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HEXVIX 85 MG POWDER AND SOLVENT FOR SOLUTION FOR INTRAVESICAL USE

Active substance(s): HEXAMINOLEVULINATE HYDROCHLORIDE / HEXAMINOLEVULINATE HYDROCHLORIDE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT

Hexvix 85 mg, powder and solvent for intravesical solution

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 an 8 mmol/l solution of hexaminolevulinate.
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM

Powder and solvent for intravesical solution.
Powder:
Solvent:

white to off-white or pale yellow
clear, colourless 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 section 5.1.

4.2

Posology and method of administration

Hexvix cystoscopy should only be performed by healthcare 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 considerably 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.
Method of administration
Precaution to be taken before handling or administrating the medicinal product.
For instructions on reconstitution of the medicinal product before administration, see section
6.6.

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.
Breast-feeding
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 haematuria 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 (TURB)
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 Organ
Class (MedDRA)

Frequency

Adverse reaction

Infections and infestations

Uncommon

Blood and lymphatic system
disorders
Immune system disorders
Metabolism and nutrition
disorders
Psychiatric disorders

Uncommon
Not known
Uncommon

Cystitis, sepsis, urinary tract
infection
White blood cell count increased,
anaemia
Anaphylactoid shock
Gout

Uncommon

Insomnia

Nervous system disorders

Common

Headache

Gastrointestinal disorders

Common

Hepatobiliary disorders

Uncommon

Skin and subcutaneous tissue
disorders
Musculoskeletal and connective
tissue disorders
Renal and urinary bladder
disorders

Uncommon

Nausea, vomiting, constipation,
diarrhoea
Increased serum bilirubin, hepatic
enzyme increased
Rash

Uncommon

Back pain

Common

Uncommon

Bladder spasm, bladder pain,
dysuria, urinary retention,
haematuria
Urethral pain, pollakuria, micturition
urgency, urinary tract disorder
Balanitis

Common

Pyrexia

Common
Uncommon

Post procedural pain
Post-operative fever

Uncommon
Reproductive system and breast
disorders
General disorders and
administration site conditions
Injury, poisoning and procedural
complications

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 Yellow
Card Scheme at: www.mhra.gov.uk/yellowcard

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 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=0.030.06 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, inuse 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.
For storage conditions after reconstitution of the medicinal product, see section 6.3.

6.5

Nature and contents of container

Pack of one 10 ml Type I colourless glass vial with butyl rubber stopper containing powder,
and one 50 ml polypropylene vial, or one 50 ml cyclic olefin copolymer syringe with plunger
stopper (bromobutyl rubber) and plunger rod, containing solvent.
Pack sizes:
Pack containing 1 vial with powder and 1 polypropylene vial with solvent
Pack containing 1 vial with powder and 1 prefilled syringe with solvent, with or without a
Mini-Spike transfer device
Not all pack sizes may be marketed.

6.6

Special precautions for disposal

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. A brief
description of the reconstitution procedure is provided below. For detailed description, see
package leaflet section Instruction for handling.
1.
2.
3.
4.
5.
6.

Using a 50 ml syringe, inject about 10 ml of the solvent into the vial of Hexvix powder.
The vial should be about ¾ full.
Without withdrawing the syringe from the vial, hold the powder vial and the syringe in a
firm grip and shake gently to ensure complete dissolution.
Withdraw all of the dissolved solution from the powder vial into the syringe.
Disconnect the empty vial from the syringe and discard the vial.
Gently mix the contents of the syringe.
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
Ipsen Limited
190 Bath Road
Slough
SL1 3XE, UK.

8

MARKETING AUTHORISATION NUMBER(S)
PL 34926/0017

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
10/09/2009

10

DATE OF REVISION OF THE TEXT
12/08/2015

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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