1.1 Limitations of Use

Cysview is not a replacement for random bladder biopsies or other procedures used in the detection of bladder cancer [ see Warnings and Precautions (5.2)].

2.1 Recommended Dose

The recommended dose for adults is 50 mL of reconstituted solution of Cysview [ see Dosage and Administration (2.2)], instilled into the bladder via a urinary catheter [ see Dosage and Administration (2.3)].

2.2 Reconstitution of Cysview

Cysview is supplied as a kit containing: a clear glass vial labeled as Cysview (hexaminolevulinate HCl) for Intravesical Solution containing 100 mg hexaminolevulinate hydrochloride as a powder, a prefilled syringe labeled as DILUENT for Cysview containing 50 mL of the diluent, and a catheter adapter. The kit may be supplied as two options; with or without a vial adapter for use during reconstitution.

Perform all steps under aseptic conditions. Wear gloves during the reconstitution procedure; skin exposure to hexaminolevulinate hydrochloride may increase the risk for sensitization to the drug.

Cysview Powder	Cysview Diluent	Plunger Rod

    Figure 1.

2.3 Bladder Instillation of Cysview

For bladder instillation of the solution of Cysview, use straight or intermittent, urethral catheters with a proximal funnel opening that will accommodate the Luer Lock adapter. Use only catheters made of vinyl (uncoated or coated with hydrogel), latex (amber or red), and silicone to instill the reconstituted Cysview. Do not use catheters coated or embedded with silver or antibiotics. In-dwelling bladder catheters (Foley catheters) may be used if the catheters are inserted shortly prior to Cysview administration and are removed following the Cysview instillation.

Use the following steps for bladder instillation of Cysview:

• Using standard sterile catheterization technique, first insert the urethral catheter into the bladder of the patient and use the catheter to completely empty the patient's bladder before instillation of Cysview.

     Figure 11.

• To attach the syringe containing the solution of Cysview to the catheter, do the following:
  • Remove the syringe cap from the syringe that contains the reconstituted solution of Cysview.
  • Attach the Luer Lock end of the (provided) catheter adapter to the syringe.
  • Insert the tapered end of the catheter adapter into the funnel opening of the catheter. See Figure 11, with the connection enlarged in the inset.
• Slowly instill the solution of Cysview into the bladder through the catheter (Figure 11), ensuring that the complete volume of the syringe (50 mL) is administered.
• After the solution is instilled, remove the catheter and instruct the patient to retain the solution within the bladder for at least 1 hour; do not exceed 3 hours [ see Cystoscopic examination (2.5)]. Patients may stand, sit and move about during the time period between instillation and start of the cystoscopic procedure.
• Evacuate the solution of Cysview from the bladder as part of routine emptying of the bladder immediately prior to the initiation of the cystoscopic procedure (refer to the Karl Storz D-Light C Photodynamic Diagnostic (PDD) System Manual for further details). Also, the patient may void and completely empty the bladder prior to the procedure.

Avoid skin contact with Cysview. If skin does come in contact with Cysview, wash immediately with soap and water and dry off. After voiding the bladder of Cysview, routinely wash the patient's perineal skin region with soap and water and dry.

2.4 Use of the Karl Storz D-Light C Photodynamic Diagnostic (PDD) System

Cysview imaging requires the use of the Karl Storz D-Light C PDD system, which consists of either:

• a light source, a camera head, a camera control unit, a light cable, and a rigid cystoscope for use with the Rigid PDD Cystoscope System, or
• a light source, a camera control unit, and a flexible video cystoscope for use with the Flexible PDD Video Cystoscope System.

The light source enables both white light cystoscopy and blue light (wavelength 360 – 450 nm) fluorescence cystoscopy. Familiarity with this system is essential before beginning the procedure and before instilling Cysview into the bladder. For system set-up and general information for the safe use of the PDD system, refer to the Karl Storz instruction manual for the PDD system and the instruction manuals for each of the system components. The PDD System is not for use by healthcare providers with green-red color blindness.

