Consumer medicine information

HEXVIX

Hexaminolevulinate

BRAND INFORMATION

Brand name

Hexvix Powder for intravesical solution

Active ingredient

Hexaminolevulinate

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using HEXVIX.

What is in this leaflet

This leaflet answers some common questions about Hexvix powder for intravesical solution and diluent.

It does not contain all the available information.

It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. In deciding to give you. Hexvix, your doctor has weighed the risks of you taking Hexvix against the benefits it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with this medicine.

You may need to read it again.

What Hexvix is used for

Hexvix is for diagnostic use only.

Hexvix blue light fluorescence cystoscopy is used as an 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.

Hexvix is not recommended for use in children.

Your doctor may have prescribed this medicine for another reason.

Ask your doctor or pharmacist if you have any questions about why this medicine has been prescribed for you.

Before you take it

When you must not use Hexvix

  1. Do not use Hexvix if you are allergic to hexaminolevulinate hydrochloride or any of the ingredients listed at the end of this leaflet.
  2. Do not use Hexvix if you have been diagnosed with porphyria.
  3. Do not use Hexvix if you are suffering from haematuria or blood in the urine.
  4. Do not use Hexvix if you have bladder inflammation, a recent urinary tract infection or BCG treatment.
  5. Do not use Hexvix if you are pregnant or intending to get pregnant.
  6. Do not breastfeed if you are using Hexvix as the drug may be found in breast milk.

Talk to your doctor if you are unsure whether you have any of the conditions listed above.

Do not use Hexvix after the expiry (EXP) printed on the pack.

It you use the medicine after the expiry date has passed, it may not work as well.

Do not use Hexvix if the packaging is torn or shows signs of tampering.

Do not use it to treat any other complaint unless your doctor says it is safe. Do not give this medicine to anyone else.

Before you start to use Hexvix

Tell your doctor if you are pregnant or intend to become pregnant.

Tell your doctor if you are breastfeeding or planning to breastfeed.

Tell your doctor if you have or have had any medical conditions, especially the following:

  • Porphyria
  • Bladder inflammation, urinary tract infection or recent BCG treatment.
  • Haematuria or blood in urine.

If you have not told your doctor about any of the above, tell them before you use this medicine.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you buy without a prescription from your pharmacy, supermarket or health food store.

Some medicines may be affected by Hexvix, or may affect how well Hexvix works.

You need to tell your doctor if you are using any other medicines.

If you are unsure whether you are taking one of the drugs that may interact with Hexvix, ask your doctor or pharmacist.

Your doctor or pharmacist can tell you what to do if you are taking any of such medicines.

If you have not told your doctor about any of these things, tell them before you take Hexvix.

How to use Hexvix

How to give it

Hexvix powder for intravesical solution and diluent will only be given in hospitals by qualified practitioners.

The bladder has to completely empty before instilling Hexvix.

The powder will be reconstituted with the entire contents of diluent.

50 mL of the reconstituted solution is instilled into the bladder through a catheter. You are required to retain the fluid for approximately 60 minutes.

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

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

How much to give

The entire content of the reconstituted solution is required to be given each time.

While you are using Hexvix

Things you must do

Be sure to keep all of your doctor appointments so that your progress can be checked.

Tell all the doctors, dentists and pharmacists who are treating you that you were administered with Hexvix.

Tell your doctor if you become or intend to become pregnant while using Hexvix.

Things you must not do

Do not use Hexvix for any other purpose.

Do not give this medicine to anyone else, even if they have the same condition as you.

Things to be careful of

If you are going to have surgery, tell the anaesthetist that you have used Hexvix.

Side Effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while using Hexvix.

All medicines can have side effects.

Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

Tell your doctor if you notice any of the following and they worry you:

  • Headache
  • Nausea
  • Vomiting
  • Constipation
  • Diarrhoea
  • Bladder spasm or contraction of the bladder without warning causing an urgent need to release urine or bladder incontinence
  • Bladder pain
  • Dysuria or painful or difficult urination
  • Urinary retention or inability to completely empty the bladder
  • Haematuria or presence of blood in the urine
  • Pyrexia or fever
  • Post procedural pain

Tell your doctor immediately if you notice any of the following:

  • Bladder spasm
  • Bladder pain
  • Blood in urine
  • Painful or difficulty in urination

These may be serious side effects of Hexvix.

If any of the above symptoms occurs or you suspect any other drug reaction, please consult your doctor immediately.

Other side effects not listed above may also occur in some patients.

Tell your doctor if you notice anything else that is making you feel unwell.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

Your doctor will monitor you very carefully for side effects.

After using Hexvix

Storage

Hexvix should be stored at 25°C.

It should be used immediately after reconstitution. If storage is necessary, hold at 2-8 °C for not more than 2 hours. The reconstituted solution, if stored at 2 – 8°C, should be allowed to warm to room temperature before instilling into the bladder.

Product description

What it looks like

Hexvix is provided as a kit containing 1 vial of the powder and 1 container of the diluent.

