Nadofaragene Firadenovec

Nadofaragene Firadenovec – Description

• Nadofaragene firadenovec is an adenovirus vector based gene therapy designed to deliver a copy of a gene encoding a human interferon-alfa 2b to the bladder urothelium after administration intravesically into the bladder.
• Nadofaragene firadenovec is indicated for adults with high-risk Bacillus Calmette-Guerin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors.
• Immunocompromised persons, including those receiving immunosuppressant therapy, may be at risk for disseminated adenovirus infection because of the possible low levels of replication-competent adenovirus; individuals who are immunosuppressed or immune-deficient should not come into contact with the medication during preparation, administration or after treatment.
• Transient and low-level shedding may occur in urine, so standard universal biohazard practices are followed after use.⁶⁸³⁵⁸

Indications & Dosage

• Bladder cancer

For the treatment of bladder cancer

For the treatment of high-risk Bacillus Calmette-Guerin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors

Precautions

•  breast-feeding
•  contraception requirements
•  immunosuppression
•  male-mediated teratogenicity
•  pregnancy
•  pregnancy testing
•  reproductive risk
•  surgery

Pregnancy

• Advise women of the potential hazard to a fetus during pregnancy. There are no adequately controlled studies of nadofaragene firadenovec in pregnant women. Additionally, animal reproductive and developmental toxicity studies have not been conducted.⁶⁸³⁵⁸

Lactation

• Consider the developmental and health benefits of breast-feeding along with the mother’s need for nadofaragene firadenovec and any potential adverse reactions on the breastfed infant. There is no information regarding the presence of nadofaragene firadenovec in human milk, the effects on the breastfed infant, or the effects on milk production.⁶⁸³⁵⁸

Interactions

• There are no drug interactions associated with Nadofaragene Firadenovec products.

Adverse Reactions

• anemia
• atrial fibrillation
•  bladder spasm
•  cerebral edema
•  chills
•  cholelithiasis
•  dehydration
•  dysuria
•  fatigue
•  fever
•  heart failure
•  hematuria
•  hyperglycemia
• hypertriglyceridemia
• hypoglycemia
•  hypophosphatemia
• infection
•  pericarditis
•  syncope
•  urinary urgency

Administration

• Other Administration Route(s)
  • Intravesical Administration
    • Premedication with an anticholinergic is recommended before each instillation of nadofaragene firadenovec.
    • Follow universal biosafety precautions for preparation and handling.
    • Individuals who are immunosuppressed or immune-deficient, should not prepare, administer, or come into contact with nadofaragene firadenovec.
    • Disposable agents that have come in contact with nadofaragene firadenovec should be placed in biohazard containers for destruction. Non-disposable equipment may be decontaminated according to the facility’s standard operating procedures.
    • Treat spills or unused portion for 15 minutes with a virucidal agent (such as sodium hypochlorite with 0.5% active chlorine or 6% hydrogen peroxide solution).⁶⁸³⁵⁸
    Preparation
    • All 4 vials of nadofaragene firadenovec must be thawed and brought to room temperature (20 to 25 degrees C; 68 to 77 degrees F) prior to use. When at room temperature, the time to thaw is approximately 8 to 10 hours when thawing in the cardboard nest or approximately 3 to 5 hours when thawing outside the cardboard nest. When in refrigerator (2 to 8 degrees C; 36 to 46 degrees F), the time to thaw is approximately 11 to 13 hours when thawing in the cardboard nest or approximately 4 to 5 hours when thawing outside the cardboard nest; subsequent time for bringing thawed vials to room temperature is approximately 6 hours in the cardboard nest or approximately 2 hours 30 minutes outside of the cardboard nest.
    • Do not expose the vials to temperatures above room temperature. Protect from light. Do NOT refreeze.
    • After thawing, gently mix the vials; do not shake. Visually inspect the vials for particulate matter and discoloration. The suspension is clear to slightly opalescent and may contain opalescent flecks. Do not use if visible particles or discoloration are observed.
    • Storage after thawing: Nadofaragene firadenovec 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).
    • Using aseptic technique, remove the cap from the nadofaragene firadenovec vial and attach a vented vial adapter per the manufacturer’s instructions.
    • Connect the syringe to the vial adaptor and withdraw the contents of the vial into a polypropylene Luer lock syringe. Repeat for the remaining 3 vials until 75 mL has been withdrawn into 1 or 2 syringes; the volumes in the syringes do not have to be equal.
    • Discard any remaining volume of nadofaragene firadenovec 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 protected from light.⁶⁸³⁵⁸
    Instillation
    • Insert 1 straight or intermittent urinary catheter with a proximal funnel opening that will accommodate the Luer lock adapter. Only use catheters made of vinyl/PVC (uncoated or coated with hydrogel), red rubber latex, or silicone to instill nadofaragene firadenovec. Do not use catheters coated or embedded with silver or antibiotics.
    • Use this catheter to completely empty the patient’s bladder before instillation. Do not remove the catheter.
    • Attach the Luer lock end of the same catheter adaptor to the syringe containing nadofaragene firadenovec and insert the tapered end of the catheter adaptor into the funnel opening of the catheter.
    • Slowly instill 75 mL of nadofaragene firadenovec into the bladder through the catheter; ensure that the complete volume is administered.
    • Retain nadofaragene firadenovec in the bladder for 1 hour after instillation. Reposition the patient approximately every 15 minutes during the 1-hour dwell time from left to right, back and abdomen, to maximize bladder surface exposure. If the patient exhibits bladder cramping or premature voiding, repositioning of the patient may be adjusted or discontinued.
    • The patient may void and completely empty the bladder 1 hour after instillation; disinfect the voided urine for 15 minutes with an equal volume of virucidal agent before flushing the toilet.
    • Instruct patients and their caregivers that for 2 days following treatment, voided urine should be disinfected for 15 minutes with an equal volume of bleach before flushing.⁶⁸³⁵⁸

Mechanism of Action

• Nadofaragene firadenovec is a non-replicating adenoviral vector-based gene therapy designed to deliver a copy of a gene encoding a human interferon-alfa (IFN-alfa) 2b to the bladder urothelium.
• Intravesical instillation results in cell transduction and transient local expression of the IFN-alfa 2b protein that is anticipated to have anti-tumor effects.⁶⁸³⁵⁸

Pharmacokinetics

• Nadofaragene firadenovec is administered by bladder instillation.⁶⁸³⁵⁸

•Route-Specific Pharmacokinetics

Other Route(s)

Intravesical Administration

• Quantifiable concentrations of the IFN-alfa 2b protein were detected in the urine of all patients in a phase 1 first-in-human study designed to determine the safety, tolerability, and maximum tolerated dose of nadofaragene firadenovec, except for 2 patients at the lowest dose level.
• Measurable vector DNA was detected in urine in both studies relative to dose level (n = 17).
• In a phase 2 study, all patients had quantifiable concentrations of IFN-alfa 2b protein in the urine at day 2 after dosing at 2 different dose levels (1 x 10¹¹ vp/mL and 3 x 10¹¹ vp/mL); concentrations were detectable for up to 12 days post-dose. Generally, higher IFN-alfa 2b concentrations and exposure were observed with increasing doses.⁶⁸³⁵⁸

Monitoring Parameters

•  pregnancy testing

Classifications

• Antineoplastic and Immunomodulating Agents
  • Antineoplastics
    •  Gene Therapy for Bladder Cancer

References

68358.Adstiladrin (nadofaragene firadenovec-vncg) inj package insert. FinVector Oy:Ferring Pharmaceuticals;2024 Aug.