2.5 Cystoscopic Examination

Cysview kit with a vial adapter

• Cysview (hexaminolevulinate hydrochloride) for Intravesical Solution, 100 mg , as a powder in a 10 mL clear glass vial.
• DILUENT for Cysview, 50 mL, in a plastic prefilled syringe.
• One vial adapter for use during reconstitution.
• One Luer Lock catheter adapter (to connect the syringe containing the reconstituted solution of Cysview to the urethral catheter for bladder instillation of Cysview).

Cysview kit without a vial adapter

• Cysview (hexaminolevulinate hydrochloride) for Intravesical Solution, 100 mg , as a powder in a 10 mL clear glass vial.
• DILUENT for Cysview, 50 mL, in a plastic prefilled syringe.
• One Luer Lock catheter adapter (to connect the syringe containing the reconstituted solution of Cysview to the urethral catheter for bladder instillation of Cysview).

Once reconstituted, the solution of Cysview contains 2 mg/mL of hexaminolevulinate hydrochloride.

5.1 Anaphylaxis

Anaphylaxis, including anaphylactoid shock, has been reported following administration of Cysview [ see Adverse Reactions (6.2)]. Prior to and during use of the Cysview, have trained personnel and therapies available for the treatment of anaphylaxis.

5.2 Failed Detection

Cysview may fail to detect some bladder tumors, including malignant lesions. Cysview is not a replacement for random biopsies or any other procedure usually performed in the cystoscopic evaluation for cancer. Do not perform cystoscopy with blue light alone as malignant lesions can be missed unless the bladder is initially examined under white light [ see Dosage and Administration (2.5) and Clinical Studies (14)].

5.3 False Positive Fluorescence

Fluorescent areas detected during blue light cystoscopy may not indicate a bladder mucosal lesion. In the controlled clinical studies, approximately 20% of the lesions detected only by blue light cystoscopy showed neither dysplasia nor carcinoma [ see Clinical Studies (14)]. False positive fluorescence may result from inflammation, cystoscopic trauma, scar tissue or bladder mucosal biopsy from a previous cystoscopic examination, and recent BCG immunotherapy or intravesical chemotherapy. In a study of patients treated with recent BCG immunotherapy or intravesical chemotherapy, the rate of false positives with blue light was 55% between 6 weeks to 90 days and 41% after 90 days; the false positive rate was 53% and 33% at the respective time intervals with white light.

The presence of urine and/or blood within the bladder may interfere with the detection of tissue fluorescence. To enhance the diagnostic utility of Cysview with the Karl Storz D-Light C PDD System:

• ensure the bladder is emptied of urine prior to the instillation of fluids at cystoscopy;
• biopsy/resect bladder mucosal lesions only following completion of both white light and blue light rigid cystoscopy;

6.1 Clinical Study 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.

In seven clinical trials, safety data were obtained from 1,628 patients, aged 32 to 96 years with a median age of 70 years, all primarily Caucasian and approximately 75% male. All patients were evaluated after a single instillation of 50 mL solution of Cysview, and 103 patients received a repeat administration of Cysview. Of these patients, 170 (10.4%) patients reported at least one adverse reaction. The most common adverse reaction was bladder spasm (reported in 2.0% of the patients) followed by dysuria, hematuria, and bladder pain. No patients experienced anaphylaxis. In the randomized controlled clinical study, adverse reactions were similar in nature and rate between the study drug group and the control group. In a controlled study using Cysview in the surveillance setting, adverse reaction types were similar [ see Clinical Studies (14)].

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Cysview. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Anaphylactoid shock, hypersensitivity reactions, bladder pain, cystitis and abnormal urinalysis have been reported during post-marketing use of Cysview.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Of 2127 subjects in clinical studies of Cysview, 67% were 65 years and over. No clinically important differences in safety or efficacy have been observed between older and younger patients in the controlled study.