Hexvix powder is a sterile, freeze-dried white to off-white or pale yellow powder. Each vial contains 100 mg of Hexaminolevulinate hydrochloride, equivalent to 85mg of the active ingredient hexaminolevulinate.

The diluent for reconstitution is a sterile, clear, colourless solution.

Ingredients

Powder

Active Ingredient:
hexaminolevulinate (as hydrochloride) 85mg.

Other Ingredients:
There are no excipients.

Diluent contains:

  • dibasic sodium phosphate dehydrate,
  • monobasic potassium phosphate
  • sodium chloride,
  • hydrochloric acid,
  • sodium hydroxide and
  • water for injections.

Manufacturer

Hexvix is supplied in Australia by:

Juno Pharmaceuticals Pty Ltd
Level 2, 6 Bond Street,
South Yarra, VIC – 3141

This leaflet was prepared in August 2016.

BRAND INFORMATION

Brand name

Hexvix Powder for intravesical solution

Active ingredient

Hexaminolevulinate

Schedule

S4

 

1 Name of Medicine

Hexvix contains hexaminolevulinate hydrochloride.

2 Qualitative and Quantitative Composition

Hexvix powder is a sterile, freeze-dried white to off-white or pale yellow powder. Each vial contains 100 mg of hexaminolevulinate hydrochloride, equivalent to 85 mg of the active ingredient hexaminolevulinate. There are no excipients.
The diluent for reconstitution is a sterile, clear, colourless solution containing dibasic sodium phosphate dihydrate, monobasic potassium phosphate, sodium chloride, hydrochloric acid, sodium hydroxide and water for injections.
After reconstitution in 50 mL of diluent, 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 List of Excipients.

3 Pharmaceutical Form

Hexaminolevulinate (as hydrochloride) 85 mg powder for intravesical solution plus diluent.

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.

4.2 Dose 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 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 noninformative.
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 cystoscopic equipment equipped with necessary filters to allow both standard white light cystoscopy and blue light (wavelength 380-450 nanometre) fluorescence cystoscopy should be used.
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.

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) Fasten the plunger rod into the rubber stopper of the syringe by turning the plunger rod clockwise until it stops.
2) Remove the cap from the syringe and keep it for later use. Connect a needle suitable for reconstitution to the syringe. Hold the syringe upright and carefully press the plunger rod upward to remove air.
3) Inject about 10 mL of this diluent into the vial of Hexvix powder. The vial should be about 3/4 full.
4) 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.
5) Withdraw all of the dissolved solution from the powder vial into the syringe.
6) Disconnect the empty vial from the syringe. Disconnect the needle from the syringe tip and discard it. Plug the syringe with the syringe cap. 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.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed (see Section 2 Qualitative and Quantitative Composition).
Hexvix is contraindicated in porphyria and gross haematuria.

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 Adverse Effects (Undesirable Effects)). Advanced life support facilities should be readily available.
Postmarketing 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.
Hexvix 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.

Use in the elderly.

See Section 4.2 Dose and Method of Administration.

Paediatric use.

No data available.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

This medicinal product must not be mixed with other medicinal products.
No specific interaction studies have been performed with hexaminolevulinate.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Hexaminolevulinate hydrochloride had no effects on fertility and reproductive performance indices in female rats at an IV dose of 100 mg/kg/day (yielding 130 times the exposure in patients at the maximum recommended dose, on a body surface area (BSA) basis, assuming 7% bioavailability in humans) from 2 weeks before mating until gestation day 6. Male fertility has not been investigated in animals.
There are no or limited data on the use of hexaminolevulinate in pregnant women. Reproductive toxicity has been investigated in rats and rabbits. The incidences of embryofetal mortality, fetal weights, and fetal abnormalities and variants, including skeletal ossification parameters did not indicate any obvious effect of treatment in rats receiving hexaminolevulinate doses up to 150 mg/kg/day IV (yielding 195 times the exposure in patients at the maximum recommended dose, on a body surface area (BSA) basis, assuming 7% bioavailability in humans) or in rabbits at up to 40 mg/kg/day IV (relative exposure based on BSA, 104 times). As a precautionary measure, (and since the animal studies were not conducted with photostimulation), it is preferable to avoid the use of Hexvix during pregnancy.
It is unknown whether hexaminolevulinate/ metabolites are excreted in human milk. A risk to the newborns/ infants cannot be excluded. The excretion of hexaminolevulinate, its metabolites or PPIX in milk has not been studied in animals. Breastfeeding should be discontinued during the treatment with Hexvix.

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 Adverse Effects (Undesirable Effects)

Hypersensitivity, including anaphylactoid shock (4 cases in > 350,000 exposures), has been reported postmarketing following exposure to Hexvix.
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.
Table 1 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).

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at http://www.tga.gov.au/reporting-problems.

