].Monitor patients for symptoms of new or worsening peripheral neuropathy and consider dose interruption or dose reduction of PADCEV when peripheral neuropathy occurs. Permanently discontinue PADCEV in patients who develop Grade >3 peripheral neuropathy [see Dosage and Administration (2.2)]. 5.5 Ocular Disorders. Ocular disorders were reported in 40% of the 384 patients treated with PADCEV in clinical trials in which ophthalmologic exams were scheduled. The majority of these events involved the cornea and included events associated with dry eye such as keratitis, blurred vision, increased lacrimation, conjunctivitis, limbal stem cell deficiency, and keratopathy. Dry eye symptoms occurred in 34% of patients, and blurred vision occurred in 13% of patients, during treatment with PADCEV. The median time to onset to symptomatic ocular disorder was 1.6 months (range: to 19.1 months). Monitor patients for ocular disorders. Consider artificial tears for prophylaxis of dry eyes and ophthalmologic evaluation if ocular symptoms occur or do not resolve. Consider treatment with ophthalmic topical steroids, if indicated after an ophthalmic exam. Consider dose interruption or dose reduction of PADCEV for symptomatic ocular disorders. 5.6 Infusion Site Extravasation. Skin and soft tissue reactions secondary to extravasation have been observed after administration of PADCEV. Of the 680 patients, 1.6% of patients experienced skin and soft tissue reactions, including 0.3% who experienced Grade 3-4 reactions. Reactions may be delayed. Erythema, swelling, increased temperature, and pain worsened until 2-7 days after extravasation and resolved within 1-4 weeks of peak. Two patients (0.3%) developed extravasation reactions with secondary cellulitis, bullae, or exfoliation. Ensure adequate venous access prior to starting PADCEV and monitor for possible extravasation during administration. If extravasation occurs, stop the infusion and monitor for adverse reactions. 5.7 Embryo-Fetal Toxicity Based on the mechanism of action and findings in animals, PADCEV can cause fetal harm when administered to pregnant woman. In animal reproduction studies, administration of enfortumab vedotin-ejfv to pregnant rats during the period of organogenesis caused maternal toxicity, embryo-fetal lethality, structural malformations and skeletal anomalies at maternal exposures similar to the clinical exposures at the recommended human dose of 1.25 mg/kg.Advise patients of the potential risk to the fetus. Advise female patients of reproductive potential to use effective contraception during treatment with PADCEV and for months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with PADCEV and for months after the last dose [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.1)].

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling:oSkin Reactions [see Boxed Warning, Warnings and Precautions (5.1)]oHyperglycemia [see Warnings and Precautions (5.2)]oPneumonitis [see Warnings and Precautions (5.3)]oPeripheral Neuropathy [see Warnings and Precautions (5.4)]oOcular Disorders [see Warnings and Precautions (5.5)]oInfusion Site Extravasation [see Warnings and Precautions (5.6)]. oSkin Reactions [see Boxed Warning, Warnings and Precautions (5.1)]. oHyperglycemia [see Warnings and Precautions (5.2)]. oPneumonitis [see Warnings and Precautions (5.3)]. oPeripheral Neuropathy [see Warnings and Precautions (5.4)]. oOcular Disorders [see Warnings and Precautions (5.5)]. oInfusion Site Extravasation [see Warnings and Precautions (5.6)]. The most common adverse reactions, including laboratory abnormalities, (>=20%) included rash, aspartate aminotransferase increased, glucose increased, creatinine increased, fatigue, peripheral neuropathy, lymphocytes decreased, alopecia, decreased appetite, hemoglobin decreased, diarrhea, sodium decreased, nausea, pruritus, phosphate decreased, dysgeusia, alanine aminotransferase increased, anemia, albumin decreased, neutrophils decreased, urate increased, lipase increased, platelets decreased, weight decreased and dry skin. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Astellas Pharma US, Inc. at 1-800-727-7003 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The pooled safety population described in the WARNINGS AND PRECAUTIONS reflect exposure to PADCEV as single agent at 1.25 mg/kg in 680 patients in EV-301, EV-201, EV-101 (NCT02091999), and EV-102 (NCT03070990). Ocular disorders reflect 384 patients in EV-201, EV-101, and EV-102. Among 680 patients receiving PADCEV, 36% were exposed for >6 months, and 9% were exposed for >=12 months. In this pooled population, the most common (>20%) adverse reactions, including laboratory abnormalities, were rash, aspartate aminotransferase increased, glucose increased, creatinine increased, fatigue, peripheral neuropathy, lymphocytes decreased, alopecia, decreased appetite, hemoglobin decreased, diarrhea, sodium decreased, nausea, pruritus, phosphate decreased, dysgeusia, alanine aminotransferase increased, anemia, albumin decreased, neutrophils decreased, urate increased, lipase increased, platelets decreased, weight decreased and dry skin.The data described in the following sections reflect exposure to PADCEV from an open-label, randomized, study (EV-301); and Cohort and Cohort of an open-label, single arm, two cohort study (EV-201). Patients received PADCEV 1.25 mg/kg on Days 1, and 15 of 28-day cycle until disease progression or unacceptable toxicity. Previously Treated Locally Advanced or Metastatic Urothelial CancerEV-301The safety of PADCEV was evaluated 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 PD-1 or PD-L1 inhibitor and platinum-based chemotherapy [see Clinical Studies (14)]. Routine ophthalmologic exams were not conducted in EV-301. The median