Consumer medicine information

Gliolan

Aminolevulinic acid hydrochloride

BRAND INFORMATION

Brand name

Gliolan

Active ingredient

Aminolevulinic acid hydrochloride

Schedule

What is in this leaflet

This leaflet answers some common questions about Gliolan. 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. Your doctor has weighed the risks of you taking Gliolan against the benefits they expect it will have for you.

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

Keep this leaflet You may need to read it again.

What Gliolan is used for

This medicine is used for the visualisation of certain brain tumours (called glioblastoma multiforme) during tumour surgery.

Gliolan contains a substance called aminolevulinic acid hydrochloride (ALA HCl). ALA HCl accumulates preferably in tumour cells where it is transformed into another similar substance. If the tumour is then exposed to blue light this new substance emits a red-violet light, which helps the surgeon to better see what is normal tissue and what is tumour tissue. This helps the surgeon to remove the tumour while sparing healthy tissue.

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

This medicine is not addictive.

This medicine is available only with a doctor’s prescription.

This medicine is not expected to affect your ability to drive a car or operate machinery.

There is not enough information to recommend the use of this medicine for children under the age of 18 years.

Before you take it

When you must not take it

Do not take this medicine if you have an allergy to:

any medicine containing aminolevulinic acid hydrochloride or porphyrins (such as heme the pigment in red blood cells)

Some of the symptoms of an allergic reaction may include:

shortness of breath
wheezing or difficulty breathing
swelling of the face, lips, tongue or other parts of the body
rash, itching or hives on the skin

Do not take this medicine if you have, or may have, acute or chronic types of porphyria Porphyria is a rare blood pigment disorder. This disorder can be inherited or acquired during your lifetime.

Do not take this medicine if you are pregnant or suspect you may be pregnant. It may affect your developing baby if you take it during pregnancy.

If you are not sure whether you should take this medicine, talk to your doctor.

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

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

Heart disease. This medicine should be used with caution because the blood pressure maybe decreased.
Liver or kidney disease. This medicine should be used with caution as there is limited information on its use in patients with poor liver or kidney function.

Tell your doctor if you are breast-feeding. It is not known whether this medicine enters breast milk. Breast-feeding mothers should not breast-feed for 24 hours after treatment with this medicine.

Your doctor can discuss with you the risks and benefits involved.

If you have not told your doctor about any of the above, tell him/her before you start taking Gliolan.

Taking other medicines

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and Gliolan may interfere with each other particularly medicines that may cause skin problems, such as sunburn, when the skin comes under strong light. These include:

Some types of antibiotics such as tetracycline’s, sulfonamides and fluoroquinolones
Hypercin extracts used to treat mild forms of depression. One case of severe sunburn lasting for 5 days has been reported in a patient after having taken this medicine and a hypericin extract.
You should not take any such products for up to 2 weeks after you have taken Gliolan.
Any medicines known to harm the liver within 24 hours of having taken Gliolan

These medicines may be affected by Gliolan or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

Taking Gliolan with food and drink

You should not drink or eat for at least 6 hours before starting anaesthesia. This medicine is generally used once only, 2-4 hours before anaesthesia for surgery.

How to take it

Follow all directions given to you by your doctor or pharmacist carefully.

This medicine is a powder that must be mixed with drinking water before use.

This will be done for you by a pharmacist or a nurse.

How much to take

The usual dose is 20 mg Gliolan per kilogram body weight. The pharmacist or nurse will calculate the exact dose you need.

How to take it

You have to drink the prepared solution 2-4 hours before start of anesthesia. The solution has a sour taste when taken orally.

When to take it

You have to drink the prepared solution 2-4 hours before start of anesthesia.

If the anesthesia/surgery is delayed by some hours, additional doses of this medicine must not be given. If the surgery is delayed by one or more days, another dose of this medicine can be taken 2-4 hours before start of anesthesia.

If you forget to take Gliolan

This medicine is given once only on the day of surgery, 2-4 hours before start of anesthesia. If you have forgotten to take this medicine during this time period, it is not advisable to take it just before start of anesthesia. In this case, anesthesia and surgery must be postponed for at least 2 hours, if possible.

If you take too much (overdose)

If you have taken more Gliolan than you should, your doctor will decide on any necessary measures to avoid any problems, including sufficient protection from strong light (for example direct sunlight).

Symptoms of an overdose may include skin rash and problems breathing.

While you are using it

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you have recently taken, or due to be given Gliolan.

Tell any other doctors, dentists, and pharmacists who treat you that you have recently taken or are due to be treated with Gliolan.

If you are going to have surgery, tell the surgeon or anaesthetist about all other medicines you have taken at least in the 4 weeks before your surgery.

If you are required to have any blood tests after your surgery, tell your doctor that you have taken this medicine. It may interfere with the results of some tests.

Things you must not do

Do not take Gliolan to treat any other complaints unless your doctor tells you to.

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

Things to be careful of

Protect your eyes and skin from strong light (for example direct sunlight or brightly focused indoor light) for 24 hours after administration of this medicine.

