2.1 Important Administration Instructions

Administer INLEXZO intravesically only. Do NOT administer by any other route. INLEXZO is co-packaged with a urinary catheter and stylet used to insert INLEXZO through the urinary catheter into the bladder. Administer using the co-packaged urinary catheter and stylet only.

INLEXZO should be inserted and removed by a trained healthcare provider. Healthcare providers should become thoroughly familiar with the insertion and removal instructions before attempting insertion or removal of INLEXZO.

Prophylactic antibiotics may be used at the discretion of the treating healthcare provider with each INLEXZO insertion and removal.

2.2 Recommended Dosage

Insert INLEXZO (225 mg of gemcitabine) into the bladder once every 3 weeks for up to 6 months (8 doses), followed by once every 12 weeks for up to 18 months (6 doses), or until persistent or recurrent NMIBC, disease progression, or unacceptable toxicity.

Remove INLEXZO after each 3-week indwelling period.

Missed Dose

If a dose is missed, it should be administered as closely as possible to the original treatment schedule.

2.3 Preparation and Intravesical Administration

See the Instructions for Useenclosed in the carton for complete information on preparation, intravesical administration, and removal of INLEXZO.

INLEXZO is a hazardous drug. Follow applicable special handling and disposal procedures while handling INLEXZO and during the insertion and removal procedure. 1

Instruct patients to drink approximately 1500 mL of fluids per day during therapy with INLEXZO to ensure adequate urine production for drug release.

Instruct patients not to empty the bladder immediately prior to the insertion procedure. Presence of urine in the bladder can facilitate deployment of INLEXZO. Patients can resume micturition after the insertion procedure.

During indwelling period of approximately 3 weeks, advise patients to avoid urine contact with skin, to void urine sitting on a toilet, to wash hands with soap and water and to wash their genital area with water after each urination, and to flush the toilet after use.

5.1 Risks in Patients with Perforated Bladder

INLEXZO may lead to systemic exposure to gemcitabine and to severe adverse reactions if administered to patients with a perforated bladder or to those in whom the integrity of the bladder mucosa has been compromised.

Evaluate the bladder before the intravesical administration of INLEXZO and do not administer to patients with a perforated bladder or mucosal compromise until bladder integrity has been restored [see Contraindications (4)].

5.2 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 83 evaluable patients with BCG-unresponsive CIS treated with INLEXZO in Cohort 2 of SunRISe-1, seven patients (8%) progressed to muscle invasive (T2 or greater) bladder cancer. Three patients (3.5%) had progression determined at the time of cystectomy. The median time between determination of persistent or recurrent CIS or T1 and progression to muscle invasive disease was 94 days.

5.3 Magnetic Resonance Imaging (MRI) Safety

INLEXZO may be used with MRI only under the specific predefined conditions provided below to avoid potential safety hazards or severe adverse reactions.

Based on clinical experience in patients treated with INLEXZO indwelling in the bladder who underwent MRI scans and nonclinical testing, INLEXZO is MR Conditional. A patient with INLEXZO indwelling in the bladder can be scanned in an MR system under the following conditions:

• Static magnetic field of 1.5-Tesla and 3-Tesla, only.
• Maximum spatial gradient magnetic field of 5000 Gauss/cm or less.
• Maximum magnetic resonance system reported, whole body averaged specific absorption rate of 2-W/kg for 60 minutes of continuous scanning (i.e., per pulse sequence or back-to-back sequences without breaks) in the Normal Operating Mode of operation for the MR system.

Under the scan conditions defined, INLEXZO is expected to produce a maximum temperature rise of 2°C after 15 minutes of continuous scanning.

In nonclinical testing, the image artifact caused by INLEXZO extends approximately 2 mm from INLEXZO using a gradient echo pulse sequence and a 3-Tesla MR system.

5.4 Embryo-Fetal Toxicity

Based on animal data and its mechanism of action, INLEXZO can cause fetal harm when administered to a pregnant woman if systemic exposure occurs [see Clinical Pharmacology (12.1)] . In animal reproduction studies, systemic administration of gemcitabine was teratogenic, embryotoxic, and fetotoxic in mice and rabbits.

Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for 6 months after final removal of INLEXZO. Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months after final removal of INLEXZO [see Use in Specific Populations (8.1, 8.3)] .

6.1 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 INLEXZO monotherapy was evaluated in Cohort 2 of SunRISe-1, a multi-center, open-label study in 85 adult patients with BCG-unresponsive NMIBC with CIS, with or without papillary tumors [see Clinical Studies (14.1)].

Patients received INLEXZO (225 mg of gemcitabine) inserted into the bladder every 3 weeks for 6 months, followed by once every 12 weeks for up to 18 months, or until unacceptable toxicity, disease persistence, recurrence, or progression [see Dosage and Administration (2.2)] .

