Hexvix® Blue-light cystoscopy

…a unique photosensitizing agent used with blue-light visualization in the detection and management of non-muscle invasive bladder cancer (NMIBC)

Hexvix® (hexaminolevulinate) is a photosensitizer approved and recommended for the detection and management of non-muscle invasive bladder cancer (NMIBC) when used in adjunct to standard white light cystoscopy. By providing enhanced visual contrast between benign and malignant cells compared to white light cystoscopy alone, Hexvix® blue-light cystoscopy enables detection and resection of additional tumors in the same procedure, which in turn improves patient outcomes and promotes efficient use of hospital resources. This advantage also helps to identify more patients at an earlier stage of cancer than white light cystoscopy alone. Hexvix® leads to the accumulation of fluorescent compounds in cancer cells that emit highly visible red light when under blue-light illumination. Visualization of the tumor cells is possible from around 1 hour after instillation.

…and how does it work?

“The principle of the method is to enhance the visual contrast between benign and malignant cells by the interaction of a specific light (blue-light bladder illumination) on a photosensitive agent having a great affinity for cancer cells.”1

Hexvix® mode of action

Once in contact with the bladder mucosa, Hexvix® penetrates rapidly proliferating cells, leading to the accumulation of fluorescent compounds within the tumor. A sufficient number of these compounds have accumulated 1 hour after Hexvix® instillation. Under subsequent blue-light illumination, the fluorescent compounds emit red light and enable specific and accurate visualization of the tumor.25

Mode of action in detail:Heme-Biosynthetic-Pathway

  • After instillation of Hexvix® solution into the bladder, Hexvix® penetrates the cellular membrane of cancer cells.
  • In these cells, Hexvix® interferes with the heme biosynthetic pathway and leads to the accumulation of photoactive porphyrins (PAPs), particularly protoporphyrin IX (PpIX); the last intermediate in heme synthesis.
  • PAPs selectively accumulate in rapidly proliferating cells (e.g. tumor cells).2
  • After 1 hour, sufficient PAPs have been generated.
  • Under blue-light illumination (blue-light cystoscopy), the PAPs emit red light, facilitating specific and accurate visualization of the tumor.
  • Diagnosis with blue-light cystoscopy relies on the selective accumulation of PpIX in neoplastic cells, with levels up to 6 times greater in tumors than in normal tissue following Hexvix® instillation.
  • This leads to a high fluorescence intensity and excellent contrast between normal and malignant urothelial cells.

The need and The benefit


Hexvix® is the only approved diagnostic agent for the detection and management of non-muscle invasive bladder cancer (NMIBC) in the EU (and in the US under the brand name Cysview®), and it is recommended by the European Association of Urology (EAU) and a number of expert panels.3, 4, 5, 6

“That we need something of therapeutic value for the diagnosis and treatment of non-muscle invasive bladder cancer (NMIBC) and carcinoma in situ (CIS) is obvious.”7

Bladder cancer is the ninth most common cancer worldwide and the second most frequent urological cancer worldwide. It is one of the most expensive cancers to manage from diagnosis to death due to the costs relating to long-term surveillance, monitoring and treatment.8, 9, 10, 11 Transurethral resection of the bladder (TURBT) represents, by far, the largest bladder cancer expenditure. The quality and result of the initial TURBT strongly determines the patient’s prognosis and overall bladder cancer treatment costs.10

Compared to standard white light cystoscopy alone…

…Hexvix® blue-light cystoscopy improves

  • Detection of non-muscle invasive bladder cancer because more lesions are visualized. 12
  • Identification of patients with Ta/T1 and CIS, which can be missed using white light cystoscopy alone.12
  • Removal of tumors because more complete resection is possible due to their improved visibility under Hexvix® blue-light cystoscopy. 12, 13

…which results in

  • More complete surgical results, leading to fewer residual tumors.13, 15
  • More accurate staging, leading to better post-operative decisions. 14

…which further leads to

  • Fewer short- and long-term recurrences.12, 13
  • A more accurate risk classification and therefore more individualized follow up (fewer cycles of TURBs and cystoscopies). 3, 15
  • Improved patient management during and after TURBT.

