ADSTILADRIN Suspension for intravesical instillation Ref.[107265] Active ingredients: Nadofaragene firadenovec

5.1 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, which can be lethal. The risk of developing muscle-invasive or metastatic bladder cancer increases the longer cystectomy is delayed in the presence of persisting CIS.

Of the patients with CIS treated with ADSTILADRIN on Study CS-003 who underwent subsequent radical cystectomy and for whom pathologic data were available, 14% (n=6) had muscle-invasive (T2 or greater) disease at cystectomy. Median time from persistence or recurrence of CIS to cystectomy in these patients was 235 days (range 38 to 582 days). Two additional patients who did not undergo cystectomy experienced progression to muscle-invasive disease during the treatment period.

If patients with CIS do not have a complete response to treatment after 3 months or if CIS recurs, consider cystectomy.

5.2 Risk of Disseminated Adenovirus Infection

Immunocompromised persons, including those receiving immunosuppressant therapy, may be at risk for disseminated adenovirus infection because of the possible presence of low levels of replication-competent adenovirus in ADSTILADRIN. Individuals who are immunosuppressed or immune-deficient should not come into contact with ADSTILADRIN.

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 × 10¹¹ 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:

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

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:

^* 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.

Risk Summary

Adequate and well-controlled studies with ADSTILADRIN have not been conducted in pregnant women. Animal reproductive and developmental toxicity studies have not been conducted with ADSTILADRIN. 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.

Risk Summary

There is no information regarding the presence of ADSTILADRIN 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 ADSTILADRIN and any potential adverse effects on the breastfed infant from ADSTILADRIN or from the underlying maternal condition.

No nonclinical or clinical studies were performed to evaluate the effect of ADSTILADRIN on fertility.

Pregnancy Testing

Verify pregnancy status in females of reproductive potential prior to initiating ADSTILADRIN.

Contraception

Females

Advise females of reproductive potential to use effective contraception during treatment with ADSTILADRIN and for 6 months following the last dose.

Males

Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ADSTILADRIN and for 3 months following the last dose.

Safety and effectiveness of ADSTILADRIN in pediatric patients have not been established.

Clinical studies of ADSTILADRIN in BCG-unresponsive high-risk NMIBC with CIS did not include sufficient numbers of patients younger than 65 years of age to determine whether safety and effectiveness differ from older patients.

8.6 Gender-specific Use

In clinical studies with ADSTILADRIN, no overall differences in safety or efficacy were observed between females and males.