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.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

Hexaminolevulinate hydrochloride is a blue light cystoscopy imaging agent. It is a white to slightly yellow powder which has been shown to add water at relative humidities higher than approximately 62% RH at room temperature. Hexaminolevulinate is freely soluble in water and sparingly soluble in hexanol and acetone.
Hexvix Solution for intravesical use is available as a kit containing Hexvix powder and a diluent for reconstitution.

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.

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, malignant lesions will glow red on a blue background. False fluorescence may be seen as a result of inflammation.

Clinical trials.

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 randomised, 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).
There were fewer patients with progression to muscle invasive disease in the Hexvix group compared with the white light group, 8 patients (3.1%) versus 16 patients (6.1%), respectively over the 4.5 years follow-up period. The difference between the groups approached statistical significance for tumor stage at worst recurrence (p = 0.066) but less so for first recurrence (p = 0.102). Fewer patients in the Hexvix group compared to white light group had to undergo cystectomy, (13 (4.8%)) patients compared to (22 (7.9%)) patients (p = 0.162).
Hospitalisation due to bladder cancer was 72 (26.6%) patients in the Hexvix group and 79 (28.2%) patients in the white light group. There were 44 (15.7%) deaths in the white light group and 39 (14.4%) in the Hexvix group with 8 (2.9%) and 6 (2.2%), known bladder cancer related deaths respectively. Patients in both groups were hospitalised for bladder cancer a mean of 1.0 times, although 20 (7.4%) patients in the Hexvix group and 13 (4.6%) patients in the white light group were hospitalised four or more times.
In an open label, randomised phase 3 two centre study patients with nonmuscle invasive papillary tumours were compared for recurrence after Hexvix and white light guided TURBT. A secondary endpoint was to detect lesion detection rates. 79 and 86 patients were eligible in the two groups respectively. Recurrence rates at 4 months after TURB were 25.3% in the Hexvix group and 34.9% in the white light group. At 12 months the recurrence rates were similar in the ITT analysis set. Of the 90 patients with at least one tumor, 44 (48.9%) had at least one tumor detected in blue light that was not detected in WL.
Sensitivity and specificity of Hexvix was determined in a phase 2 study in 52 patients with suspected primary or recurrent bladder cancer. Biopsies were taken from all fluorescent and nonfluorescent lesions as well as additional 5 random biopsies from normal bladder tissue. The lesion sensitivity under blue light cystoscopy was 76% compared to 46% under standard white light. Lesion specificity in blue light cystoscopy was 79% compared to 93% in standard white light. The specificity in blue light is related to a higher false positive, 20% vs 7% in blue and white light respectively. Of the 13 patients with CIS tumours 12 were diagnosed with Hexvix. (See Table 2).
False positive fluorescence may lead to additional biopsy. The benefit of finding more lesions that can be treated outweighs the risk of a possible extra biopsy.
An integrated analysis across the phase 3 studies indicated an overall rate of finding false positive lesions was increased after blue light cystoscopy, 17.3% for the white light cystoscopy and 21.9% for blue light cystoscopy with Hexvix.

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 low, approximately 7% (range from 5-10%), Cmax 343 nanogram/mL and tmax 1 hour.
The elimination of hexaminolevulinate is biphasic with a rapid initial disposition phase with a half-life of 39 minutes, followed by a longer second disposition phase with a half-life of approximately 76 hours.

5.3 Preclinical Safety Data

Genotoxicity.

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).
There are reports of genotoxic potential for the metabolite aminolevulinic acid (5-ALA).

Carcinogenicity.

Carcinogenicity studies have not been performed with hexaminolevulinate.

6 Pharmaceutical Particulars

6.1 List of Excipients

Hexvix powder.

No excipients.

Diluent.

Sodium chloride, hydrochloric acid, sodium hydroxide, water for injections.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

4 years.
In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

The storage conditions for the vial presentation is as below:
Store below 30°C.

After dilution with the diluent.

To reduce microbiological hazard, use as soon as practicable after reconstitution/preparation. If storage is necessary, hold at 2-8°C for not more than 2 hours. The reconstituted solution, if stored at 2-8°C, should be allowed to warm to room temperature before instilling into the bladder.

6.5 Nature and Contents of Container

Hexvix is provided as a kit containing 85 mg hexaminolevulinate (as hexaminolevulinate hydrochloride) powder and 50 mL of the reconstitution diluent.
Hexvix powder is packaged in a 10 mL type I, clear glass vial. This vial is closed with grey butyl rubber stopper and sealed with an aluminium seal. The diluent is packaged in a sterile syringe.
Hexvix powder is intended to be reconstituted with the diluent for Hexvix prior to administration.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Chemical name: (2S,5R,6R)-6-[[(2R)-2-amino-2-phenylacetyl]amino]-3,3-dimethyl-7-oxo- 4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate.

Chemical structure.


CAS number.

140898-91-5.
Molecular weight: 251.76.
Molecular formula: C11H21NO3.HCl.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription only Medicine.

Summary Table of Changes