duration of exposure to PADCEV was months (range: 0.5 to 19.4 months).Serious adverse reactions occurred in 47% of patients treated with PADCEV. The most common serious adverse reactions (>=2%) were urinary tract infection, acute kidney injury (7% each) and pneumonia (5%). Fatal adverse reactions occurred in 3% of patients, including multiorgan dysfunction (1.0%), hepatic dysfunction, septic shock, hyperglycemia, pneumonitis and pelvic abscess (0.3% each).Adverse reactions leading to discontinuation occurred in 17% of patients; the most common adverse reactions (>=2%) leading to discontinuation were peripheral neuropathy (5%) and rash (4%). Adverse reactions leading to dose interruption occurred in 61% of patients; the most common adverse reactions (>=4%) leading to dose interruption were peripheral neuropathy (23%), rash (11%) and fatigue (9%). Adverse reactions leading to dose reduction occurred in 34% of patients; the most common adverse reactions (>=2%) leading to dose reduction were peripheral neuropathy (10%), rash (8%), decreased appetite (3%) and fatigue (3%).Table summarizes the most common (>=15%) adverse reactions in EV-301.Table 3. Adverse Reactions (>=15%) in Patients Treated with PADCEV in EV-301Adverse ReactionPADCEVn=296Chemotherapyn=291All Grades%Grade 3-4%All Grades%Grade 3-4%Skin and subcutaneous tissue disordersRashIncludes: blister, blood blister, conjunctivitis, dermatitis, dermatitis bullous, drug eruption, eczema, erythema, erythema multiforme, exfoliative rash, intertrigo, palmar-plantar erythrodysesthesia syndrome, rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic, rash vesicular, skin irritation, skin exfoliation, stomatitis. 5414200.3Alopecia470380Pruritus34270Dry skin17040General disorders and administration site conditionsFatigueIncludes: fatigue, asthenia 509407PyrexiaIncludes: pyrexia, hyperthermia, hyperpyrexia, body temperature increased 222140Nervous system disordersPeripheral neuropathyIncludes: burning sensation, demyelinating polyneuropathy, dysesthesia, hypoesthesia, muscular weakness, neuralgia, neuropathy peripheral, neurotoxicity, paresthesia, peripheral motor neuropathy, peripheral sensorimotor neuropathy, peroneal nerve palsy, peripheral sensory neuropathy, gait disturbance, polyneuropathy, sensory loss 505343DysgeusiaIncludes: dysgeusia, ageusia, hypogeusia 26080Metabolism and nutrition disordersDecreased appetite415272Gastrointestinal disordersDiarrheaIncludes: diarrhea, colitis, enterocolitis 354232Nausea301252Constipation281252Abdominal PainIncludes: abdominal pain, abdominal pain upper, abdominal pain lower, abdominal discomfort, hepatic pain, abdominal tenderness, gastrointestinal pain 201143Musculoskeletal and connective tissue disordersMusculoskeletal PainIncludes: myalgia, arthralgia, back pain, bone pain, pain in extremity, musculoskeletal pain, arthritis, neck pain, non-cardiac chest pain, musculoskeletal chest pain, spinal pain, musculoskeletal stiffness, musculoskeletal discomfort 252355Eye DisordersDry eyeIncludes: blepharitis, conjunctivitis, dry eye, eye irritation, keratitis, keratopathy, lacrimation increased, Meibomian gland dysfunction, ocular discomfort, punctate keratitis 240.760.3Blood and lymphatic system disordersAnemia2063012Infections and infestationsUrinary Tract InfectionIncludes: urinary tract infection, urinary tract infection bacterial, urinary tract infection enterococcal, streptococcal urinary tract infection, escherichia urinary tract infection, pyelonephritis acute, escherichia pyelonephritis, urinary tract infection fungal, cystitis, urinary tract infection staphylococcal, urinary tract infection pseudomonal 176133Vascular disordersHemorrhageIncludes: hematuria, rectal hemorrhage, gastrointestinal hemorrhage, epistaxis, upper gastrointestinal hemorrhage, tumor hemorrhage, hemoptysis, vaginal hemorrhage, anal hemorrhage, hemorrhagic stroke, urethral hemorrhage, infusion site hemorrhage, conjunctival hemorrhage, hemorrhagic ascites, hemorrhoidal hemorrhage 173132InvestigationsWeight decreased160.370Clinically relevant adverse reactions (<15%) include vomiting (14%), aspartate aminotransferase increased (12%), hyperglycemia (10%), alanine aminotransferase increased (9%), pneumonitis (3%) and infusion site extravasation (0.7%).Table 4. Selected Laboratory Abnormalities Reported in >=15% (Grades 2-4) or >=5% (Grade 3-4) of Patients Treated with PADCEV in EV-301Laboratory AbnormalityPADCEVThe denominator used to calculate the rate varied from 262 to 287 based on the number of patients with baseline value and at least one post-treatment value.ChemotherapyGrades 2-4%Grade 3-4%Grades 2-4%Grade 3-4%HematologyLymphocytes decreased41143418Hemoglobin decreased2844214Neutrophils decreased27122517ChemistryPhosphate decreased398246Glucose increased (non-fasting)339276Creatinine increased182130Potassium decreased16273Lipase increased13874Sodium decreased8855EV-201, Cohort 1The safety of PADCEV was evaluated in EV-201, Cohort in patients (n=125) with locally advanced or metastatic urothelial cancer who had received prior treatment with PD-1 or PD-L1 inhibitor and platinum-based chemotherapy [see Clinical Studies (14)]. Patients received PADCEV 1.25 mg/kg on Days 1, and 15 of 28-day cycle until disease progression or unacceptable toxicity. The median duration of exposure to PADCEV was 4.6 months (range: 0.5-15.6).Serious adverse reactions occurred in 46% of patients treated with PADCEV. The most common serious adverse reactions (>=3%) were urinary tract infection (6%), cellulitis (5%), febrile neutropenia (4%), diarrhea (4%), sepsis (3%), acute kidney injury (3%), dyspnea (3%), and rash (3%). Fatal adverse reactions occurred in 3.2% of patients, including acute respiratory failure, aspiration pneumonia, cardiac disorder, sepsis