The benefit of Hexvix® blue-light cystoscopy compared to white light cystoscopy

Hexvix® blue-light cystoscopy has demonstrated clear benefits over white light cystoscopy alone in terms of clinical practice and patients’ experiences from diagnosis to cancer management. Hexvix® blue-light cystoscopy improves the detection of tumors, leading to improved treatment of non-muscle invasive bladder cancer (NMIBC) that results in better control of bladder cancer.

Benefits in clinical practice:

det-tre-ctrDetect more patients with bladder cancer: TURBT using Hexvix® blue-light cystoscopy significantly improves the detection of non-muscle invasive bladder cancer (NMIBC) compared to white light cystoscopy alone. 12, 16
Detect bladder cancer early: Hexvix® blue-light cystoscopy detects CIS in patients for whom white light cystoscopy alone does not detect these early-stage tumors.16
Achieve optimal surgical results: enhanced detection leads to a more complete surgical result, with fewer residual tumors and consequently a significantly reduced rate of tumor recurrence. 12, 15, 16
Improve the accuracy of staging: Hexvix® blue-light cystoscopy enables more accurate staging compared to white light cystoscopy alone, leading to improved post-operative decisions.14
Improve long-term management: Hexvix® improves identification of papillary bladder tumors and especially CIS, resulting in better management, longer recurrence-free intervals, improved patient care and reduced costs. 7, 13

Benefits to patients:

  • Patients have confidence in their diagnosis and management: Hexvix® blue-light cystoscopy can detect CIS that may be missed with white light 12, 16, 17 ; patients can be confident that their cancer is being appropriately managed from the outset.14
  • Undergo fewer procedures: using Hexvix® blue-light cystoscopy may reduce the number of repeat TURBs and cystoscopies compared to white light cystoscopy. 28, 87

The evidence for Hexvix®

Hexvix® blue-light cystoscopy significantly improves the detection of bladder tumors compared to white light cystoscopy

A number of studies have demonstrated the improved detection with Hexvix® blue-light cystoscopy compared to white light cystoscopy alone. 12, 13, 14, 15, 19, 20, 21, 22, 23

A recent published meta-analysis based on raw data shows that one single Hexvix® blue-light cystoscopy detects a significant number of additional patients with bladder cancer compared to white light cystoscopy alone. The meta-analysis confirms the findings of previous studies, which show that the benefit is particularly high in patients with carcinoma in situ (CIS) and persists in both primary and recurrent patients.16

 

Detection at a patient level

*Studies included in the meta-analyses were weighted relative to the number of patients in the study; hence the percentage varies slightly from simple numerical calculation based on the numbers at the top of the bar

*Studies included in the meta-analyses were weighted relative to the number of patients in the study; hence the percentage varies slightly from simple numerical calculation based on the numbers at the top of the bar

  • More than 25% of patients with CIS might not have had their CIS detected and received the correct treatment, such as Bacillus Calmette-Guérin (BCG), if only examined with white light cystocopy.

  • Even patients with primary Ta/T1 tumors benefit significantly from Hexvix® blue-light cystoscopy compared to white light cystocopy alone.
  • There is a significant improvement in detection of lesions with Hexvix® blue-light cystoscopy in all risk groups.

    *Studies included in the meta-analyses were weighted relative to the number of patients in the study; hence the percentage varies slightly from simple numerical calculation based on the numbers at the top of the bar

    *Studies included in the meta-analyses were weighted relative to the number of patients in the study; hence the percentage varies slightly from simple numerical calculation based on the numbers at the top of the bar

Click here for more data on detection.

