ANKTIVA Solution for injection Ref.[109663] Active ingredients: Nogapendekin alfa

5.1 Risk of 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 77 evaluable patients with BCG-unresponsive CIS treated with ANKTIVA with BCG in QUILT-3.032, 10% (n=8) progressed to muscle invasive (T2 or greater) bladder cancer, including 7 during the treatment period. Three patients had progression determined at the time of cystectomy. The median time between determination of persistent or recurrent CIS and progression to muscle-invasive disease was 107 days (range: 0–210).

If patients with CIS do not have a complete response to treatment after a second induction course of ANKTIVA with BCG, reconsider cystectomy.

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 ANKTIVA with BCG was evaluated in Cohort A of QUILT-3.032, a single-arm, multicenter clinical study in 88 patients with BCG-unresponsive high-grade NMIBC with CIS with or without Ta/T1 papillary disease [see Clinical Studies (14)]. Patients received 400 mcg ANKTIVA with BCG weekly for 6 consecutive weeks during induction and then once a week for every 3 weeks at 4, 7, 10, 13, and 19 months for patients with no or low grade disease. Patients with persistent CIS or high grade Ta at 3 months were eligible to receive a second induction. Patients with ongoing CR at 25 months were eligible to receive additional instillations once a week every 3 weeks at months 25, 31, and 37. The median number of doses of ANKTIVA with BCG administered to patients was 12 (range 2–30) doses. The median duration of exposure to ANKTIVA with BCG was 7.1 months (range: 0.26 to 36.3 months).

Serious adverse reactions occurred in 16% of patients receiving ANKTIVA with BCG. Serious adverse reactions that occurred in ≥2% of patients who received ANKTIVA with BCG included hematuria (3.4%). A fatal adverse reaction of cardiac arrest occurred in 1 (1.1%) patient receiving ANKTIVA with BCG.

Permanent discontinuation of ANKTIVA with BCG due to adverse reactions occurred in 7% of patients. Adverse reactions (>2%) resulting in permanent discontinuation of ANKTIVA with BCG included musculoskeletal pain (2.3%).

Dosage interruptions due to adverse reactions occurred in 34% of patients receiving ANKTIVA with BCG. Adverse reactions (≥5%) that resulted in interruption of ANKTIVA with BCG were urinary tract infection (10%), dysuria (8%), hematuria (6%), and bladder irritation (6%).

Dosage reductions due to adverse reactions were not permitted for ANKTIVA; however, dose reduction of BCG was allowed for adverse reactions and occurred in 3.4% of patients including (>1%) urinary tract infection (2.3%), hematuria (1.1%), urinary frequency (1.1%), and bladder irritation (1.1%).

The most common (≥15%) adverse reactions, including laboratory test abnormalities, were increased creatinine, dysuria, hematuria, urinary frequency, micturition urgency, urinary tract infection, increased potassium, musculoskeletal pain, chills and pyrexia.

Table 1 summarizes the adverse reactions in Cohort A of QUILT-3.032.

Table 1. Adverse Reactions Occurring in ≥15% of Patients in Cohort A in QUILT-3.032:

¹ Includes other related terms

Clinically relevant adverse reactions in <15% of patients who received ANKTIVA with BCG included fatigue (14%), nausea (14%), bladder irritation (11%), diarrhea (9%), and nocturia (7%).

Table 2 summarizes the laboratory test abnormalities occuring in ≥15% of patients in QUILT-3.032.

Table 2. Select Laboratory Test Abnormalities (≥15%) That Worsened From Baseline in Patients in Cohort A of QUILT-3.032:

¹ The denominator used to calculate the rates was 88 based on the number of patients with a baseline value and at least one posttreatment value.

Risk Summary

Systemic exposure of nogapendekin alfa inbakicept-pmln following intravesical administration of the approved dosage of ANKTIVA was below the limit of quantitation [see Clinical Pharmacology 12.3)].

Based on its mechanism of action, ANKTIVA may cause fetal harm when administered to a pregnant woman if systemic exposure occurs [see Clinical Pharmacology (12.1)]. There are no available data on ANKTIVA use in pregnant women to inform a drug-associated risk. Animal reproductive and developmental toxicity studies have not been conducted with nogapendekin alfa inbakicept-pmln. Advise pregnant women and females of reproductive potential of the potential risk to a fetus.

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

Risk Summary

There are no data on the presence of nogapendekin alfa inbakicept-pmln in human milk, or the effects on the breastfed child, or on milk production. Systemic exposure of nogapendekin alfa inbakicept-pmln in patients receiving intravesical administration of the approved dosage of ANKTIVA was below the limit of quantitation [see Clinical Pharmacology (12.3)], indicating any amount in the milk will be low. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ANKTIVA and any potential adverse effects on the breastfed child from ANKTIVA or from the underlying maternal condition.

Based on its mechanism of action, ANKTIVA may cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Pregnancy Testing

Verify pregnancy status in females of reproductive potential prior to initiating treatment with ANKTIVA.

Contraception

Advise females of reproductive potential to use effective contraception during treatment with ANKTIVA and for 1 week after the last dose.

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

Of the total number of patients in clinical studies of ANKTIVA for BCG-unresponsive NMIBC, 84% were 65 years of age or older and 40% were 75 years or older. Clinical studies of ANKTIVA did not include sufficient numbers of younger adult patients to determine if patients 65 years of age and older respond differently than younger adult patients.