and pneumonitis (each 0.8%). Adverse reactions leading to discontinuation occurred in 16% of patients; the most common adverse reaction leading to discontinuation was peripheral neuropathy (6%). Adverse reactions leading to dose interruption occurred in 64% of patients; the most common adverse reactions leading to dose interruption were peripheral neuropathy (18%), rash (9%) and fatigue (6%). Adverse reactions leading to dose reduction occurred in 34% of patients; the most common adverse reactions leading to dose reduction were peripheral neuropathy (12%), rash (6%) and fatigue (4%).Table summarizes the All Grades and Grades 3-4 adverse reactions reported in patients in EV-201, Cohort 1.Table 5. Adverse Reactions Reported in >=15% (All Grades) or >=5% (Grade 3-4) of Patients Treated with PADCEV in EV-201 Cohort 1Adverse ReactionPADCEVn=125All Grades%Grade 3-4%Any10073General disorders and administration site conditionsFatigueIncludes: asthenia and fatigue 566Nervous system disordersPeripheral neuropathyIncludes: hypoesthesia, gait disturbance, muscular weakness, neuralgia, paresthesia, peripheral motor neuropathy, peripheral sensory neuropathy and peripheral sensorimotor neuropathy. 564Dysgeusia420Metabolism and nutrition disordersDecreased appetite522Skin and subcutaneous tissue disordersRashIncludes: dermatitis acneiform, dermatitis bullous, dermatitis contact, dermatitis exfoliative, drug eruption, erythema, erythema multiforme, exfoliative rash, palmar-plantar erythrodysesthesia syndrome, photosensitivity reaction, rash, rash erythematous, rash generalized, rash macular, rash maculo-papular, rash papular, rash pustular, rash pruritic, rash vesicular, skin exfoliation, stasis dermatitis, and symmetrical drug-related intertriginous and flexural exanthema (SDRIFE) and urticaria. 5213Alopecia500Dry skin260PruritusIncludes: pruritus and pruritus generalized 262Gastrointestinal disordersNausea453DiarrheaIncludes: colitis, diarrhea and enterocolitis 426Vomiting182Eye disordersDry eyeIncludes: blepharitis, conjunctivitis, dry eye, eye irritation, keratitis, keratopathy, lacrimation increased, limbal stem cell deficiency, Meibomian gland dysfunction, ocular discomfort, punctate keratitis, tear break up time decreased 400Clinically relevant adverse reactions (<15%) include herpes zoster (3%), pneumonitis (2%) and infusion site extravasation (2%).Table 6. Selected Laboratory Abnormalities Reported in >=15% (Grades 2-4) or >=5% (Grade 3-4) of Patients Treated with PADCEV in EV-201, Cohort 1Laboratory AbnormalityPADCEVGrades 2-4Denominator for each laboratory parameter is based on the number of patients with baseline and post-treatment laboratory value available for 121 or 122 patients.%Grade 3-4%HematologyHemoglobin decreased3410Lymphocytes decreased3210Neutrophils decreased145ChemistryPhosphate decreased3410Glucose increased (non-fasting)278Creatinine increased202Potassium decreased19Includes Grade (potassium 3.0-3.5 mmol/L) Grade 4. 1Lipase increased149Sodium decreased88Urate increased77EV-201, Cohort 2The safety of PADCEV was evaluated in EV-201, Cohort 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 PD-1 or PD-L1 inhibitor and were not eligible for cisplatin-based chemotherapy. The median duration of exposure was 5.98 months (range: 0.3 to 24.6 months).Serious adverse reactions occurred in 39% of patients treated with PADCEV. The most common serious adverse reactions (>=3%) were pneumonia, sepsis and diarrhea (5% each). Fatal adverse reactions occurred in 8% of patients, including acute kidney injury (2.2%), metabolic acidosis, sepsis, multiorgan dysfunction, pneumonia and pneumonitis (1.1% each).Adverse reactions leading to discontinuation occurred in 20% of patients; the most common adverse reaction (>=2%) leading to discontinuation was peripheral neuropathy (7%). Adverse reactions leading to dose interruption occurred in 60% of patients; the most common adverse reactions (>=3%) leading to dose interruption were peripheral neuropathy (19%), rash (9%), fatigue (8%), diarrhea (5%), aspartate aminotransferase increased (3%) and hyperglycemia (3%). Adverse reactions leading to dose reduction occurred in 49% of patients; the most common adverse reactions (>=3%) leading to dose reduction were peripheral neuropathy (19%), rash (11%) and fatigue (7%).Table summarizes the All Grades and Grades 3-4 adverse reactions reported in patients in EV-201, Cohort 2.Table 7. Adverse Reactions >=15% (All Grades) or >=5% (Grades 3-4) in Patients Treated with PADCEV in EV-201, Cohort 2Adverse ReactionPADCEVn=89All Grades(%)Grades 3-4(%)Skin and subcutaneous tissue disordersRashIncludes: blister, conjunctivitis, dermatitis bullous, dermatitis exfoliative generalized, eczema, erythema, erythema multiforme, intertrigo, palmar-plantar erythrodysesthesia syndrome, rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash vesicular, skin exfoliation, stomatitis 6617Alopecia530Pruritus353Dry skin191Nervous system disordersPeripheral neuropathyIncludes: demyelinating polyneuropathy, gait disturbance, hypoesthesia, motor dysfunction, muscle atrophy, muscular weakness, paresthesia, peripheral motor neuropathy, peripheral sensorimotor neuropathy, peroneal nerve palsy, peripheral sensory neuropathy 588DysgeusiaIncludes: dysgeusia, ageusia, hypogeusia 290General disorders and administration site conditionsFatigueIncludes: fatigue, asthenia 4811Metabolism and nutrition disordersDecreased appetite406Hyperglycemia169Blood and lymphatic disordersAnemia3811Gastrointestinal disordersDiarrheaIncludes: diarrhea, colitis, enterocolitis 368Nausea301InvestigationsWeight decreased351Eye disordersDry eyeIncludes: blepharitis, conjunctivitis, dry eye, eye irritation, keratitis, keratopathy, lacrimation increased, limbal stem cell