In a phase III study of 58 patients with CIS: 17

  • More lesions were found by Hexvix® blue-light cystoscopy than by white light cystoscopy, in 42% of patients (n=22).
  • Of a total 113 CIS lesions in these 58 patients, Hexvix® blue-light cystoscopy detected 92% (n=104), while 68% (n=77) were detected by white light cystoscopy alone.

In another phase III study: 12

  • 32% of the patients with CIS were detected with Hexvix® blue-light cystoscopy only.
  • Ta/T1 tumors that had not been seen under conventional white light cystoscopy were detected in 16% (n=47) of the patients by using Hexvix® blue-light cystoscopy.

*NMIBC=non-muscle invasive bladder cancer
*NMIBC=non-muscle invasive bladder cancer

Hexvix® blue-light cystoscopy leads to more appropriate treatment decisions

Hexvix® blue-light cystoscopy reduces tumor recurrence by up to 12 months

The recent meta-analysis by Burger et al confirms that the improved detection with Hexvix® blue-light cystoscopy is associated with a significant overall reduction in recurrence at 12 months of approximately 11% and 16.6% in patients with CIS or T1 tumors, respectively, which might translate into less frequent need for resection. 16

Graph 5

Reduction in the risk of recurrence was confirmed at a patient level

  • By 10.9% overall (p=0.006, RR=0.761) and in all risk groups
  • The highest reduction was observed in the low-risk group 16.8% (p=0.029, RR=0.561)
  • Prior intravesical therapy did not affect the ability of Hexvix® blue-light cystoscopy to identify additional patients with Ta/T1 or CIS (Note: only one recurrence study provided information on prior therapy)

In a phase III study: 12

  • In patients with Ta/T1 lesions, Hexvix® blue-light cystoscopy demonstrated a 16% relative reduction of tumor recurrence, compared to white light cystoscopy alone.
  • During the 9-month follow up (intent to treat) there was tumor recurrence in 47% of patients (n=128/271) in the Hexvix® blue-light group and 56% (n=157/280) in the white light group.
  • The absolute decrease in tumor recurrence for patients in the Hexvix® group was 9%. This means that only 11 patients need to be treated to avoid one recurrence.

In another study: 15

  • Recurrence rate at 12 months for patients with Ta/T1 lesions was 47% (n=35/74) following white light TURB and 31% (n=18/59) following Hexvix® blue-light TURB.
  • Kaplan-Meier analyses showed that the recurrence-free period was significantly longer in the Hexvix® blue-light TURB group than in the white light TURB group.

They also found that Hexvix® blue-light cystoscopy after complete white light TURB identified residual tumor tissue in 44 of 90 patients (49%): 15

  • In 37 of 83 (45%) patients, residual Ta tumor was found.
  • In 3 of 7 (43%) patients, residual T1 was found.
  • In four cases, CIS was found.

In a phase III study, use of Hexvix® blue-light cystoscopy led to more complete management than was planned with white light cystoscopy alone:14

  • Additional post-operative procedures were recommended in 10% of patients (n=15) when they were re-examined using Hexvix® blue-light cystoscopy.

    Jocham-data-cakes

  • More extensive treatment was done intraoperatively in a further 7% (n=10) following re-examination with Hexvix® blue-light cystoscopy.
  • The reason for more complete management was improved tumor detection compared to white light cystoscopy.
  • Of all tumors, 96% were detected with Hexvix® blue-light cystoscopy compared with 77% using standard white light cystoscopy.
  • The difference was particularly noticeable for dysplasia (93% vs. 48%), CIS (95% vs., 68%) and superficial papillary tumors (96% vs. 85%).
  • Overall, one in five patients (22%) with tumors received more appropriate treatment at the time of the study, because of the more exact assessment of risk categories following Hexvix® blue-light cystoscopy compared to white light cystoscopy.

