Source: Health Products Regulatory Authority (IE) Revision Year: 2022 Publisher: Photocure ASA, Hoffsveien 4, NO-0275 Oslo, N/A, Norway
Pharmacotherapeutic group: Other diagnostic agents
ATC code: V04CX06
After intravesical instillation of hexaminolevulinate, porphyrins will accumulate intracellularly in bladder wall lesions. The intracellular porphyrins (including PpIX) are photoactive, fluorescing compounds which emit red light upon blue light excitation. As a result, premalignant and malignant lesions will glow red on a blue background. False fluorescence may be seen as a result of inflammation.
In vitro studies have shown a considerable build-up of porphyrin fluorescence in malignant urothelium after exposure to hexaminolevulinate.
In humans, a higher degree of accumulation of porphyrins in lesions compared to normal bladder urothelium has been demonstrated with Hexvix. After instillation of the reconstituted solution for 1 hour and subsequent illumination with blue light, tumours can be readily visualized by fluorescence.
Clinical studies using Hexvix included 1174 evaluable patients with known bladder cancer or high suspicion of bladder cancer or in surveillance of bladder cancer, who underwent white light, followed by blue light cystoscopy, and biopsies.
In the clinical studies, the patients had known or suspected bladder cancer by cystoscopy or positive urine cytology.
In studies in patients with increased risk of carcinoma in situ (CIS), significantly more CIS and papillary lesions were detected after blue light cystoscopies, as compared to standard white light cystoscopy. The detection rate for CIS was 49.5% for standard white light cystoscopy and 95.0% for blue light cystoscopy, and the detection rate for papillary lesions ranged between 85.4% and 94.3% for white light and between 90.6% and 100% for blue light cystoscopy.
One of the above studies was designed to investigate the influence of patient management according to the European Association of Urology Recommendations on treatment of superficial bladder cancer. In 17% of patients, findings after blue light cystoscopy led to more complete therapy, and in 5.5% of patients less complete therapy was identified using only blue light cystoscopy. Reasons for more complete therapy was improved tumour detection compared to standard cystoscopy, and included more pTa lesions (20% of the patients), more CIS lesions (14%), and more pT1 lesions (11%) only detected with Hexvix cystoscopy.
A randomized, white light only comparative study was undertaken in patients with papillary tumors and increased risk of recurrence. A within patient comparison showed that a total of 16.4% (47/286) of patients with pTa/pT1 lesions had additional such lesions detected with Hexvix blue light cystoscopy only. Patients with pTa/pT1 lesions were followed for 9 months after cystoscopy, and the proportion of patients with recurrence was lower in the Hexvix group (47%, 128/271) than in the white light only cystoscopy group (56.1%, 157/280) in the ITT population, where all patients with missing data were assumed to have recurrence. The number of patients with missing data in the study was too high (56/128 and 59/157, in the Hexvix and control groups respectively) for the difference to be considered statistically robust (p=0.03-0.06 pending on ways to handle missing data). Further follow-up information was obtained for 86% of the participants. Median follow-up in the white light only and Hexvix groups were 53 and 55 months, respectively. The patients in the Hexvix group had a median of 7 months longer time to recurrence and recurrence-free survival (16 months in the Hexvix group versus 9 months in the white light group, p=0.04-0.06, pending on handling of missing data and deaths).
The overall rate of finding false positive lesions was increased after blue light cystoscopy, 17.3% for white light cystoscopy and 21.9% for blue light cystoscopy.
A prospective, within patient controlled study showed that blue light flexible cystoscopy with hexaminolevulinate improves detection of tumours compared to white light flexible cystoscopy. Patients with bladder cancer in follow up for tumour recurrence underwent a surveillance examination with white light and blue light flexible cystoscopy. 21% (13/63) of patients had histologically confirmed malignancy detected only with blue light flexible cystoscopy and not by white light examination. 46% (6/13) of patients recurred with high grade pTa or CIS.
In vivo autoradiography studies in rats after intravesical administration have shown high concentrations of hexaminolevulinate in the bladder wall.
After intravesical instillation of radiolabelled hexaminolevulinate in healthy volunteers, the systemic bioavailability of total radioactivity was approximately 5-10%.
Studies in rats and dogs have not indicated any risks for systemic toxicity.
Seven-day intravesical tolerance studies, without light exposure, were performed in rats and dogs. The study in rats showed cases of leukocytosis, suggesting a proinflammatory activity of hexaminolevulinate. Cases of azotemia, red coloured urine and weight loss were also seen. In dogs treated with hexaminolevulinate there was a marginally increased incidence and severity of transition cell hyperplasia and basophilia in the urinary epithelium.
A local lymph node assay in mice has demonstrated that hexaminolevulinate has a potential to cause skin sensitisation.
Potential genotoxicity has been investigated in vitro in procaryotic and eucaryotic cells in the presence and absence of photoactivating illumination and in vivo. All the studies of genotoxic potential were negative (Ames test, TK assay, in vivo micronucleus cell model, chromosome aberrations in CHO cells, and Comet assay on vesical samples from a dog local tolerance study with blue light activation).
Reproductive toxicity has been investigated in rats and rabbits. The incidences of embryo-fetal mortality, fetal weights, and the fetal abnormalities and variants, including skeletal ossification parameters did not indicate any obvious effect of treatment. There were no effects on female fertility and on early embryonic development when investigated in rats.
Carcinogenicity studies have not been performed with hexaminolevulinate.
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