deficiency, Meibomian gland dysfunction, ocular discomfort, punctate keratitis, tear break up time decreased 300Clinically relevant adverse reactions (<15%) include vomiting (13%), aspartate aminotransferase increased (12%), lipase increased (11%), alanine aminotransferase increased (10%), pneumonitis (4%) and infusion site extravasation (1%).Table 8. Selected Laboratory Abnormalities Reported in >=15% (Grades 2-4) or >=5% (Grades 3-4) of Patients Treated with PADCEV in EV-201, Cohort 2Laboratory AbnormalityPADCEVN=88Based on the number of patients with baseline value and at least one post-treatment value.Grades 2-4%Grade 3-4%HematologyLymphocytes decreased4315Hemoglobin decreased345Neutrophils decreased209ChemistryGlucose increased (non-fasting)3613Phosphate decreased257Creatinine increased233Lipase increased1811Urate increased99Potassium increased86Sodium decreased77. 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 population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Skin and subcutaneous tissue disorders: Epidermal necrosis, Stevens-Johnson syndrome, toxic epidermal necrolysis [see Warnings and Precautions (5.1)]. Blood and lymphatic system disorders: Neutropenia, febrile neutropenia, and neutrophil count decreased.. 6.3 Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the trials described below with the incidence of antibodies in other trials or other enfortumab vedotin-ejfv products may be misleading.Following administration of PADCEV 1.25 mg/kg; 16/590 (2.7%) patients tested positive for anti-therapeutic antibody (ATA) against enfortumab vedotin-ejfv at one or more post-baseline time points. Due to the limited number of patients with ATA against enfortumab vedotin-ejfv, no conclusions can be drawn concerning potential effect of immunogenicity on efficacy, safety or pharmacokinetics.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Enfortumab vedotin-ejfv is an ADC. The antibody is human IgG1 directed against Nectin-4, an adhesion protein located on the surface of cells. The small molecule, MMAE, is microtubule-disrupting agent, attached to the antibody via protease-cleavable linker. Nonclinical data suggest that the anticancer activity of enfortumab vedotin-ejfv is due to the binding of the ADC to Nectin-4-expressing cells, followed by internalization of the ADC-Nectin-4 complex, and the release of MMAE via proteolytic cleavage. Release of MMAE disrupts the microtubule network within the cell, subsequently inducing cell cycle arrest and apoptotic cell death.. 12.2 Pharmacodynamics In an exposure-response analysis, higher enfortumab vedotin-ejfv exposure was associated with higher incidence of some adverse reactions (e.g., Grade >=2 peripheral neuropathy, Grade >=3 hyperglycemia). The exposure-response relationship for efficacy has not been fully characterized.Cardiac ElectrophysiologyAt the recommended dose, PADCEV had no large QTc prolongation (>20 msec).. 12.3 Pharmacokinetics Population pharmacokinetic analysis included data from 748 patients based on five studies. Enfortumab vedotin-ejfv pharmacokinetics were characterized after single and multiple doses in patients with locally advanced or metastatic urothelial carcinoma and other solid tumors. The exposure parameters of ADC and unconjugated MMAE (the cytotoxic component of enfortumab vedotin-ejfv) are summarized in Table below. Peak ADC concentrations were observed near the end of intravenous infusion while peak MMAE concentrations were observed approximately days after enfortumab vedotin-ejfv dosing. Minimal accumulation of the ADC and MMAE was observed following repeat administration of enfortumab vedotin-ejfv in patients. Steady-state concentrations of ADC and MMAE were reached after treatment cycle.Table 9. Exposure parameters of ADC and unconjugated MMAE after first treatment cycle of 1.25 mg/kg of enfortumab vedotin-ejfv dose of Days 1, and 15Cmax maximum concentration, AUC0-28d area under the concentration-time curve from time zero to 28 days, Ctrough,0-28d pre-dose concentration on day 28ADCMean (+- SD)Unconjugated MMAEMean (+- SD)Cmax 28 (6.1) ug/mL5.5 (3.0) ng/mLAUC0-28d 110 (26) ugd/mL85 (50) ngd/mLCtrough,0-28d 0.31 (0.18) ug/mL0.81 (0.88) ng/mLDistributionThe estimated mean steady-state volume of distribution of ADC was 12.8 liters following administration of enfortumab vedotin-ejfv. Plasma protein binding of MMAE ranged from 68% to 82%, in vitro.EliminationADC and MMAE exhibited multi-exponential declines with an elimination half-life of 3.6 days and 2.6 days, respectively. The mean clearance (CL) of enfortumab vedotin-ejfv and unconjugated MMAE in patients was 0.11 L/h and 2.11 L/h, respectively, in patients. Elimination of MMAE appeared to be limited by its rate of release from enfortumab vedotin-ejfv. MetabolismEnfortumab vedotin-ejfv catabolism has not been studied in humans; however, it is expected to undergo catabolism to small peptides, amino acids, unconjugated MMAE, and unconjugated MMAE-related catabolites. Enfortumab vedotin-ejfv releases MMAE via proteolytic cleavage, and MMAE is primarily metabolized by CYP3A4 in vitro.ExcretionThe excretion of enfortumab vedotin-ejfv is not fully characterized. Following single-dose of another ADC that contains MMAE, 17% of the total MMAE administered was recovered in feces and 6% in urine over 1-week period, primarily as unchanged drug. similar excretion profile of MMAE is expected after enfortumab vedotin-ejfv administration.Specific PopulationsBased on population pharmacokinetic analysis, no clinically significant differences in the pharmacokinetics of enfortumab vedotin-ejfv were observed based on age (24 to 90 years), sex, or race/ethnicity (Caucasian, Asian, Black, or others).Hepatic ImpairmentBased on population pharmacokinetics analysis, there