Nadofaragene firadenovec

Adequate and well-controlled studies with nadofaragene firadenovec have not been conducted in pregnant women. Animal reproductive and developmental toxicity studies have not been conducted with nadofaragene firadenovec. Advise pregnant women of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

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. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for nadofaragene firadenovec and any potential adverse effects on the breastfed infant from nadofaragene firadenovec or from the underlying maternal condition.

No animal studies have been conducted to evaluate the effects of nadofaragene firadenovec on carcinogenesis, mutagenesis, or impairment of fertility.

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 nadofaragene firadenovec was evaluated in Study CS-003, a multicenter, single-arm, open-label study in 157 U.S. patients 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 × 10¹¹ vp/mL) nadofaragene firadenovec administered intravesically once every 3 months for up to 12 months. 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 nadofaragene firadenovec was 2 (range 1 to 5).

Serious adverse reactions occurred in 11% of patients who received nadofaragene firadenovec. Serious adverse reactions occurring in >1% of patients included coronary artery disease and hematuria (blood in urine).

Permanent discontinuation of nadofaragene firadenovec due to an adverse reaction occurred in 3 (1.9%) patients. Adverse reactions that resulted in permanent discontinuation of nadofaragene firadenovec included bladder spasm instillation site discharge, and benign neoplasm of the bladder.

Dosage interruptions of nadofaragene firadenovec 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 nadofaragene firadenovec in CS-003.

Clinically relevant adverse reaction in <10% of patients who received nadofaragene firadenovec include syncope (fainting) (1.3%).

Table 1. Adverse Reactions (>10%) in Patients with NMIBC in CS-003:

^* Graded per NCI CTCAE v4.03; there were no Grade 3 or 4 reactions.

Clinically relevant adverse reactions in <10% of patients who received nadofaragene firadenovec 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:

^* 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.