Gemcitabine Intravesical

INLEXZO is indicated for the treatment of adult patients with Bacillus Calmette-Guérin (BCG)-unresponsive, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS), with or without papillary tumors. INLEXZO is a nucleoside metabolic inhibitor-containing intravesical system, indicated for the treatment of adult patients with Bacillus Calmette-Guérin (BCG)-unresponsive, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors. ( 1 )

One single-dose 225 mg strength gemcitabine intravesical system consisting of a flexible bi-oval shaped tube containing an almost white to light pink-brown colored component at the center surrounded by off white to light blue components. One single-dose 225 mg gemcitabine intravesical system ( 3 )

INLEXZO is contraindicated in patients with: Perforation of the bladder [see Warnings and Precautions (5.1) ] . Prior hypersensitivity reactions to gemcitabine or any component of the product. Perforation of the bladder ( 4 , 5.1 ) Prior hypersensitivity reaction to gemcitabine or any component of the product ( 4 )

Risks in Patients with Perforated Bladder : Evaluate the bladder before the intravesical insertion of INLEXZO. Do not administer to patients with a perforated bladder or in whom the integrity of the bladder mucosa has been compromised. ( 4 , 5.1 ) Risk of Metastatic Bladder Cancer with Delayed Cystectomy : Delaying cystectomy can lead to the development of metastatic bladder cancer, which can be lethal. ( 5.2 ) Magnetic Resonance Imaging (MRI) Safety : INLEXZO can only be safely scanned with MRI under certain conditions. ( 5.3 ) Embryo-Fetal Toxicity : Can cause fetal harm. Advise patients of the potential risk to a fetus and to use effective contraception. ( 5.4 , 8.1 , 8.3 )

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) ] .

The most common (>15%) adverse reactions, including laboratory abnormalities, are 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. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Janssen Biotech, Inc. at 1-800-526-7736 (1-800-JANSSEN) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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. Table 1: Adverse Reactions Occurring in >15% of Patients in SunRISe-1 Adverse Reaction INLEXZO N=85 All Grades % Grade 3 or 4 % Urinary frequency 48 0 Urinary tract infection Includes other related terms 44 6 Dysuria 42 0 Micturition urgency 34 0 Urinary tract pain 26 7 Hematuria 24

2.4 Bladder irritation 16 0 Other clinically significant adverse reactions (<15%) included fatigue (14%), genital pain (12%), diarrhea (11%), urinary incontinence (9%), urinary retention (7%), and nocturia (4.7%). Table 2: Select Laboratory Abnormalities (>15%) That Worsened from Baseline in Patients Who Received INLEXZO in SunRISe-1 Laboratory Abnormality INLEXZO The denominator used to calculate the rate varied from 82 to 83 based on the number of patients with a baseline value and at least one post-treatment value. All Grades (%) Grade 3 or 4 (%) Hematology Decreased Hemoglobin 31

1.2 Decreased Lymphocytes 24

4.8 Chemistry Increased Lipase 28 12 Increased Creatinine 24 0 Increased Potassium 22

1.2 Increased AST 17

1.2 Decreased Sodium 16

4.8 Increased ALT 16 1.2

Lactation : Advise not to breastfeed. ( 8.2 )

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.

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.