was 37% AUC0-28d increase in unconjugated MMAE exposure observed in patients with mild hepatic impairment (total bilirubin of to 1.5 ULN and AST any, or total bilirubin <=ULN and AST >ULN, n=65) compared to normal hepatic function. Enfortumab vedotin-ejfv has only been studied in limited number of patients with moderate hepatic impairment and has not been evaluated in patients with severe hepatic impairment. The effect of moderate or severe hepatic impairment (total bilirubin >1.5 ULN and AST any) or liver transplantation on the pharmacokinetics of ADC or unconjugated MMAE is unknown.Renal ImpairmentThe pharmacokinetics of enfortumab vedotin-ejfv and unconjugated MMAE were evaluated after the administration of 1.25 mg/kg of enfortumab vedotin-ejfv to patients with mild (creatinine clearance; CrCL >60-90 mL/min; n=272), moderate (CrCL 30-60 mL/min; n=315) and severe (CrCL <30 mL/min; n=25) renal impairment. No significant differences in exposure (AUC) of ADC and MMAE were observed in patients with mild, moderate or severe renal impairment compared to patients with normal renal function. The effect of end stage renal disease with or without dialysis on the pharmacokinetics of ADC or unconjugated MMAE is unknown.Drug Interaction TrialsNo clinical trials evaluating the drug-drug interaction potential of enfortumab vedotin-ejfv have been conducted. Physiologically Based Pharmacokinetic (PBPK) Modeling Predictions:Dual P-gp and Strong CYP3A4 Inhibitor: Concomitant use of enfortumab vedotin-ejfv with ketoconazole (a dual P-gp and strong CYP3A4 inhibitor) is predicted to increase unconjugated MMAE Cmax by 15% and AUC by 38%.Dual P-gp and Strong CYP3A4 Inducer: Concomitant use of enfortumab vedotin-ejfv with rifampin (a dual P-gp and strong CYP3A4 inducer) is predicted to decrease unconjugated MMAE Cmax by 28% and AUC by 53%.Sensitive CYP3A substrates: Concomitant use of enfortumab vedotin-ejfv is predicted not to affect exposure to midazolam (a sensitive CYP3A substrate).In Vitro Studies Transporter Systems: MMAE is substrate of P-glycoprotein (P-gp), but not an inhibitor of P-gp.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES 14.1 Metastatic Urothelial Cancer Previously Treated Locally Advanced or Metastatic Urothelial CarcinomaEV-301The efficacy of PADCEV was evaluated in EV-301 (NCT03474107), an open-label, randomized, multicenter trial that enrolled 608 patients with locally advanced or metastatic urothelial cancer who received prior treatment with PD-1 or PD-L1 inhibitor and platinum-based chemotherapy. Patients were randomized 1:1 to receive either PADCEV 1.25 mg/kg on Days 1, and 15 of 28-day cycle or investigators choice of chemotherapy. Randomization was stratified by ECOG PS (0 vs 1), region of world (Western Europe vs US vs Rest of World), and presence of liver metastasis.Patients were excluded if they had active central nervous system (CNS) metastases, ongoing sensory or motor neuropathy >=Grade 2, or uncontrolled diabetes defined as hemoglobin A1C (HbA1c) >=8% or HbA1c >=7% with associated diabetes symptoms.The median age was 68 years (range: 30 to 88 years) and 77% were male. Racial demographics were reported as White (52%), Asian (33%), Black (0.7%), Native Hawaiian or Other Pacific Islander (0.2%) or not reported (15%). Nine percent of patients were Hispanic or Latino. All patients had baseline Eastern Cooperative Oncology Group (ECOG) performance status of (40%) or (60%). Thirty-four percent of patients had tumors located in the upper tract that included the renal pelvis and ureter. Eighty percent of patients had visceral metastases including 31% with liver metastases. Seventy-six percent of patients had pure transitional cell carcinoma (TCC) histology; 14% had TCC with other histologic variants; and 10% had other tumor histologies including adenocarcinoma and squamous cell carcinoma. The median number of prior therapies was (range to >=3). Sixty-three percent of patients received prior cisplatin-based regimens, 26% received prior carboplatin-based regimens, and an additional 11% received both cisplatin and carboplatin-based regimens. Patients on the control arm received docetaxel (38%), paclitaxel (36%) or vinflunine (25%).The major efficacy outcome measures were overall survival (OS), progression free survival (PFS), and overall response rate (ORR) assessed by investigator using RECIST v1.1. Efficacy results were consistent across all stratified patient subgroups.Table 10 and Figures 2-3 summarize the efficacy results for EV-301.Table 10. Efficacy Results in EV-301EndpointPADCEVN=301ChemotherapyN=307Overall SurvivalBased on log-rank test. Stratification factors were ECOG PS, region and liver metastasisNumber (%) of patients with events134 (44.5)167 (54.4)Median in months (95% CI)12.9 (10.6, 15.2)9.0 (8.1, 10.7)Hazard ratio (95% CI)0.70 (0.56, 0.89)p-value0.0014Progression Free SurvivalNumber (%) of patients with events201 (66.8)231 (75.2)Median in months (95% CI)5.6 (5.3, 5.8)3.7 (3.5, 3.9)Hazard ratio (95% CI)0.62 (0.51, 0.75)p-value<0.0001Overall Response Rate (CR PR)Based on Cochran-Mantel-Haenszel test. Stratification factors were ECOG PS, region and liver metastasis.ORR (%) (95% CI)40.6 (34.9, 46.5)17.9 (13.7, 22.8)p-value<0.0001 Complete response rate (%)4.92.7 Partial response rate (%)35.815.2Figure 2. Kaplan Meier Plot of Overall Survival Figure 3. Kaplan Meier Plot of Progression Free Survival EV-201, Cohort 1The efficacy of PADCEV was also investigated in Cohort of EV-201, single-arm, multi-cohort, multicenter trial that enrolled 125 patients with locally advanced or metastatic urothelial cancer who received prior treatment with PD-1 or PD-L1 inhibitor and platinum-based chemotherapy. Patients were excluded if they had active central nervous system (CNS) metastases, ongoing sensory or motor neuropathy >=Grade 2, heart failure, or uncontrolled diabetes defined as hemoglobin A1C (HbA1c) >=8% or HbA1c >=7% with associated diabetes symptoms. PADCEV was administered at dose of 1.25 mg/kg, as an intravenous (IV) infusion on days 1, 8, and 15 of each 28-day cycle.The median age was 69 years (range: 40 to 84 years) and 70% were male. Racial demographics were reported as White (85%), Asian (9%), Black (2%), Other (0.8%) or not reported (4%). Four percent of patients were Hispanic or Latino. All patients had baseline Eastern Cooperative Oncology Group (ECOG) performance status of (32%) or (68%). Ninety percent of patients had visceral metastases including 40% with liver metastases. Approximately two-thirds (67%) of patients had pure transitional cell carcinoma (TCC) histology; 33% had TCC with other histologic variants. The median number of prior systemic therapies was (range: to 6). Sixty-six percent of patients received prior cisplatin-based regimens, 26% received prior carboplatin-based regimens, and an additional 8% received both cisplatin and carboplatin-based regimens.The major efficacy outcome measures were confirmed objective response rate (ORR) and duration of response (DOR) assessed by blinded independent central review (BICR) using RECIST v1.1.Efficacy results are presented in Table 11. Table 11. Efficacy Results in EV-201, Cohort (BICR Assessment)EndpointPADCEVn=125NE not estimableConfirmed ORR (95% CI)44% (35.1, 53.2) Complete Response Rate (CR)12% Partial Response Rate (PR)32%MedianBased on patients (N=55) with response by BICR. Duration of Response, months (95% CI)7.6 (6.3, NE)Cisplatin Ineligible Patients with Locally Advanced or Metastatic Urothelial Carcinoma The efficacy of PADCEV was also evaluated in Cohort of EV-201, single-arm, multi-cohort, multicenter trial in 89 patients with locally advanced or metastatic urothelial cancer who received prior treatment with PD-1 or PD-L1 inhibitor, and were cisplatin ineligible and did not receive platinum in the locally advanced or metastatic setting. Patients were excluded if they had active CNS metastases, ongoing sensory or motor neuropathy >=Grade 2, heart failure, or uncontrolled diabetes defined as hemoglobin A1C (HbA1c) >=8% or HbA1c >=7% with associated diabetes symptoms. PADCEV was administered at dose of 1.25 mg/kg, as an intravenous (IV) infusion on days 1, 8, and 15 of each 28-day cycle.The median age was 75 years (range: 49 to 90 years), 74% were male. Racial demographics were reported as White (70%), Asian (22%) or not reported (8%). One percent of patients were Hispanic or Latino. Patients had baseline ECOG performance status of (42%), (46%) and (12%). Forty-three percent of patients had tumors located in the upper tract that included the renal pelvis and ureter. Seventy-nine percent of patients had visceral metastases and 24% had liver metastases. Reasons for cisplatin ineligibility included: 66% with baseline creatinine clearance of 30 59 mL/min, 7% with ECOG PS of 2, 15% with Grade or greater hearing loss, and 12% with more than one cisplatin-ineligibility criteria. Seventy percent of patients had TCC histology; 13% had TCC with squamous differentiation and 17% had TCC with other histologic variants. The median number of prior systemic therapies was (range: to 4). Efficacy results are presented in Table 12 below.Table 12. Efficacy Results in EV-201, Cohort (BICR Assessment)NE not estimableEndpointPADCEVN=89Confirmed ORR (95% CI)51% (39.8, 61.3) Complete Response Rate (CR)22% Partial Response Rate (PR)28%MedianBased on patients (N=45) with response by BICR Duration of Response, months (95% CI)13.8 (6.4, NE). Figure 1. Kaplan Meier Plot of Overall Survival. Figure 2. Kaplan Meier Plot of Progression Free Survival.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION oFor 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)oThe recommended dose of PADCEV is 1.25 mg/kg (up to maximum dose of 125 mg) given as an intravenous infusion over 30 minutes on Days 1, and 15 of 28-day cycle until disease progression or unacceptable toxicity. (2.1)oAvoid use in patients with moderate or severe hepatic impairment (8.6). oFor 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). oThe recommended dose of PADCEV is 1.25 mg/kg (up to maximum dose of 125 mg) given as an intravenous infusion over 30 minutes on Days 1, and 15 of 28-day cycle until disease progression or unacceptable toxicity. (2.1). oAvoid use in patients with moderate or severe hepatic impairment (8.6). 2.1 Recommended Dosage The recommended dose of PADCEV is 1.25 mg/kg (up to maximum of 125 mg for patients >=100 kg) administered as an intravenous infusion over 30 minutes on Days 1, and 15 of 28-day cycle until disease progression or unacceptable toxicity. 2.2 Dose Modifications Table 1. Dose ModificationsAdverse ReactionSeverityGrade is mild, Grade is moderate, Grade is severe, Grade is life-threatening.Dose ModificationSkin Reactions[see Boxed Warning, Warnings and Precautions (5.1)]Suspected SJS or TENImmediately withhold, consult specialist to confirm the diagnosis. If not SJS/TEN, see Grade skin reactions.Confirmed SJS or TEN; Grade or recurrent Grade skin reactionsPermanently discontinue.Grade (severe) skin reactionsWithhold until Grade <=1, then resume treatment at the same dose level or consider dose reduction by one dose level.Hyperglycemia[see Warnings and Precautions (5.2)]Blood glucose >250 mg/dLWithhold until elevated blood glucose has improved to <= 250 mg/dL, then resume treatment at the same dose level.Pneumonitis[see Warnings and Precautions (5.3)]Grade 2Withhold until Grade <= for persistent or recurrent Grade pneumonitis, consider dose reduction by one dose level. Grade >=3Permanently discontinue.Peripheral