The median number of doses of INLEXZO administered to patients was 9 (range: 1 to 14) doses. The median duration of exposure to INLEXZO was 41 weeks (range: 1 to 108 weeks).

Serious adverse reactions occurred in 24% of patients receiving INLEXZO. Serious adverse reactions that occurred in >2% of patients included urinary tract infection, hematuria, pneumonia, and urinary tract pain. Fatal adverse reactions occurred in 1.2% of patients who received INLEXZO, including cognitive disorder.

Permanent discontinuation of INLEXZO due to an adverse reaction occurred in 7% of patients. Adverse reactions which resulted in permanent discontinuation of INLEXZO in >1% of patients included bladder irritation, urinary frequency, cognitive disorder, hydronephrosis, and urinary tract disorder.

Dosage interruptions of INLEXZO due to an adverse reaction occurred in 41% of patients. Adverse reactions which required dosage interruption in >3% of patients included urinary tract infection, urinary tract pain, hematuria, urinary frequency, micturition urgency, dysuria, and genital pain.

The most common (>15%) adverse reactions, including laboratory abnormalities, were urinary frequency, urinary tract infection, dysuria, micturition urgency, decreased hemoglobin, increased lipase, urinary tract pain, decreased lymphocytes, hematuria, increased creatinine, increased potassium, increased AST, decreased sodium, bladder irritation, and increased ALT.

Table 1 summarizes the adverse reactions in SunRISe-1.

Other clinically significant adverse reactions (<15%) included fatigue (14%), genital pain (12%), diarrhea (11%), urinary incontinence (9%), urinary retention (7%), and nocturia (4.7%).

8.1 Pregnancy

Risk Summary

Based on animal data and its mechanism of action, INLEXZO can cause fetal harm when administered to a pregnant woman if systemic exposure occurs [see Clinical Pharmacology (12.1)] . There are no available data on the use of INLEXZO in pregnant women to inform a drug-associated risk. In animal reproduction studies, systemic administration of gemcitabine was teratogenic, embryotoxic, and fetotoxic in mice and rabbits (see Data) . Advise pregnant women and females of reproductive potential of the potential risk to a fetus.

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

Data

Animal Data

Gemcitabine is embryotoxic in mice. Daily systemic dosing of gemcitabine to pregnant mice increased the incidence of fetal malformation (cleft palate, incomplete ossification) at doses of 1.5 mg/kg/day. Gemcitabine was embryotoxic and fetotoxic in rabbits. Daily systemic dosing of gemcitabine to pregnant rabbits resulted in fetotoxicity (decreased fetal viability, reduced litter sizes, and developmental delays) and increased the incidence of fetal malformations (fused pulmonary artery, absence of gall bladder) at doses of 0.1 mg/kg/day.

8.2 Lactation

Risk Summary

There is no information regarding the presence of gemcitabine or its metabolites in human milk, or their effects on the breastfed infant or milk production following INLEXZO administration. Because of the potential for serious adverse reactions in breastfed infants, advise women not to breastfeed during treatment and for 1 week after final removal of INLEXZO.

8.3 Females and Males of Reproductive Potential

INLEXZO can 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 INLEXZO.

Contraception

Females

Advise females of reproductive potential to use effective contraception during treatment and for 6 months after final removal of INLEXZO.

Males

Because of the potential for genotoxicity, advise males with female partners of reproductive potential to use effective contraception during treatment and for 3 months after final removal of INLEXZO [see Nonclinical Toxicology (13.1)] .

Infertility

Males

Based on animal studies, INLEXZO may impair fertility in males of reproductive potential [see Nonclinical Toxicology (13.1)] . It is not known whether these effects on fertility are reversible.

8.4 Pediatric Use

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

8.5 Geriatric Use

Of the patients given INLEXZO monotherapy in Cohort 2 of SunRISe-1, 72% were 65 years of age or older and 34% were 75 years or older. There were insufficient numbers of patients <65 years of age to determine if these patients respond differently to patients 65 years of age and older.

12.1 Mechanism of Action

Gemcitabine kills cells undergoing DNA synthesis and blocks the progression of cells through the G1/S-phase boundary. Gemcitabine is metabolized by nucleoside kinases to diphosphate (dFdCDP) and triphosphate (dFdCTP) nucleosides. Gemcitabine diphosphate inhibits ribonucleotide reductase, an enzyme responsible for catalyzing the reactions that generate deoxynucleoside triphosphates for DNA synthesis, resulting in reductions in deoxynucleotide concentrations, including dCTP. Gemcitabine triphosphate competes with dCTP for incorporation into DNA. The reduction in the intracellular concentration of dCTP by the action of the diphosphate enhances the incorporation of gemcitabine triphosphate into DNA (self-potentiation). After the gemcitabine nucleotide is incorporated into DNA, only one additional nucleotide is added to the growing DNA strands, which eventually results in the initiation of apoptotic cell death.

