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INLEXZO contains gemcitabine hydrochloride, a nucleoside metabolic inhibitor. Gemcitabine hydrochloride is 2’-deoxy-2’,2’- difluorocytidine monohydrochloride (b-isomer) with a molecular formula of C9H11F2N3O4 • HCl, and a molecular weight of 299.66. The structural formula is:
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INLEXZO is a sterile, non-resorbable intravesical system containing the equivalent of 225 mg gemcitabine (present as 256.3 mg of gemcitabine hydrochloride).
INLEXZO is a bi-oval-shaped tube containing an almost white to light pink-brown colored gemcitabine component at the center surrounded on each side by off white to light blue-colored osmotic components.
The silicone tube contains two lumens, the larger one containing the drug components and silicone spacers, and the smaller one containing a superelastic nitinol wire in a predefined shape (wireform). Both lumens are capped with a silicone adhesive. The lumen containing the gemcitabine and osmotic components has a single delivery orifice. INLEXZO’s coiled dimensions are approximately 5.5 cm wide × 4.5 cm high.
INLEXZO is co-packaged with a sterile urinary catheter and a sterile stylet, required for transurethral insertion into the bladder. The urinary catheter and stylet are made of thermoplastic elastomer and polyethene, and consist of the following components:
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 |
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| All Grades % |
Grade 3 or 4 % |
|||
| Urinary frequency | 48 | 0 | ||
| Urinary tract infection1 | 44 | 6 | ||
| Dysuria | 42 | 0 | ||
| Micturition urgency1 | 34 | 0 | ||
| Urinary tract pain1 | 26 | 7 | ||
| Hematuria1 | 24 | 2.4 | ||
| Bladder irritation1 | 16 | 0 | ||
|
1Includes other related terms |
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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 | INLEXZO1 | |||
| 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 | ||
|
1 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. |
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No information provided
Included as part of the PRECAUTIONS section.
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)].
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.
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:
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.
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)].
No information provided
INLEXZO is contraindicated in patients with:
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.
The exposure-response relationship and time-course of pharmacodynamic response for the safety and effectiveness of INLEXZO have not been fully characterized.
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 Cmax after 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.
Advise patients to read the FDA-approved patient labeling (Patient Information).