Neuropathy[see Warnings and Precautions (5.4)]Grade 2Withhold until Grade <=1, then resume treatment at the same dose level (if first occurrence). For recurrence, withhold until Grade <=1, then resume treatment reduced by one dose level.Grade >=3Permanently discontinue.Other nonhematologic toxicity[see Adverse Reactions (6)]Grade 3Withhold until Grade <= 1, then resume treatment at the same dose level or consider dose reduction by one dose level.Grade 4Permanently discontinue.Hematologic toxicity[see Adverse Reactions (6)]Grade 3, or Grade thrombocytopeniaWithhold until Grade <= 1, then resume treatment at the same dose level or consider dose reduction by one dose level.Grade 4Withhold until Grade <= 1, then reduce dose by one dose level or discontinue treatment.Table 2. Recommended Dose Reduction ScheduleDose LevelStarting dose1.25 mg/kg up to 125 mgFirst dose reduction1.0 mg/kg up to 100 mgSecond dose reduction0.75 mg/kg up to 75 mgThird dose reduction0.5 mg/kg up to 50 mg. 2.3 Instructions for Preparation and Administration oAdminister PADCEV as an intravenous infusion only.oPADCEV is hazardous drug. Follow applicable special handling and disposal procedures.1Prior 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 Ringers Injection, USP. Reconstitution in single-dose vial1.Follow procedures for proper handling and disposal of anticancer drugs.2.Use appropriate aseptic technique for reconstitution and preparation of dosing solutions.3.Calculate the recommended dose based on the patients weight to determine the number and strength (20 mg or 30 mg) of vials needed.4.Reconstitute each vial as follows and, if possible, direct the stream of SWFI along the walls of the vial and not directly onto the lyophilized powder:a.20 mg vial: Add 2.3 mL of SWFI, resulting in 10 mg/mL PADCEV. b.30 mg vial: Add 3.3 mL of SWFI, resulting in 10 mg/mL PADCEV.5.Slowly swirl each vial until the contents are completely dissolved. Allow the reconstituted vial(s) to settle for at least minute until the bubbles are gone. DO NOT SHAKE THE VIAL. Do not expose to direct sunlight.6.Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The reconstituted solution should be clear to slightly opalescent, colorless to light yellow and free of visible particles. Discard any vial with visible particles or discoloration.7.Based upon the calculated dose amount, the reconstituted solution from the vial(s) should be added to the infusion bag immediately. This product does not contain preservative. If not used immediately, reconstituted vials may be stored for up to 24 hours in refrigeration at 2C to 8C (36 to 46 F). DO NOT FREEZE. Discard unused vials with reconstituted solution beyond the recommended storage time.Dilution in infusion bag8.Withdraw the calculated dose amount of reconstituted solution from the vial(s) and transfer into an infusion bag. 9.Dilute PADCEV with either 5% Dextrose Injection, 0.9% Sodium Chloride Injection, or Lactated Ringers Injection. The infusion bag size should allow enough diluent to achieve final concentration of 0.3 mg/mL to mg/mL PADCEV. 10.Mix diluted solution by gentle inversion. DO NOT SHAKE THE BAG. Do not expose to direct sunlight. 11.Visually inspect the infusion bag for any particulate matter or discoloration prior to use. The reconstituted solution should be clear to slightly opalescent, colorless to light yellow and free of visible particles. DO NOT USE the infusion bag if particulate matter or discoloration is observed.12.Discard any unused portion left in the single-dose vials.Administration13.Immediately administer the infusion over 30 minutes through an intravenous line. 14.If the infusion is not administered immediately, the prepared infusion bag should not be stored longer than hours at 2C to 8C (36 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. oAdminister PADCEV as an intravenous infusion only.. oPADCEV is hazardous drug. Follow applicable special handling and disposal procedures.1. 1.Follow procedures for proper handling and disposal of anticancer drugs.. 2.Use appropriate aseptic technique for reconstitution and preparation of dosing solutions.. 3.Calculate the recommended dose based on the patients weight to determine the number and strength (20 mg or 30 mg) of vials needed.. 4.Reconstitute each vial as follows and, if possible, direct the stream of SWFI along the walls of the vial and not directly onto the lyophilized powder:a.20 mg vial: Add 2.3 mL of SWFI, resulting in 10 mg/mL PADCEV. b.30 mg vial: Add 3.3 mL of SWFI, resulting in 10 mg/mL PADCEV.. a.20 mg vial: Add 2.3 mL of SWFI, resulting in 10 mg/mL PADCEV. b.30 mg vial: Add 3.3 mL of SWFI, resulting in 10 mg/mL PADCEV.. 5.Slowly swirl each vial until the contents are completely dissolved. Allow the reconstituted vial(s) to settle for at least minute until the bubbles are gone. DO NOT SHAKE THE VIAL. Do not expose to direct sunlight.. 6.Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The reconstituted solution should be clear to slightly opalescent, colorless to light yellow and free of visible particles. Discard any vial with visible particles or discoloration.. 7.Based upon the calculated dose amount, the reconstituted solution from the vial(s) should be added to the infusion bag immediately. This product does not contain preservative. If not used immediately, reconstituted vials may be stored for up to 24 hours in refrigeration at 2C to 8C (36 to 46 F). DO NOT FREEZE. Discard unused vials with reconstituted solution beyond the recommended storage time.. 8.Withdraw the calculated dose amount of reconstituted solution from the vial(s) and transfer into an infusion bag. 9.Dilute PADCEV with either 5% Dextrose Injection, 0.9% Sodium Chloride Injection, or Lactated Ringers Injection. The infusion bag size should allow enough diluent to achieve final concentration of 0.3 mg/mL to mg/mL PADCEV. 