Hexaminolevulinate is an optical imaging agent indicated for intravesical use in the cystoscopic detection of carcinoma of the bladder, including carcinoma in situ, among patients suspected or known to have lesion(s) on the basis of a prior cystoscopy, or in patients undergoing surveillance cystoscopy for carcinoma of the bladder. It is used with the Karl Storz D-light Photodynamic Diagnostic (PDD) system to perform Blue Light Cystoscopy (BLC) as an adjunct to white light cystoscopy. Hexaminolevulinate is not intended to be a replacement for random bladder biopsies or other diagnostic procedures used in the detection of bladder cancer.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Injectable Administration
-Visually inspect product for particulate matter and discoloration prior to administration.
Other Injectable Administration
Intravesical Administration
-Avoid skin contact with hexaminolevulinate. If skin does come in contact, immediately wash with soap and water and dry off.
Reconstitution:
-Wear gloves during reconstitution procedure; skin exposure may increase risk for sensitization to hexaminolevulinate.
-Hexaminolevulinate is supplied as a kit containing 2 vials: 1 containing 100 mg hexaminolevulinate powder and 1 containing 50 mL of diluent.
-Use a 50 mL syringe with a Luer Lock tip during reconstitution to ensure 2 mg/mL final concentration and to ensure a stable syringe-catheter connection for bladder instillation.
-Withdraw 50 mL from the diluent vial into the 50 mL syringe.
-Inject 10 mL of the diluent into the powder vial. Without removing the needle from the powder vial, gently shake to dissolve the powder in the diluent, holding the syringe and powder vial firmly in 1 hand.
-Withdraw all of the dissolved solution into the syringe. Remove the needle from the syringe and discard. Place the syringe cap back on the syringe, and gently mix the contents of the syringe.
-The reconstituted solution should be colorless to pale yellow, clear to slightly opalescent, and free from particles.
-Peel the detachable portion of the label from the powder vial, and affix it to the syringe containing the reconstituted solution. Add 2 hours to the time of reconstitution and write the resulting expiration time on the label.
-Storage: Use immediately after preparation. May be refrigerated at 2 to 8 degrees C (36 to 46 degrees F) until use, but discard unused solution after 2 hours.
Bladder instillation:
-Insert a straight or intermittent urethral catheter with a proximal funnel opening that will accommodate the Luer Lock adapter into the bladder under aseptic conditions. Completely drain the bladder prior to hexaminolevulinate administration.
-Use only catheters made of vinyl (uncoated or coated with hydrogel), latex (amber or red), and silicone to instill the reconstituted hexaminolevulinate. Do not use catheters coated or embedded with silver or antibiotics. Indwelling bladder catheters (Foley catheters) may be used if the catheters are inserted shortly prior to hexaminolevulinate administration and are removed after hexaminolevulinate instillation.
-Attach the Luer Lock end of the catheter adapter to the syringe. Insert the tapered end of the catheter adapter into the funnel opening of the catheter.
-Slowly instill the entire 50 mL of hexaminolevulinate solution into the bladder through the catheter.
-After instillation, remove the catheter and instruct the patient to retain the solution within the bladder for at least 1 hour, but not more than 3 hours. Patients may stand, sit, and move about during the time between instillation and the cystoscopic procedure.
-Evacuate the hexaminolevulinate solution as part of the routine emptying of the bladder immediately prior to initiation of the cystoscopic procedure.
-After voiding the bladder of hexaminolevulinate, wash the patient's perineal skin region with soap and water and dry.
Cystoscopic examination:
-Initiate cystoscopic examination within 30 minutes after evacuation of hexaminolevulinate from the bladder, but no less than 1 hour or more than 3 hours after hexaminolevulinate administration. If the patient did not retain the hexaminolevulinate in the bladder for at least 1 hour after instillation, allow 1 hour to pass from the time of hexaminolevulinate instillation to the start of the cystoscopic examination. Efficacy of hexaminolevulinate has not been established when retained in the bladder for less than 1 hour.
-After evacuation of the bladder, fill the bladder with clear fluid (standard bladder irrigation fluid) to distend the bladder wall for cystoscopic visibility. Ensure adequate irrigation during procedure; blood, urine, or floating particles may interfere with visualization.
-Perform a complete cystoscopic exam of the bladder under white light, and then repeat the examination under blue light, unless the examination under white light reveals extensive mucosal inflammation. Do not perform blue light cystoscopy if white light cystoscopy reveals extensive mucosal inflammation.
-During blue light cystoscopy, abnormalities of the bladder mucosa are characterized by the detection of red, homogenous, and intense fluorescence. Margins of abnormal lesions are typically well-demarcated, in contrast to the normal urothelium, which appears blue.
-Register and document the location and appearance (e.g., papillary, flat) of suspicious lesions or abnormalities seen under either white or blue light.
-A red fluorescence is expected at the bladder outlet and prostatic urethra. This fluorescence occurs in normal tissue and is usually less intense and more diffuse than fluorescence in bladder mucosa associated with malignant lesions.
-Tangential light may give false fluorescence. To avoid this, hold the endoscope perpendicular and close to the bladder wall with the bladder distended. In addition, false fluorescence may result from scope trauma from a previous cystoscopic examination or bladder inflammation.
-Malignant lesions may not fluoresce after hexaminolevulinate instillation, particularly if the lesions are coated with necrotic tissue as necrotic cells typically do not fluoresce. Specifically, blue light may fail to detect T2 tumors which have a tendency to be necrotic on the surface.