12.1 Mechanism of Action

Cysview is an ester of the heme precursor, aminolevulinic acid. After bladder instillation, Cysview enters the bladder mucosa and is proposed to enter the intracellular space of mucosal cells where it is used as a precursor in the formation of the photoactive intermediate protoporphyrin IX (PpIX) and other photoactive porphyrins (PAPs). PpIX and PAPs are reported to accumulate preferentially in neoplastic cells as compared to normal urothelium, partly due to altered enzymatic activity in the neoplastic cells. After excitation with light at wavelengths between 360 and 450 nm, PpIX and other PAPs return to a lower energy level by fluorescing, which can be detected and used for cystoscopic detection of lesions. The fluorescence from tumor tissue appears bright red and demarcated, whereas the background normal tissue appears dark blue. Similar processes may occur in inflamed cells.

12.2 Pharmacodynamics

In vitro studies have shown increased porphyrin fluorescence in normal urothelium after exposure to Cysview. In the human bladder, a greater accumulation of porphyrins is proposed in neoplastic or inflamed cells, compared to normal urothelium. After bladder instillation of Cysview for approximately 1 hour and subsequent illumination with blue light at wavelengths 360 – 450nm, the porphyrins will fluoresce red [ see Dosage and Administration (2.5)] .

12.3 Pharmacokinetics

After bladder instillation of [ 14C]-labeled Cysview (100 mg) for approximately 1 hour in healthy volunteers, absolute bioavailability of Cysview was 7% (90% confidence interval [CI]: 5%-10%). The [ 14C]-labeled substance(s) showed biphasic elimination, with an initial elimination half-life of 39 minutes, followed by a terminal half-life of approximately 76 hours. Whole blood analysis showed no evidence of significant binding of Cysview to erythrocytes. An in vitro study showed that Cysview underwent rapid metabolism in human blood.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No studies in animals have been conducted to evaluate the carcinogenic potential of hexaminolevulinate hydrochloride.

Hexaminolevulinate hydrochloride was not mutagenic in in vitro reverse mutation tests in bacteria, or in chromosome aberration tests in human peripheral blood lymphocytes, and was negative in an in vivo micronucleus test in mice after intravenous injection of doses up to 45 mg/kg in the absence of light activation. Adequate studies have not been performed to evaluate the genetic toxicity of hexaminolevulinate hydrochloride in the presence of light activation.

Adequate reproductive and developmental toxicity studies in animals have not been performed to evaluate the effects of hexaminolevulinate hydrochloride on fertility.

13.2 Animal Toxicology and/or Pharmacology

Dose dependent neurological effects such as tremor, increased motor activity, and increased startle and touch escape responses were observed immediately after dosing at doses ≥ 30 mg/kg (24 times human systemic exposure based on the body surface area, using 10% as the upper level of 90% confidence interval of bioavailability) in a single-dose rat study. The animals recovered to normal status by 60 min after dosing. Adverse neurological effects were also noted in other single- or repeat-dose toxicity studies.

Hexaminolevulinate hydrochloride had moderate to strong potential to cause skin sensitization based on a local lymph node assay in mouse.

Study 1: A prospective, multicenter, controlled clinical trial in adult patients with known or suspected bladder cancer who were randomized to either white light (WL) cystoscopy (control group, n = 384) or WL followed by blue light (BL) cystoscopy (study drug group, n = 395). Only the study drug group patients received Cysview by bladder instillation prior to cystoscopy. After bladder evacuation of Cysview, bladder lesion mapping was performed initially using the Karl Storz PDD system in the WL mode followed by lesion mapping in the BL mode. Control group patients underwent only WL cystoscopy with lesion mapping. The average age of the randomized patients was 69 years (range 24 to 96); 78% were male and 94% were Caucasian. All patients had previously undergone cystoscopy.

The main diagnostic efficacy outcome was assessed within the study drug group. This assessment compared lesions detected during an initial cystoscopic examination to their centralized histologic findings (the standard of truth). Following the initial diagnostic cystoscopy, patients within both study groups who had histologically confirmed Ta and/or T1 lesions underwent follow-up WL cystoscopy at 3, 6 and 9 months; these histologic evaluations were based upon the site assessments at both the initial and follow-up cystoscopy.

