2.1 Recommended Dose

The recommended dose for adults is 100 mg of CYSVIEW administered by bladder instillation.

Reconstitute the CYSVIEW 100 mg powder in the vial with the supplied diluent to a final volume of 50 mL. Administer the entire 50 mL dose via a urinary catheter. The solution should be retained in the bladder for 1 hour to 3 hours following instillation. [see Dosage and Administration (2.2, 2.3)].

2.2 Reconstitution of CYSVIEW

General Instructions

• CYSVIEW is supplied as a kit with diluent for reconstitution, with or without a vial adapter for use during reconstitution [see How Supplied/Storage and Handling (16)].
• Perform all steps using aseptic technique.
• Wear gloves during the reconstitution procedure; skin exposure to CYSVIEW may increase the risk of sensitization to the drug.
• Reconstituted CYSVIEW has a concentration of 2 mg/mL hexaminolevulinate hydrochloride and appears as a colorless to pale yellow, clear to slightly opalescent solution free from visible particles.
• If not immediately used, store the reconstituted solution in the labeled syringe under refrigeration at 2°C to 8°C (36°F to 46°F) for up to 2 hours. The solution should be discarded if not used within 2 hours.

Reconstitution Using a Vial Adapter

	CYSVIEW Powder	Diluent	Plunger Rod	Vial Adapter
Figure A. Components of CYSVIEW and Attachment of Plunger Rod to Diluent Syringe

1.

Fasten the plunger rod into the rubber stopper of the prefilled syringe by turning the plunger rod clockwise until it stops (see Figure A).

Figure B. Connection of Vial Adapter to CYSVIEW Vial

2.

Remove the plastic cap from the vial. Remove the TyveK® cover from the vial adapter blister package. Do not remove the vial adapter from the package. Place the CYSVIEW vial on a flat surface. Using the blister package to hold the vial adapter, connect to the vial with a downward vertical motion. The vial adapter snaps onto the vial as the spike penetrates the rubber stopper of the vial. Remove the plastic blister package and discard it. Take care not to touch the exposed end of the vial adapter (see Figure B).

Figure C. Injection of Diluent into CYSVIEW Vial

3.

Remove the cap from the prefilled syringe and carefully retain it for subsequent reattachment to the syringe. Hold the prefilled syringe upright and carefully press the plunger rod upward to remove air. Connect the syringe to the vial adapter. Inject about 10 mL of the diluent from the prefilled syringe down into the vial. The vial should be about ¾ full (see Figure C).

Figure D. Dissolution of CYSVIEW Powder in Diluent

4.

Without disconnecting the vial adapter from the vial, hold the vial and syringe in a firm grip and gently shake to dissolve the powder in the diluent. The powder normally dissolves almost immediately (see Figure D).

Figure E. Withdrawal of Reconstituted CYSVIEW from Vial

5.

Turn the vial upside down and withdraw all of the dissolved solution from the vial back into the syringe (see Figure E).
Do not inject large amounts of air or diluent when vial is inverted as it may block the venting action of the vial adapter. If this occurs, turn the vial upright and pull back on the plunger rod in the syringe.

Figure F. Final Preparation of Reconstituted CYSVIEW Solution

6.

Disconnect the empty vial with the vial adapter from the syringe tip and discard it. Plug the syringe with the syringe cap. Gently mix the contents of the syringe (see Figure F).

7.

Peel off the detachable portion of the syringe label. On the syringe label, add 2 hours to the present time and write the resulting expiration time and date.

Reconstitution Without Using a Vial Adapter

	CYSVIEW Powder	Diluent	Plunger Rod
Figure G. Components of CYSVIEW and Attachment of Plunger Rod to Diluent Syringe

1.

Fasten the plunger rod into the rubber stopper of the prefilled syringe by turning the plunger rod clockwise until it stops (see Figure G).

Figure H. Injection of Diluent into CYSVIEW Vial

2.

