Nadofaragene Firadenovec-Vncg

1 INDICATIONS AND USAGE ADSTILADRIN ® is indicated for the treatment of adult patients with high-risk Bacillus Calmette-Guérin (BCG)-unresponsive non-Muscle Invasive Bladder Cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors. ADSTILADRIN is a non-replicating adenoviral vector-based gene therapy indicated for the treatment of adult patients with high-risk Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors. ( 1 )

2 DOSAGE AND ADMINISTRATION Important Administration Instructions ADSTILADRIN is for intravesical instillation only. ADSTILADRIN is not for intravenous use, topical use, or oral administration. Premedication with an anticholinergic is recommended before each instillation of ADSTILADRIN. ( 2.1 ) Administer ADSTILADRIN by intravesical instillation only. ( 2.1 ) ADSTILADRIN is not for intravenous use, topical use, or oral administration. The dose is 75 mL of ADSTILADRIN at a concentration of 3 x 10 11 viral particles (vp)/mL, instilled once every three (3) months. ( 2.1 ) Allow ADSTILADRIN to be left in the bladder for 1 hour following instillation 2.1 Dose The recommended dose of ADSTILADRIN is 75 mL at a concentration of 3 x 10 11 viral particles (vp)/mL instilled once every three (3) months into the bladder via a urinary catheter [ see Dosage and Administration (2.2) ]. Premedication with an anticholinergic is recommended before each instillation of ADSTILADRIN. 2.2 Preparation and Handling ADSTILADRIN is a non-replicating adenoviral vector-based gene therapy. Follow universal biosafety precautions for handling. Individuals who are immunosuppressed or immune-deficient, should not prepare, administer, or come into contact with ADSTILADRIN [ see Warnings and Precautions ( 5 ) ]. ADSTILADRIN is provided as a sterile frozen suspension. All four vials of ADSTILADRIN must be thawed and brought to room temperature (20°C to 25°C [68°F to 77°F]) prior to use. WHEN THAWING AT ROOM TEMPERATURE Frozen ADSTILADRIN vials will thaw in approximately 3 to 5 hours outside the cardboard nest when placed at room temperature (up to 25°C [77ºF]) (8 to 10 hours inside the nest). WHEN THAWING IN REFRIGERATOR Frozen ADSTILADRIN vials will thaw in approximately 4 to 5 hours outside the cardboard nest when placed in the refrigerator (up to 8°C [46ºF]) (11 to 13 hours inside the nest). Subsequent time for bringing thawed ADSTILADRIN to room temperature is approximately 2 hours 30 minutes outside of the cardboard nest (6 hours inside the nest). Do not expose the vials to higher temperatures. Protect from light. DO NOT refreeze. The vials may be moved between refrigerator and room temperature if the total storage time at each condition is not exceeded (24 hours at room temperature and 7 days refrigerated including thawing time). Inspection and Preparing ADSTILADRIN for instillation Visually inspect all 4 vials for visible particles and discoloration. The suspension is clear to slightly opalescent and may contain opalescent flecks. Do not use if visible particles or discoloration are observed. Mix gently. Do not shake. Items required for instillation: • Four (4) thawed vials of ADSTILADRIN • Four (4) vented vial adapters suitable for a standard 20 mLvial • Two (2) standard 50 or 60 mL polypropylene Luer lock syringes or one (1) Luer lock syringe equal to or greater than 75 mL (max 100 mL) • Two (2) Luer lock adapters - One (1) straight, or intermittent, urethral catheter with a proximal funnel opening that will accommodate the Luer lock adapter. - Use only catheters made of vinyl/PVC (uncoated or coated with hydrogel), red rubber latex or silicone to instill ADSTILADRIN. Do not use catheters coated or embedded with silver or antibiotics. 1. Using aseptic technique, remove the cap from an ADSTILADRIN vial and attach a vented vial adapter according to manufacturer's instructions. 