-Avoid prolonged blue light exposure. Studies have not evaluated the potential for adverse effects from blue light. In clinical trials, cumulative blue light exposure from bladder evaluation, mapping, and resection did not exceed 32 minutes for any procedure.
-For rigid cystoscopy, perform biopsy and/or resection of suspicious lesions by transurethral resection of the bladder (TURB) only after completing white and blue light cystoscopic examinations with bladder mapping.
-Obtain biopsies of abnormal areas identified during either white or blue light examination and perform resections. Always check for the completeness of the resections under both white light and blue light before finalizing the TURB procedure.
Safety data were assessed in 7 clinical trials that included 1,628 patients who received a single instillation of hexaminolevulinate. In clinical trials, bladder spasm (2%) was the most frequent adverse reaction followed by dysuria, hematuria, and bladder discomfort. In postmarketing experience, bladder discomfort, cystitis, and abnormal urinalysis have also been reported.
Anaphylactoid reactions, including anaphylactic shock, have been reported after hexaminolevulinate administration. Use caution prior to and during the administration of hexaminolevulinate. Ensure that appropriate personnel and therapies are available for the treatment of anaphylaxis. No patients experienced anaphylactic reactions in the clinical trials; however, reports of anaphylaxis have been observed in postmarketing experience.
Hexaminolevulinate is contraindicated for use in patients with a known hypersensitivity to hexaminolevulinate or any derivative of aminolevulinic acid. Anaphylaxis, including anaphylactoid shock, has been reported after the administration of hexaminolevulinate. Prior to and during hexaminolevulinate administration, have trained personnel and therapies used for the treatment of anaphylaxis readily available.
Hexaminolevulinate may fail to detect some bladder tumors, including some malignant lesions, and 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. Malignant lesions can be missed if the bladder is not initially examined under white light.
The diagnostic accuracy of hexaminolevulinate may be decreased in patients who have recently received intravesical chemotherapy or Bacillus Calmette-Guerin (BCG) immunotherapy. In a study of patients recently treated with BCG or intravesical chemotherapy, the rate of false positive fluorescence with blue light was 55% between 6 weeks to 90 days and 41% after 90 days; the false positive rates were 53% and 33% at the respective time intervals with white light.
The use of hexaminolevulinate is contraindicated in patients with gross hematuria or porphyria. The presence of urine or blood in the bladder may interfere with accurate detection of tissue fluorescence. To enhance the diagnostic utility, ensure the bladder is emptied of urine prior to the instillation of fluids at cystoscopy.
In clinical trials, some fluorescent areas detected during blue light cystoscopy were not bladder mucosal lesions. Approximately 20% of lesions detected only by blue light cystoscopy showed neither dysplasia nor carcinoma. False positive fluorescence may result from inflammation, cystoscopic trauma, scar tissue, or bladder mucosal biopsy from a previous cystoscopic examination. To improve the diagnostic utility of hexaminolevulinate with the Karl Storz D-Light C PDD system, ensure both white light and blue light rigid cystoscopy are completed before performing a biopsy or resection of bladder mucosal lesions.
There are no available data on the use of hexaminolevulinate in human pregnancy to inform a drug associated risk of adverse developmental outcomes. Adequate reproductive and developmental toxicity studies in animals have not been performed. Systemic absorption after hexaminolevulinate administration is expected to be minimal.
There are no data on the presence of hexaminolevulinate in human or animal milk, the effects on a breast-fed infant, or the effects on milk production. Systemic exposure after hexaminolevulinate administration is expected to be minimal. The lack of clinical data during breast-feeding precludes a determination of risk. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for hexaminolevulinate and any potential adverse effects on the breast-fed infant from hexaminolevulinate or the underlying maternal condition.
For cystoscopic bladder cancer diagnosis, including carcinoma in situ, in patients undergoing surveillance cystoscopy and in patients with suspected or known lesions on a prior cystoscopy:
Intravesical dosage:
Adults: 100 mg (50 mL) instilled into the bladder by urinary catheter.
Maximum Dosage Limits:
-Adults
100 mg (50 mL) intravesically.
-Geriatric
100 mg (50 mL) intravesically.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
There are no drug interactions associated with Hexaminolevulinate products.
Hexaminolevulinate is an optical imaging agent that is instilled intravesically for use with photodynamic blue light cystoscopy as an adjunct to white light cystoscopy for the detection of bladder cancer. It is an ester of the heme precursor, aminolevulinic acid. Hexaminolevulinate enters the bladder mucosa and subsequently 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). Compared to normal urothelium, PAPs and PpIX are believed to accumulate preferentially in 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. Of note, a similar process may occur in inflamed cells.
Hexaminolevulinate is an imaging agent that is administered intravesically. In healthy volunteers, hexaminolevulinate showed biphasic elimination with an initial elimination half-life of 39 minutes, followed by a terminal half-life of approximately 76 hours. In an in vitro study, hexaminolevulinate underwent rapid metabolism in human blood. Whole blood analysis showed no binding of hexaminolevulinate to erythrocytes. In vitro studies have shown increased porphyrin fluorescence in normal urothelium after hexaminolevulinate exposure. Accumulation of porphyrins is proposed in neoplastic or inflamed cells. After bladder instillation of hexaminolevulinate for approximately 1 hour and subsequent illumination with blue light at wavelengths 360 to 450 nm, the porphyrins will fluoresce red.
Affected cytochrome P450 isoenzymes and drug transporters: none
-Route-Specific Pharmacokinetics
Other Route(s)
Intravesical Administration
In healthy volunteers, [14-C]-labeled hexaminolevulinate instilled in the bladder for approximately 1 hour resulted in an absolute bioavailability of 7%.