Hexvix® blue-light cystoscopy improves long-term outcomes compared to white light cystoscopy

Analysis of long-term follow-up data (4.5 years):13

Grossman-kaplan-plot

7_months_difference

  • After initial resection, 32% (n=83) of patients in the white light group and 38% (n=97) of patients who underwent Hexvix® blue-light cystoscopy remained tumor free.
  • T2–4 bladder cancer occurred twice as often in the white light group (16 patients, 6%) compared to the blue-light group (8 patients, 3%). However, these differences were not significant.
  • The cystectomy rate was 8% (n=22/280) for patients who were initially resected using white light alone and 5% (n=13/271) for patients who received Hexvix® blue-light cystoscopy.
  • There were also small increases in overall and disease-specific survival but the study was not sufficiently powered to detect possible statistical improvements in these outcomes.
  • The median time to recurrence was significantly better in the group randomized to Hexvix® blue-light cystoscopy than those in the white light cystoscopy group (16.4 vs. 9.4 months).

This long-term data showed that:24

  • Patients in the blue-light cystoscopy group had a lower recurrence rate and a longer disease-free interval compared to those in the white light cystoscopy group.
  • There was a trend toward a lower rate of cystectomy in the blue-light cystoscopy group compared to the white light cystoscopy group, which was possibly an indirect indicator of lower disease progression.

For further reading: Read clinical summaries

Safety


In clinical studies, Hexvix blue-light cystoscopy has been well tolerated as an adjunctive procedure to standard white light cystoscopy 2, 1217, 26

business-peopleHexvix blue-light cystoscopy has an excellent safety profile and the adverse reactions reported are typically those associated with standard cystoscopy/TURBT and symptoms generally seen in the bladder cancer population 2, 1217

Adverse events reported by patients were those typically associated with standard cystoscopy/TURBT of the bladder and symptoms seen in the general bladder cancer population. Most of these adverse events were transient, mild or moderate in intensity and regarded as not related to Hexvix® blue-light cystoscopy but rather to the underlying disease or the surgical procedure 2, 12, 15, 17

The most frequently reported adverse events considered related to Hexvix® blue-light cystoscopy were bladder spasm (2.4%), dysuria (1.8%), bladder pain (1.7%) and hematuria (1.7%). 26

Safety-figurer

No clinically significant changes in laboratory safety parameters or vital signs related to Hexvix blue-light cystoscopy has been reported from clinical studies. 2, 17

Postmarketing experience from more than 300,000 patients confirms the excellent safety profile seen in the clinical studies. The possibility of hypersensitivity reactions including anaphylactic/anaphylactoid reactions should always be considered as in any other procedure involving medication. Hypersensitivity reactions, including anaphylactic shock has been reported. 26

To report an adverse event related to Hexvix® blue-light cystoscopy please contact us directly here: safety@photocure.no

About the procedure

Prosedyre-no text

Hexvix® blue-light cystoscopy is indicated as adjunct to standard white light cystoscopy to contribute to the diagnosis and management of bladder cancer in patients with known or high suspicion of bladder cancer.26

How does it work?

Hexvix® is a photosensitizing agent which under subsequent blue-light illumination makes the cancer cells appear with a red fluorescent color. The blue-light is a result of filters in the light source and in the cystoscope itself and can easily be switched on and off by the click of a button, giving you the benefit of both modes. Click here to learn more about the principle of blue-light cystoscopy.

The benefits of being able to alternate between the two modes are many:


  • An improved detection of non-muscle invasive bladder cancer (NMIBC) due to the illumination of cancerous cells.12, 16 Click here to read more about the benefits of Hexvix®.
  • A more complete removal of tumors during resection by controlling the area with blue-light after resection to see if there are any remnant tumors.15
  • A more correct staging of the cancer, as you may find additional worrisome tumors, such as CIS, that you would not have spotted with white light alone.12, 14, 16
  • An improved surgical outcome as a result of an improved detection and resection which can lead to more adequate patient management and follow-up.7, 13

A blue-light enabled equipment can be acquired from any one of these three manufacturers:

If you recently purchased new equipment from one of these, you may only need an upgrade. Please feel free to contact us using the contact form if you have any questions regarding the equipment.