12.2 Pharmacodynamics

The exposure-response relationship and time-course of pharmacodynamic response for the safety and effectiveness of INLEXZO have not been fully characterized.

12.3 Pharmacokinetics

The systemic exposure of gemcitabine and the inactive uracil metabolite (2´-deoxy-2´,2´-difluorouridine [dFdU]), were evaluated between Days 2 and 7 during the indwelling period. The plasma gemcitabine concentrations were below the lower limit of quantification (0.1 µg/mL) in all patients at all time points. Eighteen patients (17%) had at least one quantifiable plasma dFdU concentration above the lower limit of quantification (0.1 µg/mL) and the maximum observed plasma dFdU concentration was 0.4 µg/mL. Plasma concentrations of both gemcitabine and dFdU are estimated to be less than 1% of the expected C maxafter intravenous administration of gemcitabine.

Excretion

Gemcitabine and dFdU are excreted in urine throughout the indwelling period for INLEXZO. Of the total gemcitabine dose, 77% was excreted by Day 7 and 99% was excreted by Day 21 in urine as gemcitabine and dFdU.

Mean urinary excretion on Days 2 through 5 ranged from 21 to 32 mg per day excreted in the urine as gemcitabine and dFdU.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term animal studies to evaluate the carcinogenic potential of gemcitabine have not been conducted. Gemcitabine was mutagenic in an in vitromouse lymphoma (L5178Y) assay and was clastogenic in an in vivomouse micronucleus assay.

Dedicated animal fertility studies have not been conducted with gemcitabine intravesical system. Gemcitabine intraperitoneal doses of 0.5 mg/kg/day in male mice resulted in moderate to severe hypospermatogenesis, decreased fertility, and decreased implantations. In female mice, fertility was not affected but maternal toxicities were observed at 1.5 mg/kg/day administered intravenously and fetotoxicity or embryo lethality were observed at 0.25 mg/kg/day administered intravenously.

14.1 BCG-unresponsive NMIBC

The efficacy of INLEXZO was evaluated in Cohort 2 of SunRISe-1 (NCT04640623), a single-arm, multi-center trial in 83 adults with BCG-unresponsive, NMIBC with CIS, with or without papillary tumors (T1, or high-grade Ta) following transurethral resection.

BCG-unresponsive NMIBC CIS was defined as persistent or recurrent CIS alone or with Ta/T1 disease within 12 months of adequate BCG therapy. Adequate BCG therapy was defined as a minimum administration of at least five of six doses of an initial induction course plus either of: at least two of three doses of maintenance therapy or at least two of six doses of a second induction course. Prior to treatment, all patients had undergone transurethral resection of bladder tumor (TURBT) to remove all resectable disease (Ta and T1 components). Residual CIS (Tis components) not amenable to complete resection was permitted. The trial included patients who were ineligible for or who had elected not to undergo radical cystectomy and excluded patients with extra-vesical (i.e., urethra, ureter, or renal pelvis), muscle invasive (T2-T4), locally advanced, or metastatic urothelial carcinoma.

Patients received INLEXZO (225 mg of gemcitabine) into the bladder every 3 weeks for 6 months, followed by once every 12 weeks for up to 18 months, or until unacceptable toxicity, persistence or recurrence of CIS and/or high-grade papillary disease, or progression [see Dosage and Administration (2.2)]. Tumor status was assessed every 12 weeks during the initial two years of treatment, after which cystoscopy was performed at least every 24 weeks. Mandatory biopsies were performed 24 and 48 weeks after treatment initiation.

The major efficacy outcome measures were complete response rate at any time (defined as negative results for cystoscopy [with TURBT and centrally-reviewed biopsies as applicable] and centrally-reviewed urine cytology) and duration of response.

The median age of patients was 71 years (range: 40 to 88); 80% male; 87% White, 10% Asian, 2.4% Black or African American and 1.2% race not reported; 10% were of Hispanic or Latino ethnicity, 89% identified as not Hispanic or Latino, and 1.2% were ethnicity unknown or not reported. Baseline ECOG performance status was 0 (92%) or 1 (8%). Tumor pattern at study entry was CIS only (67%), CIS with high-grade Ta only (22%), and CIS with T1 (11%). All patients had predominant urothelial carcinoma including 1 patient (1.2%) with squamous differentiation. The median number of prior instillations of BCG was 12 (range: 7 to 42).

Efficacy results are summarized in Table 3.

Storage

Store in the original carton at 20°C to 25°C (68°F to 77°F); with excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

Handling

INLEXZO is a hazardous drug. Follow applicable special handling and disposal procedures. 1