Side effects

Some of the side effects listed are due to a combination of the medicine, anaesthesia and the surgery. Other side effects may occur after having taken Gliolan and before start of anaesthesia.

Ask your doctor or pharmacist to answer any questions you may have.

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

nausea (unsettled stomach)
vomiting (sickness)
skin reaction, which may look like sunburn
decrease in your blood pressure, which you experience as feeling weak or dizzy.

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

neurological disorders (disorders that affect the nervous system) like:
- hemiparesis (partial paralysis of one side of the body),
- aphasia (total or partial loss of ability to use or understand language),
- convulsions (seizures) and
- hemianopsia (blindness for half the field of vision in one or both eyes);
thromboembolism (blood clots that may obstruct blood vessels). The symptoms may include:
- paresthesias (abnormal nerve sensations such as pins-and-needles, tingling, burning, prickling or similar feelings)
- weakness
- numbness;
pulmonary embolism (a blood clot that moves to the lungs). The symptoms are typically sudden in onset and may include:
- chest pain
- shortness of breath or rapid breathing
- cough
- fast heart rate or palpitations;
Symptoms of brain oedema (swelling of the brain) that can include one or more of the following:
- headache
- neck pain
- nausea or vomiting
- dizziness.

The following side effects can also occur however these would only be found when your doctor does tests after surgery to check your progress;

mild alterations of blood cell counts (red and white cells, platelets)
slight increase of some enzymes (transaminases, γ-GT, amylase),
or
bilirubin (a bile pigment produced in the liver by breakdown of red blood pigment in the blood)

These side effects are usually mild and short-lived and will completely resolve within a few weeks. Usually you would not experience any symptoms at all when these changes occur.

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

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

Product description

What it looks like

This medicine is a powder for oral solution. It is a white to off-white cake powder stored in a glass vial.

When the powder is dissolved in water the solution is clear and colourless, to slightly yellowish fluid.

Gliolan is provided in a glass vial and presented in packs of 1, 2 and 10 vials. Not all pack sizes may be marketed.

Ingredients

Gliolan contains aminolevulinic acid hydrochloride as the active ingredient.

One vial contains 1.5 g aminolevulinic acid hydrochloride (ALA HCl), equivalent to 1.17 g of aminolevulinic acid, hydrochloride (ALA HCl).

One mL of reconstituted solution contains 30 mg aminolevulinic acid hydrochloride (ALA HCl), equivalent to 23.4 mg of aminolevulinic acid.

This medicine does not contain lactose, sucrose, gluten, tartrazine or any other azo dyes.

Sponsor

Gliolan is supplied in Australia by:

Specialised Therapeutics Glio Pty Ltd
Level 2, 17 Cotham Road
Kew, Victoria 3101
Ph: 1300 798 820
Fax: 1800 798 829
www.stbiopharma.com.au

Gliolan is supplied in New Zealand by:

Specialised Therapeutics Limited
Level 1, The Lane,
Botany Town Centre
588 Chapel Road, East Tamaki,
Auckland 2013, New Zealand
Tel: +64 9801 0299
Fax: +64 9801 0118

Under licence from: photonamic GmbH & Co. KG

This leaflet was prepared in May 2018.

30 mg/mL: AUST R number 202549

Published by MIMS October 2018

BRAND INFORMATION

Brand name

Gliolan

Active ingredient

Aminolevulinic acid hydrochloride

Schedule

1 Name of Medicine

Aminolevulinic acid hydrochloride 30 mg/mL powder for oral solution.

2 Qualitative and Quantitative Composition

One vial contains 1.5 g of aminolevulinic acid hydrochloride (ALA HCl), equivalent to 1.17 g of aminolevulinic acid.
One mL of reconstituted solution contains 30 mg of aminolevulinic acid hydrochloride (ALA HCl), equivalent to 23.4 mg of aminolevulinic acid.

Excipient(s) with known effect.

For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Gliolan is supplied in a vial as a powder for oral solution.
The powder is a white to off-white cake.

4 Clinical Particulars

4.1 Therapeutic Indications

Gliolan is indicated in adult patients for visualisation of malignant tissue during surgery for malignant gliomas that are glioblastoma multiforme (GBM) on preoperative imaging, and who are intended for resection of the tumour.

4.2 Dose and Method of Administration

Dose.

The recommended dose is 20 mg aminolevulinic acid hydrochloride per kilogram body weight.
Special populations.

Elderly.

There are no special instructions for use in elderly patients with regular organ function.

Renal or hepatic impairment.

No trials have been performed in patients with clinically relevant hepatic or renal impairment. Therefore, Gliolan should be used with caution in such patients.

Paediatric population.

The safety and efficacy of ALA in children and adolescents aged 0 to 18 years has not yet been established. No data are available.

Method of administration.