For details regarding the principle of blue-light cystoscopy, click here.

Improving the patient pathway

Following first cystoscopy in the operating room to diagnose and guide resection of non-muscle-invasive bladder cancer, the ongoing pathway for non-muscle-invasive bladder cancer (NMIBC) patient is characterized by a cycle of follow-up cystoscopies and TURBTs. This need for long-term surveillance and management is driven by the high rate of recurrence and possible progression, making bladder cancer one of the most expensive cancers to manage.10

Longer time to recurrence, which would lead to prolonged time without having to undergo surgery (with all its risks and possible complications), will therefore give the patient improved quality of life. Hexvix® blue-light cystoscopy has been shown in clinical trials to delay the time to recurrence of NMIBC by up to 7 months.
For more details, read about our Health Economics.7
patient_pathway

Performing Hexvix® blue-light cystoscopy

There are two types of cystoscopy, flexible and rigid:

  • Rigid cystoscopy in the operating room (OR) under general anesthetic; critical for an accurate first diagnosis and to guide and assess the completeness of TURBT.
  • Flexible cystoscopy in the outpatient (OP) setting (does not require general anesthetic): can be used as part of the work up of a patient with bladder symptoms, before transferral to the OR for rigid cystoscopy to confirm bladder cancer and guide TURBT, if applicable.

Rigid cystoscopy/TURBT in the OR

The correct use of Hexvix® and the equipment is important to safeguard an optimal treatment. Performing a Hexvix® blue-light cystoscopy is very similar to a standard white light cystoscopy. Further down you will find the procedure described in three simple steps. 27, 28How-to-use_1

“Its handling is simple and perfectly adapted to the current endoscopic equipment.” 1

1) Preparing and mixing Hexvix® is easy. In only a few steps the drug is prepared and ready to be instilled in the patient. A full description on how to mix Hexvix® can be found here.

2) Instill Hexvix® A solution of Hexvix® is instilled into the bladdeadministeringr. Hexvix® is converted to the photoactive porphyrin (PAP), mainly protoporphyrin IX, which selectively accumulates in rapidly proliferating cells (e.g. tumors). After a period of only one hour, sufficient PAPs have been generated specifically in neoplastic bladder tissue to allow fluorescence cystoscopy to take place. During a Hexvix® blue-light cystoscopy, blue-light causes the PAP within tumors to fluoresce a red color, which contrasts to the normal mucosa. Hexvix® shows high specificity for tumors.result

3) Perform Hexvix® blue-light cystoscopy combined with white light. The cystoscopic examination in blue-light should start within approximately one hour following bladder evacuation. A Hexvix® blue-light cystoscopy is superior to a white light cystoscopy alone.

The procedure itself is quite similar to a standard white light cystoscopy.

We recommend that you:27, 28

  1. Inspect the entire bladder in white light before switching to blue-light mode and repeating the inspection. Make note of any additional lesions found
  2. Remove any large tumors in white light mode before switching to blue-light mode for removal of smaller ones
  3. Examine all areas in blue-light mode to ensure that there are no tumor remnants left in the bladder at the end of the procedure

Click below for more details on how to perform a Hexvix® blue-light cystoscopy:

Watch the videos with courtesy of Maximillian Burger, Germany, on how to perform a Hexvix® blue-light cystoscopy:


Flexible cystoscopy in the Out Patient setting

In 2014, a panel of European expert urologists provided advice on the optimal use of Hexvix® BLFC, based on the recent evidence: 67

“There may be a role for BLC in the outpatient setting, and it may come to be of benefit, e.g. in ruling out lesions (especially CIS) and thereby preventing the need for hospital admission and TURBT.”67

“Before such a strategy could be routinely adopted (at least in high-risk patients), the impact on cost and time of patients would need to be balanced against the potential reduction in hospitalization costs for the proportion of patients who would benefit.” 67

Current experience with Hexvix® Blue Light Flexible Cystoscopy

Seven studies have reported experience with Hexvix® BLFC in clinical practice as described in the table below. 2930, 31, 32, 33, 34, 73

Despite the differing cystoscopic technologies used and the heterogeneous patient populations investigated in these studies, the findings from all seven studies point consistently in the same direction.