2. Connect the syringe to the vial adapter and withdraw the contents of the vial into the syringe. Repeat steps 1-2 for the remaining three (3) vials until 75 mL has been withdrawn into one (1) or two (2) syringes. The volumes in the syringes do not have to be equal. 3. Discard any remaining volume according to universal precautions. If unable to administer the suspension shortly after withdrawal, the solution may be stored in syringes for up to 6 hours at room temperature (20°C to 25°C [68°F to 77°F]) protected from light. Treat any ADSTILADRIN spills or unused portion with a virucidal agent (such as sodium hypochlorite with 0.5% active chlorine or 6% hydrogen peroxide solution) for 15 minutes. Disposable materials that have come into contact with ADSTILADRIN should be placed in biohazard containers for destruction. Non-disposable equipment may be decontaminated according to the facility's standard operating procedures. [ see Patient Counseling Information ( 17 ) ]. 2.3 Bladder instillation of ADSTILADRIN Premedication with an anticholinergic before each instillation of ADSTILADRIN is recommended. ADSTILADRIN must be brought to room temperature before administration [ see Dosage and Administration (2.2) ]. Before administering ADSTILADRIN to the patient, insert one straight, or intermittent, urinary catheter with a proximal funnel opening that will accommodate the Luer lock adapter. Use only catheters made of vinyl/PVC (uncoated or coated with hydrogel), red rubber latex or silicone to instill ADSTILADRIN. Do not use catheters coated or embedded with silver or antibiotics. Use the catheter to completely empty the patient's bladder before instillation of ADSTILADRIN. Do not remove the catheter. Attach the Luer lock end of the same catheter adapter to the syringe containing ADSTILADRIN and insert the tapered end of the catheter adapter into the funnel opening of the catheter. Slowly instill 75 mL of ADSTILADRIN into the bladder through the catheter, ensuring that the complete volume is administered. After the instillation, ADSTILADRIN should be retained in the bladder for 1 hour. During the 1-hour dwell time, the patient should reposition approximately every 15 minutes from left to right, back and abdomen to maximize bladder surface exposure. If, during the dwell time, the patient exhibits bladder cramping or premature voiding, repositioning of the patient may be adjusted or discontinued. Evacuate ADSTILADRIN from the bladder as part of routine emptying of the bladder, or the patient may void and completely empty the bladder after 1 hour has elapsed. Voided urine should be disinfected for 15 minutes with an equal volume of virucidal agent before flushing of the toilet. [ see Patient Counseling Information ( 17 ) ].

6 ADVERSE REACTIONS The most common (>10%) adverse reactions, including laboratory abnormalities (>15%), were glucose increased, instillation site discharge, triglycerides increased, fatigue, bladder spasm, micturition (urination urgency), creatinine increased, hematuria (blood in urine), phosphate decreased, chills, pyrexia (fever), and dysuria (painful urination). ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Ferring Pharmaceuticals at 1-888-337-7464 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of ADSTILADRIN was evaluated in Study CS-003, a multicenter, single-arm, open-label study in 157 U.S. patients [ see Clinical Studies ( 14 ) ] with high-risk BCG‑unresponsive NMIBC, 107 of whom had BCG-unresponsive carcinoma in situ (CIS) with or without papillary tumors. Patients received 75 mL (3 x 10 11 vp/mL) ADSTILADRIN administered intravesically once every 3 months for up to 12 months [ see Clinical Studies ( 14 ) ]. All patients with an absence of high-risk recurrence or progression were offered continued treatment every 3 months beyond 12 months. The median number of instillations of ADSTILADRIN was 2 (range 1 to 5). Serious adverse reactions occurred in 11% of patients who received ADSTILADRIN. Serious adverse reactions occurring