Hexaminolevulinate Hydrochloride

CYSVIEW is indicated for the cystoscopic detection of carcinoma of the bladder, including carcinoma in situ (CIS), in adult patients: With suspected or known lesion(s) based on a prior cystoscopy Undergoing surveillance cystoscopy for bladder cancer 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) ] . CYSVIEW is an optical imaging agent indicated for the cystoscopic detection of carcinoma of the bladder, including carcinoma in situ (CIS), in adult patients: With suspected or known lesion(s) on the basis of a prior cystoscopy Undergoing surveillance cystoscopy for bladder cancer Limitations of Use CYSVIEW is not a replacement for random bladder biopsies or other procedures used in the detection of bladder cancer. ( 1 , 5.2 )

For intravesical solution: 100 mg of hexaminolevulinate hydrochloride as a white to off-white or pale yellow freeze-dried powder for reconstitution with the supplied diluent. For intravesical solution: 100 mg of hexaminolevulinate hydrochloride for reconstitution with the supplied diluent

CYSVIEW is contraindicated in patients with: Porphyria Known hypersensitivity to hexaminolevulinate or any derivative of aminolevulinic acid Porphyria Known hypersensitivity to hexaminolevulinate or aminolevulinate derivatives ( 4 )

Anaphylaxis: Have trained personnel and therapies available. ( 5.1 ). Failed Detection: CYSVIEW may not detect all malignant lesions. Always perform white light cystoscopy followed by blue light cystoscopy. Do not biopsy with blue light only. ( 5.2 ) False fluorescence may occur due to inflammation, cystoscopic trauma, scar tissue, previous bladder biopsy, recent BCG therapy, or chemotherapy. ( 5.3 )

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.

The following clinically significant adverse reaction is discussed elsewhere in the Prescribing Information: Anaphylaxis [see Warnings and Precautions (5.1) ] . The most common adverse reaction was bladder spasm followed by dysuria, hematuria, and bladder pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Photocure Inc. at 1-855-297-8439 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 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.

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.