The Nordic Feasibility Study was conducted at three centers in Norway and Sweden (75 patients). The aim of this study was to investigate the feasibility of Hexvix® BLFC in the OP setting and collect observations and practical experience. As summarized in the table below, this study demonstrated that Hexvix® BLFC in the OP setting was feasible, effective, well tolerated and extremely practical.73

Slides figure 21 V4-01

Potential benefits of Hexvix® blue-light flexible cystoscopy (BLFC)

Hexvix® BLFC for surveillance in the OP setting is likely to have an increasing role in clinical practice through potential benefits that could improve patient outcomes:

  • More appropriate referral to the OR of patients who require further assessment with a rigid cystoscope or re-TURBT for tumor recurrence, as well as identification of patients who do not need to be referred, including those whose lesions can be fulgurated in an OP setting
  • Securing the patient’s and doctor’s confidence in the success of the initial resection or intravesical therapy, meaning that patients can be offered the most appropriate ongoing follow up and effective interventions
  • Improving and optimising patient management

 

 

Feedback from experts indicates that Hexvix® BLFC could be of benefit across all levels of bladder cancer risk.67 In addition, in patients considered to be elderly or frail and at high risk of complications from surgery, it has been shown that Hexvix® BLFC OP laser ablation can avoid the need for hospitalization and treatment in the OR under general anesthesia.5

Slides figure 5 V4-01

“By securing improved detection and limiting the number of patients who have to be referred to the operating room to have their tumors removed, we can avoid the need for general anesthesia and overnight hospital stays, thus taking the pressure off hospital services and reducing the burden of disease on patients”.

Please click here for press release.

Hexvix® BLFC practical considerations

(i) Patient flow

The time added to standard white light flexible cystoscopy (WLFC) for Hexvix® BLFC in an OP setting has been evaluated and calculated in the Nordic Feasibility Study. The additional time required for each individual process within BLFC is summarized in the diagram below.

The use of blue-light flexible cystoscopy within the outpatient setting offers a feasible approach to cystoscopy which is straightforward to implement. Although overall treatment time is extended for both the patient and urologist, the greatest impact is associated with the required waiting time for the patient following instillation of the solution of Hexvix® in the bladder. In contrast to standard WLFC, the patient must wait for 45–60 minutes before beginning the cystoscopy—this period provides the time needed for formation and sufficient accumulation of photoactive porphyrins in tumor cells. In terms of logistics, it is important that patients are made aware of the need to arrive at the clinic in sufficient time and that they have somewhere to wait between Hexvix® instillation and the cystoscopy procedure. This waiting time need not affect the schedule of the assigned urologist, who requires on average only an additional 7 minutes for the cystoscopic examination.

(ii) Equipment required

The following equipment is required to undertake Hexvix® BLFC:

  • A blue-light enabled videoscope from one of the recommended manufacturers, Karl Storz or Richard Wolf

Equipment required

Training

Peer-to-peer interaction and on-site training is the most beneficial method to truly master the unique Hexvix® blue-light cystoscopy procedure. We offer a variety of training options, as well as advice on how to optimize your clinic’s performance regarding lean processes and procedure compliance.

Please contact Photocure for more information.

Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

Hexvix 85 mg, powder and solvent for solution for intravesical use

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial of powder contains 85 mg hexaminolevulinate (as hexaminolevulinate hydrochloride).

After reconstitution in 50 ml of solvent, 1 ml of the solution contains 1.7 mg hexaminolevulinate which corresponds to a 8 mmol/l solution of hexaminolevulinate.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Powder and solvent for solution for intravesical use.