Remove the plastic cap from the vial. Remove the cap from the prefilled syringe and carefully retain it for subsequent reattachment to the syringe. Attach a needle to the prefilled syringe. Hold the prefilled syringe upright and carefully press the plunger rod upward to remove air. Penetrate the stopper of the CYSVIEW vial with the needle and inject about 10 mL of the diluent from the prefilled syringe down into the vial. The vial should be about ¾ full (see Figure H).

Figure I. Dissolution of CYSVIEW Powder in Diluent

3.

Without withdrawing the needle from the vial, hold the vial and syringe in a firm grip and gently shake to dissolve of the powder in the diluent. The powder normally dissolves almost immediately (see Figure I).

Figure J. Withdrawal of Reconstituted CYSVIEW from Vial

4.

Turn the vial upside down and withdraw all of the dissolved solution from the vial back into the syringe (see Figure J).

Figure K. Final Preparation of Reconstituted CYSVIEW Solution

5.

Remove the needle from the vial, disconnect the needle from the syringe tip and discard it. Plug the syringe with the syringe cap. Gently mix the contents of the syringe (see Figure K).

6.

Peel off the detachable portion of the syringe label. On the syringe label, add two hours to the present time and write the resulting expiration time and date.

2.3 Administration Instructions

Catheter Requirements

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.

Instructions for Bladder Instillation of CYSVIEW

1.

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 L. Connection of Catheter Adapter and Instillation of CYSVIEW

2.

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 L).

3.

Slowly instill the solution of CYSVIEW into the bladder through the catheter, ensuring that the complete volume of the syringe (50 mL) is administered (see Figure L).

4.

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 Dosage and Administration (2.5)]. Patients may stand, sit and move about during the time period between instillation and start of the cystoscopic procedure.

5.

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. Also, the patient may void and completely empty the bladder prior to the procedure.

6.

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 Blue Light Imaging Devices

Use CYSVIEW with the KARL STORZ D-Light C Photodynamic Diagnostic (PDD) System or other FDA-authorized imaging device intended to perform blue light cystoscopy (BLC) with hexaminolevulinate hydrochloride in the indicated population. The light source enables both white light cystoscopy and blue light (wavelength between 360 nm and 450 nm) fluorescence cystoscopy.

For system set-up and general information for the safe use of a blue light imaging device, refer to the instruction manual for each of the system components.

Certain blue light imaging devices may not be suitable for use by healthcare providers with green-red color blindness. See the instruction manual from the device manufacturer before use.

2.5 Cystoscopic Examination

User Training

Training and proficiency in cystoscopic procedures are essential prior to the use of CYSVIEW. Carefully review the instruction manual provided with the blue light imaging device. For additional training in the use of a blue light imaging device, contact the manufacturer's representative.

CYSVIEW Administration and Cystoscopic Timing

• Instill CYSVIEW into the bladder and retain in the bladder for a minimum of 1 hour and a maximum of 3 hours [see Dosage and Administration (2.3)].
• Initiate the cystoscopic examination within 30 minutes after evacuation of CYSVIEW from the bladder, but no less than 1 hour or more than 3 hours after CYSVIEW instillation.
• If the patient did not retain CYSVIEW in the bladder for 1 hour, allow 1 hour to pass from the instillation of Cysview into the bladder to the start of the cystoscopic examination.