in >1% of patients included coronary artery disease and hematuria (blood in urine). Permanent discontinuation of ADSTILADRIN due to an adverse reaction occurred in 3 (1.9%) patients. Adverse reactions that resulted in permanent discontinuation of ADSTILADRIN included bladder spasm instillation site discharge, and benign neoplasm of the bladder. Dosage interruptions of ADSTILADRIN due to an adverse reaction occurred in 54 (34%) patients. Adverse reactions in >10% of patients that required dosage interruption included instillation site discharge, bladder spasm, and micturition urgency. The most common (>10%) adverse reactions, including laboratory abnormalities (>15%), were glucose increased, instillation site discharge, triglycerides increased, fatigue, bladder spasm, micturition (urination) urgency, creatinine increased, hematuria (blood in urine), phosphate decreased, chills, dysuria, and pyrexia (fever). Tables 1 and 2 summarize adverse reactions and laboratory abnormalities, respectively, in patients on ADSTILADRIN in CS-003. Clinically relevant adverse reaction in <10% of patients who received ADSTILADRIN include syncope (fainting) (1.3%). Table 1: Adverse Reactions (>10%) in Patients with NMIBC in CS-003 Adverse Reaction Graded per NCI CTCAE v4.03; there were no Grade 4 or 5 reactions. ADSTILADRIN (n=157) (%) Grade 1 and 2 % Grade 3 % General disorders and administration site conditions - - Instillation site discharge 33 0 Fatigue 24 0 Pyrexia 16 0 Chills 15 0 Renal and urinary disorders - - Bladder spasm 20 1 Micturition urgency 19 1 Hematuria 17 1 Dysuria 16 0 Clinically relevant adverse reactions in <10% of patients who received ADSTILADRIN included coronary artery disease (1.3%), acute coronary syndrome (1.3%), atrial fibrillation (1.3%), dehydration (1.3%), hypoglycemia (low blood sugar) (1.3%), syncope (fainting) (1.3%), heart failure (0.6%), pericarditis, (0.6%), brain edema (swelling) (0.6%), bile duct stone (0.6%), and sepsis (0.6%). Table 2 summarizes the laboratory abnormalities in CS-003. Table 2: Selected Laboratory Abnormalities (>15.0%) That Worsened from Baseline in Patients with NMIBC in CS-003 Laboratory Abnormality ADSTILADRIN The denominator used to calculate the rate varied from 148 to 156 based on the number of patients with a baseline value and at least one post-treatment value. (All Grades, %) ADSTILADRIN (Grade 3 or 4, %) Chemistry - - Glucose increased 38 6 Triglycerides increased 30 1.9 Creatinine increased 17 0 Phosphate decreased 16 1.4 Hematology - - Hemoglobin decreased 16 0.6

12.3 Pharmacokinetics Nonclinical data Human IFN protein in urine, and vector-specific DNA in blood and tissue samples, were detectable following ADSTILADRIN dosing in monkeys, with higher levels at higher doses. All monkeys had vector-specific DNA in the bladder tissue at necropsy on Days 8 and 98 (i.e., seven days after the first and second dose, respectively). Vector-specific DNA was also detected in a limited number of monkeys in the liver, kidney and gonad. At Day 148, only one animal showed vector-specific DNA in one tissue (kidney). Clinical data ADSTILADRIN biodistribution and shedding were investigated in two clinical studies. Only a single patient receiving a second dose in one study (Phase 2 study) at dose level of 3 x 10 11 vp/mL (2.25 x 10 13 vp) had measurable vector DNA in blood; no other patients in either study had measurable vector DNA at one hour post-dosing in blood. In urine, measurable vector DNA was detected in both studies. Generally, a higher frequency of detection of urine samples positive for vector-derived DNA, and persistence of vector-derived DNA, correlated with increasing dose level. At the dose level of 3 x 10 11 vp/mL (2.25 x 10 13 vp), one patient (out of 4 enrolled) had detectable levels of vector DNA at Day 14 in the Phase 1 study and 16 subjects (out of 19 at visit) had detectable levels of vector DNA at Day 12 in the Phase 2 study.