Powder: white to off-white or pale yellow
Solvent: clear, colorless solution

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

This medicinal product is for diagnostic use only.

Hexvix blue light fluorescence cystoscopy is indicated as adjunct to standard white light cystoscopy to contribute to the diagnosis and management of bladder cancer in patients with known or high suspicion of bladder cancer. See 5.1.

4.2 Posology and method of administration

Hexvix cystoscopy should only be performed by health care professionals trained specifically in Hexvix cystoscopy. The bladder should be drained before the instillation.

Adults (including the elderly):
50 ml of 8 mmol/l reconstituted solution (see section 6.6) is instilled into the bladder through a catheter. The patient should retain the fluid for approximately 60 minutes.

Following evacuation of the bladder, the cystoscopic examination in blue light should start within approximately 60 minutes. The cystoscopic examination should not be performed more than 3 hours after Hexvix is instilled in the bladder.

Also if the retention time in the bladder is considerable shorter than one hour, examination should start no earlier than after 60 minutes. No minimum retention time has been identified making examination non-informative.

For optimal visualisation it is recommended to examine and map the entire bladder under both white and blue light before any surgical measures are initiated. Biopsies of all mapped lesions should normally be taken under white light and complete resection should be verified by switching to blue light.

Only CE marked cystoscopic equipment should be used, equipped with necessary filters to allow both standard white light cystoscopy and blue light (wavelength 380–450 nm) fluorescence cystoscopy.

The light doses given during cystoscopy will vary. Typical total light doses (white light and blue light) range between 180 and 360 J at an intensity of 0.25 mW/cm2.

Children and adolescents:
There is no experience of treating patients below the age of 18 years.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Porphyria.

4.4 Special warnings and precautions for use

The possibility of hypersensitivity including serious anaphylactic/anaphylactoid reactions should always be considered (see section 4.8). Advanced life support facilities should be readily available.

Post-marketing experience with repeated use of Hexvix does not indicate that it represents a risk when used in follow-up in patients with bladder cancer, however no specific studies have been conducted.

Hexaminolevulinate should not be used in patients at high risk of bladder inflammation, e.g. after BCG therapy, or in moderate to severe leucocytouria. Widespread inflammation of the bladder should be excluded by cystoscopy before the product is administered. Inflammation may lead to increased porphyrin build up and increased risk of local toxicity upon illumination, and false fluorescence.

If a wide-spread inflammation in the bladder becomes evident during white light inspection, the blue light inspection should be avoided.

There is an increased risk of false fluorescence in the resection area in patients who recently have undergone surgical procedures of the bladder.

4.5 Interaction with other medicinal products and other forms of interaction

No specific interaction studies have been performed with hexaminolevulinate.

4.6 Fertility, pregnancy and lactation

Pregnancy
There are no or limited data on the use of hexaminolevulinate in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to the reproductive toxicity (see section 5.3). As a precautionary measure, it is preferable to avoid the use of Hexvix during pregnancy.

Breastfeeding
It is unknown whether hexaminolevulinate/metabolites are excreted in human milk. A risk to the newborns/infants cannot be excluded. Breast-feeding should be discontinued during the treatment with Hexvix.

Fertility
Animal studies do not indicate effects on female fertility (see section 5.3). Male fertility has not been investigated in animals.

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed.

4.8 Undesirable effects

Most of the reported adverse reactions were transient and mild or moderate in intensity. The most frequently reported adverse reactions from clinical studies were bladder spasm, reported by 2.4 % of the patients, dysuria by 1.8%, bladder pain by 1.7 % and hematuria by 1.7%, of the patients. The adverse reactions that were observed were expected, based on previous experience with standard cystoscopy and transurethral resection of the bladder (TURBT) procedures.

