nadofaragene firadenovec (Rx)

>10%

Glucose increased, all grades (38%)

Instillation site discharge (33%)

Triglycerides increased, all grades (30%)

Fatigue (24%)

Bladder spasm (20%)

Micturition urgency (19%)

Hematuria (17%)

Creatinine increased, all grades (17%)

Chills (16%)

Dysuria (16%)

Phosphate decreased, all grades (16%)

Hemoglobin decreased (16%)

Pyrexia (15%)

1-10%

Glucose increased, Grade 3 or 4 (6%)

Triglycerides increased, Grade 3 or 4 (1.9%)

Phosphate decreased, Grade 3 or 4 (1.4%)

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%)

<1%

Heart failure (0.6%)

Pericarditis, (0.6%)

Brain edema (swelling) (0.6%)

Bile duct stone (0.6%)

Sepsis (0.6%)

Hemoglobin decreased (0.6%)

Contraindications

Hypersensitivity reactions to interferon alfa or to any component of the product

Cautions

Risk of muscle invasive or metastatic bladder cancer with delayed cystectomy

• Delaying cystectomy in patients with BCG-unresponsive CIS could lead to development of muscle invasive or metastatic bladder cancer
• Risk of developing muscle-invasive or metastatic bladder cancer increases the longer cystectomy is delayed in the presence of persisting CIS
• Median time from persistence or recurrence of CIS to cystectomy in these patients was 235 days
• If patients with CIS do not have a complete response to treatment after 3 months or if CIS recurs, consider cystectomy

Risk of disseminated adenovirus infection

• Owing to possible presence of low levels of replication-competent adenovirus in drug, immunocompromised persons, including those receiving immunosuppressant therapy, may be at risk for disseminated adenovirus infection
• Avoid exposing immunosuppressed or immune-deficient individuals to nadofaragene firadenovec

Pregnancy

No adequate and well-controlled studies have been conducted in pregnant females

Advise pregnant females of potential risk to a fetus

Verify pregnancy status in females of reproductive potential before initiating

Contraception

• Females of reproductive potential: Use effective contraception during treatment and for 6 months following last dose
• Males with female partners of reproductive potential: Use effective contraception during treatment and for 3 months following last dose

Lactation

There is no information regarding drug presence in human milk, effects on breastfed infants, or effects on milk production

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Non-replicating adenoviral vector-based gene therapy delivers a copy of a gene encoding a human interferon-alfa 2b (IFNα2b) to bladder urothelium

Intravesical instillation results in cell transduction and transient local expression of IFNα2b protein that is anticipated to have antitumor effects

Absorption

One patient receiving a second dose at dose level of 3 x 10¹¹ vp/mL (2.25 x 10¹³ vp) had measurable vector DNA in blood; no other patients in either study had measurable vector DNA at 1 hr postdosing in blood

Intravesicular Bladder Preparation

Drug is a nonreplicating adenoviral vector-based gene therapy

Follow universal biosafety precautions for handling

Immunosuppressed or immune-deficient individuals should not prepare, administer, and avoid exposure to nadofaragene firadenovec

Remove 4 vials from freezer; allow vials to thaw at room temperature (20-25ºC [68-77ºF]) until liquid; do NOT expose vials to higher temperatures; protect from light

Drug must be calibrated to room temperature (20-25ºC [68-77ºF]) before use

Time for thawing and calibrating drug to room temperature: ~8-10 hr (thawing vials in cardboard nest); ~3-5 hr (thawing vials outside cardboard nest); Do NOT refreeze

Visually inspect vials for visible particles and discoloration; suspension is clear to slightly opalescent and may contain opalescent flecks; discard if visible particles or discoloration observed

Mix gently; do not shake

Using aseptic technique, remove cap from vial and attach vented vial adapter according to manufacturer’s instructions

Connect syringe to vial adapter and withdraw contents of vial into syringe; repeat steps for remaining 3 vials until 75 mL has been withdrawn into 1-2 syringes

Note: Volumes in syringes do not have to be equal

Discard any unused product according to universal precautions

Use syringe(s) within 1 hr of drawing up

Intravesicular Bladder Administration

Intravesical instillation only

Not for IV use, topical use, or oral administration

Premedicate with an anticholinergic is recommended before each instillation

Before administering, insert 1 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; do NOT use catheters coated or embedded with silver or antibiotics

Use catheter to completely empty patient’s bladder before instillation; do not remove catheter

Attach Luer lock end of same catheter adaptor to drug-containing syringe and insert tapered end of the catheter adaptor into funnel opening of catheter

Slowly instill 75 mL of nadofaragene firadenovec into bladder through catheter, ensuring that complete volume is administered

After instillation, retain drug in bladder for 1 hr

During 1-hour dwell time, reposition patient approximately every 15 minutes from left to right, back and abdomen to maximize bladder surface exposure

If, during dwell time, bladder cramping or premature voiding occurs, repositioning of patient may be adjusted or discontinued

Evacuate drug from bladder as part of routine emptying of bladder, or may void and completely empty bladder after 1 hr has elapsed

Disinfect voided urine for 30 minutes with an equal volume of virucidal agent before flushing of toilet

Storage

Unopened vials

Ship frozen at ≤ -60ºC (≤ -76ºF) in an insulated shipping box that will maintain required temperature for ≥72 hr after being sealed

Upon receipt, store cartons as indicated below

• In a freezer ≤ -60ºC (≤ -76ºF) until expiration date printed on carton
• In a freezer between -25º to -15ºC (-13°ºF to 5º) up to 3 months, without exceeding original expiration date on vial and outer carton
• When stored in freezer, note date of placement in freezer
• Additionally, write date on outer carton for when to discard carton if not used
• Instillation dates should be 3 months apart, but not past the original expiry date; discard date supersedes original expiration

Thawed vials

• May be stored at room temperature (20-25ºC [68-77ºF]) or refrigerated at 2-8ºC (36-46ºF) for up to 24 hr
• Do NOT refreeze

Drawn up syringes

• Use within 1 hr of drawing up

Decontamination and biohazard handling

• Treat any spills with a virucidal agent (eg, sodium hypochlorite with 0.5% active chlorine or 6% hydrogen peroxide solution) for 30 min
• Place disposable materials that have come into contact in biohazard containers for destruction
• Decontaminate non-disposable equipment according to facility’s standard operating procedures