Diagnostic efficacy assessed the number of patients within the study drug group who had at least one additional Ta or T1 bladder cancer detected only by BL; the proportion of these patients was compared to a proposed threshold proportion of 10%. Within the study drug group, 286 patients had at least one Ta and/or T1 lesion, including 47 patients who had at least one of the lesions detected only by BL (see Table 1).

Some malignant lesions were detected only by WL or BL (see Table 2).

Among the lesions detected only by BL, 23% were negative for any carcinoma-related pathology, including dysplasia. Among the lesions detected only by WL, 17% were negative for any carcinoma-related pathology, including dysplasia.

Study 2: A prospective, open-label, within-patient controlled clinical trial using BL cystoscopy in the detection of bladder cancer during surveillance cystoscopy. Patients with bladder cancer in follow-up for tumor recurrence (n=304) received Cysview by bladder instillation. The average age of the patients was 69 years (range 35 to 92); 80% were male and 89% were Caucasian. After bladder evacuation of Cysview, a standard WL cystoscopy was performed, followed by BL cystoscopy using the KARL STORZ D-Light C Photodynamic Diagnostic (PDD) System with the Flexible PDD Videoscope System. Suspected malignant lesions were counted and evaluated. Patients with suspected recurrence (n=103), underwent a Cysview instillation followed by WL and BL rigid cystoscopy in the operating room (OR), including lesion mapping, using the KARL STORZ D-Light C PDD System with the Rigid PDD Cystoscope System. The suspicious lesions were biopsied and surgically removed by TURB. Cysview efficacy assessed the proportion of patients with malignancy detected only with blue light cystoscopy and not WL cystoscopy during the surveillance cystoscopic examination. The assessment was performed at patient level, and compared malignancy detected during the surveillance cystoscopic examination to the centralized histologic findings (the standard of truth) obtained in the OR examination.

Table 3 shows patient-level detection of malignancy suspected in cystoscopic surveillance stage that was verified in the OR stage (n=103). Among the 103 patients, 63 patients had malignancy confirmed: 49 patients had malignancy detected by both WL and BL; 1 patient had malignancy detected by WL only; and 13 patients had malignancy detected by BL only [12.6% with 95% CI (7%, 21%), p<0.0001*]. Among these 103 patients, 40 patients had false positive detections: 17 patients had false positive detection by both WL and BL; 3 patients had false positive detection by WL only; and 20 patients had false positive detection by BL only.

Among 26 patients with confirmed CIS malignancy, 9 patients had CIS malignancy detected by BL only and 17 patients had CIS malignancy detected by both WL and BL.

In the same study, there were 315 lesions detected during the cystoscopy in the OR. Table 4 shows the detection of lesions by type of malignancy.

Cysview kit with a vial adapter

• Cysview (hexaminolevulinate hydrochloride) for Intravesical Solution, 100 mg, as a powder in a 10 mL clear glass vial.
• One plastic prefilled syringe of DILUENT for Cysview, 50 mL.
• One vial adapter for use during reconstitution. The vial adapter is either a "West Vented Vial Adapter" or a "West Mixject Dispensing Pin".
• One Luer Lock catheter adapter (to connect the syringe containing the reconstituted solution of Cysview to the urethral catheter for bladder instillation of Cysview).

NDC 10511-3001-2

Cysview kit without a vial adapter

• Cysview (hexaminolevulinate hydrochloride) for Intravesical Solution, 100 mg , as a powder in a 10 mL clear glass vial.
• One plastic prefilled syringe of DILUENT for Cysview, 50 mL.
• One Luer Lock catheter adapter (to connect the syringe containing the reconstituted solution of Cysview to the urethral catheter for bladder instillation of Cysview).

NDC 10511-3001-3

Storage

Store Cysview (hexaminolevulinate hydrochloride) Kit for Intravesical Solution at 20°-25°C (68°-77°F); excursions are permitted to 15°-30°C (59°-86°F). Do not use beyond the expiry date printed on the carton.

Use the solution of Cysview shortly after reconstitution. If unable to use within this time period, the reconstituted solution can be stored under refrigeration at 2°-8°C (36°-46°F) for up to 2 hours in the labeled syringe.