The table below includes adverse reactions from clinical trials and spontaneous reporting. The adverse reactions are classified by System Organ Class and frequency, using the following convention: Very common (>1/10), Common (>1/100 to < 1/10), Uncommon (> 1/1,000 to < 1/100), Rare (> 1/10,000 to < 1/1,000), Very rare (< 1/10,000), Not known (cannot be estimated from the available data).

 

System OrganClass (MedDRA)  Frequency Adverse reaction
Infections and infestations Uncommon Cystitis, sepsis, urinary tract infection
Blood and lymphatic systemdisorders Uncommon White blood cell count increased,anaemia
Immune system disorders Not known Anaphylactoid shock
Metabolism and nutrition disorders Uncommon Gout
Psychiatric disorders Uncommon Insomnia
Nervous system disorders Common Headache
Gastrointestinal disorders Common Nausea, vomiting, constipation, diarrhea
Hepatobiliary disorders Uncommon Increased serum bilirubin, hepatic enzyme increased
Skin and subcutaneous tissue disorders Uncommon Rash
Musculosceletal and connective tissue disorders Uncommon Back pain
Renal and urinary bladder disorders Common Bladder spasm, bladder pain, dysuria, urinary retention, haematuria
Uncommon Urethral pain, pollakuria, micturition urgency, urinary tract disorder
Reproductive system and breast disorders Uncommon Balanitis
General disorders and administration site conditions Common Pyrexia
Injury, poisoning and procedural complications Common Post procedural pain
Uncommon Post-operative fever

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V*

4.9 Overdose

No case of overdose has been reported.

No adverse events have been reported with prolonged instillation times exceeding 180 minutes (3 times the recommended instillation time), in one case 343 minutes. No adverse events have been reported in the dose-finding studies using twice the recommended concentration of hexaminolevulinate.

There is no experience of higher light intensity than recommended or prolonged light exposure.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Other diagnostic agents, ATC code: V04CX

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 1072 evaluable patients with known bladder cancer or high suspicion 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 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 study 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.

 

Mechanism of Action:

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.

5.2 Pharmacokinetic properties

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%.

5.3 Preclinical safety data

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.

 

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Powder: None

Solvent:

  • Disodium phosphate dihydrate
  • Potassium dihydrogen phosphate
  • Sodium chloride
  • Hydrochloric acid
  • Sodium hydroxide
  • Water for injections

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products.

6.3 Shelf life

3 years

After dilution with the solvent: Chemical and physical stability of the solution has been demonstrated for 2 hours at 2°C – 8°C. From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 2 hours at 2°C – 8°C.

 6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

Solution (after reconstitution): See section 6.3.

6.5 Nature and content of container

Pack of one 10 ml Type I colourless glass vial with butyl rubber stopper containing powder, and one 50 ml polypropylene vial containing solvent.

6.6 Special precautions for disposal and other handling

No special requirements for disposal.

Hexaminolevulinate may cause sensitisation by skin contact.

Handling instructions for the pharmacist or other healthcare professionals:

All steps should be performed with sterile equipment and under aseptic conditions.

  1. Withdraw 50.0 ml of the solvent for Hexvix into a sterile 50 ml syringe.
  2. Inject about 10 ml of this solvent into the vial of Hexvix powder.
  3. Without withdrawing the needle from the vial, hold the powder vial and the syringe in a firm grip and shake gently to ensure complete dissolution.
  4. Withdraw all of the dissolved solution from the powder vial into the syringe. Gently mix the contents of the syringe.
  5. Hexvix is now reconstituted and ready for use. The appearance of the reconstituted solution is clear to slightly opalescent, and colourless to pale yellow.

For single use only. Any unused product should be discarded.

7 MARKETING AUTHORISATION HOLDER

Name and address of MA holder per country

8 MARKETING AUTHORISATION NUMBER

MA number specific per country

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation (Sweden): 17 September 2004
Date of latest renewal (Sweden): 17 September 2009

10 DATE OF REVISION OF THE TEXT

English version approved 12 August 2015