10.Mix diluted solution by gentle inversion. DO NOT SHAKE THE BAG. Do not expose to direct sunlight. 11.Visually inspect the infusion bag for any particulate matter or discoloration prior to use. The reconstituted solution should be clear to slightly opalescent, colorless to light yellow and free of visible particles. DO NOT USE the infusion bag if particulate matter or discoloration is observed.. 12.Discard any unused portion left in the single-dose vials.. 13.Immediately administer the infusion over 30 minutes through an intravenous line. 14.If the infusion is not administered immediately, the prepared infusion bag should not be stored longer than hours at 2C to 8C (36 to 46 F). DO NOT FREEZE.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics Population pharmacokinetic analysis included data from 748 patients based on five studies. Enfortumab vedotin-ejfv pharmacokinetics were characterized after single and multiple doses in patients with locally advanced or metastatic urothelial carcinoma and other solid tumors. The exposure parameters of ADC and unconjugated MMAE (the cytotoxic component of enfortumab vedotin-ejfv) are summarized in Table below. Peak ADC concentrations were observed near the end of intravenous infusion while peak MMAE concentrations were observed approximately days after enfortumab vedotin-ejfv dosing. Minimal accumulation of the ADC and MMAE was observed following repeat administration of enfortumab vedotin-ejfv in patients. Steady-state concentrations of ADC and MMAE were reached after treatment cycle.Table 9. Exposure parameters of ADC and unconjugated MMAE after first treatment cycle of 1.25 mg/kg of enfortumab vedotin-ejfv dose of Days 1, and 15Cmax maximum concentration, AUC0-28d area under the concentration-time curve from time zero to 28 days, Ctrough,0-28d pre-dose concentration on day 28ADCMean (+- SD)Unconjugated MMAEMean (+- SD)Cmax 28 (6.1) ug/mL5.5 (3.0) ng/mLAUC0-28d 110 (26) ugd/mL85 (50) ngd/mLCtrough,0-28d 0.31 (0.18) ug/mL0.81 (0.88) ng/mLDistributionThe estimated mean steady-state volume of distribution of ADC was 12.8 liters following administration of enfortumab vedotin-ejfv. Plasma protein binding of MMAE ranged from 68% to 82%, in vitro.EliminationADC and MMAE exhibited multi-exponential declines with an elimination half-life of 3.6 days and 2.6 days, respectively. The mean clearance (CL) of enfortumab vedotin-ejfv and unconjugated MMAE in patients was 0.11 L/h and 2.11 L/h, respectively, in patients. Elimination of MMAE appeared to be limited by its rate of release from enfortumab vedotin-ejfv. MetabolismEnfortumab vedotin-ejfv catabolism has not been studied in humans; however, it is expected to undergo catabolism to small peptides, amino acids, unconjugated MMAE, and unconjugated MMAE-related catabolites. Enfortumab vedotin-ejfv releases MMAE via proteolytic cleavage, and MMAE is primarily metabolized by CYP3A4 in vitro.ExcretionThe excretion of enfortumab vedotin-ejfv is not fully characterized. Following single-dose of another ADC that contains MMAE, 17% of the total MMAE administered was recovered in feces and 6% in urine over 1-week period, primarily as unchanged drug. similar excretion profile of MMAE is expected after enfortumab vedotin-ejfv administration.Specific PopulationsBased on population pharmacokinetic analysis, no clinically significant differences in the pharmacokinetics of enfortumab vedotin-ejfv were observed based on age (24 to 90 years), sex, or race/ethnicity (Caucasian, Asian, Black, or others).Hepatic ImpairmentBased on population pharmacokinetics analysis, there was 37% AUC0-28d increase in unconjugated MMAE exposure observed in patients with mild hepatic impairment (total bilirubin of to 1.5 ULN and AST any, or total bilirubin <=ULN and AST >ULN, n=65) compared to normal hepatic function. Enfortumab vedotin-ejfv has only been studied in limited number of patients with moderate hepatic impairment and has not been evaluated in patients with severe hepatic impairment. The effect of moderate or severe hepatic impairment (total bilirubin >1.5 ULN and AST any) or liver transplantation on the pharmacokinetics of ADC or unconjugated MMAE is unknown.Renal ImpairmentThe pharmacokinetics of enfortumab vedotin-ejfv and unconjugated MMAE were evaluated after the administration of 1.25 mg/kg of enfortumab vedotin-ejfv to patients with mild (creatinine clearance; CrCL >60-90 mL/min; n=272), moderate (CrCL 30-60 mL/min; n=315) and severe (CrCL <30 mL/min; n=25) renal impairment. No significant differences in exposure (AUC) of ADC and MMAE were observed in patients with mild, moderate or severe renal impairment compared to patients with normal renal function. The effect of end stage renal disease with or without dialysis on the pharmacokinetics of ADC or unconjugated MMAE is unknown.Drug Interaction TrialsNo clinical trials evaluating the drug-drug interaction potential of enfortumab vedotin-ejfv have been conducted. Physiologically Based Pharmacokinetic (PBPK) Modeling Predictions:Dual P-gp and Strong CYP3A4 Inhibitor: Concomitant use of enfortumab vedotin-ejfv with ketoconazole (a dual P-gp and strong CYP3A4 inhibitor) is predicted to increase unconjugated MMAE Cmax by 15% and AUC by 38%.Dual P-gp and Strong CYP3A4 Inducer: Concomitant use of enfortumab vedotin-ejfv with rifampin (a dual P-gp and strong CYP3A4 inducer) is predicted to decrease unconjugated MMAE Cmax by 28% and AUC by 53%.Sensitive CYP3A substrates: Concomitant use of enfortumab vedotin-ejfv is predicted not to affect exposure to midazolam (a sensitive CYP3A substrate).In Vitro Studies Transporter Systems: MMAE is substrate of P-glycoprotein (P-gp), but not an inhibitor of P-gp.