Cystoscopic Examination with White and Blue Light

• Empty the patient's bladder and then fill the bladder with a clear fluid (standard bladder irrigation fluid) to distend the bladder wall. Ensure adequate irrigation during examination of the bladder; blood, urine or floating particles in the bladder can interfere with visualization under both white and blue light cystoscopy.
• First, perform a complete cystoscopic examination of the entire bladder using white light. If this initial examination does not reveal widespread mucosal inflammation, proceed to repeat the full examination using blue light.
• Under blue light, abnormal lesions typically demonstrate homogenous and intense red fluorescence with well-demarcated margins, contrasting with the blue appearance of normal urothelium. Register and map the location and appearance of any suspicious lesions or other abnormalities identified under either white or blue light.
• For accurate interpretation, consider the following:
  • Less intense, more diffuse red fluorescence is expected in normal tissue at the bladder outlet and the prostatic urethra and should be distinguished from malignant lesions.
  • To avoid false fluorescence from tangential light, hold the endoscope perpendicular and close to the bladder wall with the bladder distended.
  • False positive fluorescence can result from scope trauma from a previous cystoscopic examination or bladder inflammation [see Warnings and Precautions (5.3)].
  • Malignant lesions may not fluoresce, particularly if they are coated with necrotic tissue. Necrotic cells generally do not fluoresce [see Warnings and Precautions (5.2)].
• Avoid prolonged blue light exposure, as potential adverse effects have not been studied. In clinical trials, the cumulative blue light exposure time for evaluation, mapping, and resection did not exceed 32 minutes for any procedure [see Clinical Studies (14)].
• Only after completing white and blue light examinations and mapping should you proceed with biopsy and/or resection of suspicious lesions by transurethral resection of the bladder (TURB). Before finalizing the TURB procedure, confirm the completeness of the resections under both white and blue light.

5.1 Anaphylaxis

Anaphylaxis, including anaphylactic shock, has been reported following administration of CYSVIEW [see Adverse Reactions (6.2)]. Prior to and during use of 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)].

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:

• Ensure the bladder is emptied of urine prior to the instillation of fluids at cystoscopy.
• Rinse the bladder as needed during cystoscopy to optimize visualisation.
• Biopsy/resect bladder mucosal lesions only following completion of both white light and blue light rigid cystoscopy.

5.3 False Positive Fluorescence

Fluorescent areas detected during blue light cystoscopy may not indicate a bladder mucosal lesion. In 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, and scar tissue from bladder mucosal biopsy from a previous cystoscopic examination, or following intravesical treatment such as 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.

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 CYSVIEW was evaluated in 1,628 patients in seven clinical trials. Patients were aged 32 to 96 years with a median age of 70 years, 77% male, 88% White, 3% Black or African American, and 9% of unspecified racial group. All patients were evaluated after a single instillation of 100 mg of CYSVIEW, and 103 patients received a repeat administration of CYSVIEW [see Clinical Studies (14)].

The most common adverse reaction was bladder spasm (reported in 2% of the patients) followed by dysuria, hematuria, and bladder pain.

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:

Anaphylactic shock, hypersensitivity reactions, bladder pain, cystitis, and abnormal urinalysis.

8.1 Pregnancy

Risk Summary

There are no available data on CYSVIEW use in pregnant women to inform a drug associated risk of adverse developmental outcomes. Adequate reproductive and developmental toxicity studies in animals have not been performed. Systemic absorption following administration of CYSVIEW is expected to be minimal [see Clinical Pharmacology (12.3)].

The background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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.

8.2 Lactation

Risk Summary

There are no data on the presence of hexaminolevulinate in human or animal milk, the effects on a breastfed infant, or the effects on milk production. Systemic absorption following administration of CYSVIEW is expected to be minimal [see Clinical Pharmacology (12.3)]. The lack of clinical data during lactation precludes a clear determination of the risk of CYSVIEW to an infant during lactation; therefore, the development and health benefits of breastfeeding should be considered along with the mother's clinical need for CYSVIEW and any potential adverse effects on the breastfed infant from CYSVIEW or from the underlying maternal condition.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Of 2,127 subjects in clinical studies of CYSVIEW, 67% were 65 years and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects.

12.1 Mechanism of Action

Hexaminolevulinate is an ester of the heme precursor, aminolevulinic acid. After bladder instillation, hexaminolevulinate 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 nm 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 nm – 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 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 in the presence of light activation.

Adequate reproductive and developmental toxicity studies in animals have not been performed to evaluate the effects of hexaminolevulinate 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 had moderate to strong potential to cause skin sensitization based on a local lymph node assay in mouse.

Storage and Handling

Store the CYSVIEW kit at 20°C to 25°C (68°F to 77°F); excursions are permitted to 15°C to 30°C (59°F to 86°F).

After reconstitution, use the CYSVIEW solution immediately. Alternatively, the solution may be stored in the labeled syringe under refrigeration at 2°C to 8°C (36°F to 46°F) for up to 2 hours.