The solution should be administered orally three hours (range 2-4 hours) before anaesthesia. Use of ALA under conditions other than the ones used in the clinical trials entail an undetermined risk.
If the surgery is postponed by more than 12 hours, surgery should be re-scheduled for the next day or later. Another dose of this medicine can be taken 2 - 4 hours before anaesthesia.
For instructions on reconstitution of the medicine before administration, see Section 6.6 Special Precautions for Disposal.

4.3 Contraindications

Hypersensitivity to ALA or porphyrins or to any of the excipients listed in List of Excipients).
Acute or chronic types of porphyria.
Pregnancy (see Section 4.6 Fertility, Pregnancy and Lactation; Section 5.3 Preclinical Safety Data for further information).

4.4 Special Warnings and Precautions for Use

Gliolan should only be used by experienced neurosurgeons conversant with surgery of malignant gliomas and in-depth knowledge of functional brain anatomy who have completed a training course in fluorescence-guided surgery.
ALA-induced fluorescence of brain tissue does not provide information about the tissue's underlying neurological function. Therefore, resection of fluorescing tissue should be weighed up carefully against the neurological function of fluorescing tissue.
Special care must be taken in patients with a tumour in the immediate vicinity of an important neurological function and pre-existing focal deficits (e.g. aphasia, vision disturbances and paresis etc.) that do not improve on corticosteroid treatment. Fluorescence-guided resection in these patients has been found to impose a higher risk of critical neurological deficits. A safe distance to eloquent cortical areas and subcortical structures of at least 1 cm should be maintained independent of the degree of fluorescence.
In all patients with a tumour in the vicinity of an important neurological function, either pre- or intraoperative measures should be used to localise that function relative to the tumour in order to maintain safety distances.
False negative and false positive results may occur with the use of 5-ALA for intraoperative visualisation of malignant glioma. Non-fluorescing tissue in the surgical field does not rule out the presence of tumour in patients with glioma. On the other hand, fluorescence may be seen in areas of abnormal brain tissue (such as reactive astrocytes, atypical cells), necrotic tissue, inflammation, infections (such as fungal or bacterial infections and abscesses), CNS lymphoma or metastases from other tumour types.
After administration of Gliolan, exposure of eyes and skin to strong light sources (e.g. operating illumination, direct sunlight or brightly focused indoor light) should be avoided for 24 hours.
Co-administration with other potentially phototoxic substances (e.g. tetracyclines, sulfonamides, fluoroquinolones, hypericin extracts) should be avoided (see Section 5.3 Preclinical Safety Data).
Within 24 hours after administration, other potentially hepatotoxic medicinal products should be avoided.
In patients with pre-existing cardiovascular disease, Gliolan should be used with caution since literature reports have shown decreased systolic and diastolic blood pressures, pulmonary artery systolic and diastolic pressure as well as pulmonary vascular resistance.

Use in the elderly.

See Section 4.2 Dose and Method of Administration, Special populations.

Paediatric use.

See Section 4.2 Dose and Method of Administration, Special populations.

Effects on laboratory tests.

See Section 4.8 Adverse Effects (Undesirable Effects).

4.5 Interactions with Other Medicines and Other Forms of Interactions

Patients should not be exposed to any photosensitising agent up to 2 weeks after administration of Gliolan.
In the absence of compatibility studies, Gliolan must not be mixed with other medicinal products, see Section 6.6 Special Precautions for Disposal.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There are no data available regarding the influence of Gliolan on fertility.
(Category C)
There are no or limited amount of data from the use of Gliolan in pregnant woman. Some limited animal studies suggest an embryotoxic activity of ALA plus light exposure (see Section 5.3 Preclinical Safety Data). Therefore, Gliolan should not be used during pregnancy.
It is unknown whether ALA or its metabolite protoporphyrin IX (PPIX) is excreted in human breast milk. The excretion of ALA or PPIX in milk has not been studied in animals. Breast-feeding should be interrupted for 24 hours after treatment with Gliolan.

4.7 Effects on Ability to Drive and Use Machines

Not relevant, as the surgical procedure itself will have an influence on the ability to drive and use machines.

4.8 Adverse Effects (Undesirable Effects)

Summary of the safety profile.

Adverse reactions observed after the use of Gliolan for fluorescence-guided glioma resection are divided into the following two categories:
immediate reactions occurring after oral administration of the medicinal product before anaesthesia (= active substance-specific side effects);
combined effects of ALA, anaesthesia, and tumour resection (= procedure-specific side effects).
Side effects of concern were photosensitivity as substance-related effect; neurological disorders (e.g. convulsions, hemiparesis, and aphasia); pulmonary embolism that were more frequent in patients receiving ALA and surgery; and anaemia, thrombocytopenia and leukocytosis seen with equal frequency after surgery, with and without ALA. Further frequently observed side effects are vomiting, nausea and increase of blood bilirubin, alanine aminotransferase, aspartate aminotransferase, gamma glutamyltransferase and blood amylase.

Tabulated summary of adverse reactions.

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).

Substance specific side effects.

See Table 1.

Procedure related side effects.

The extent and frequency of procedure related neurological side effects depends on the localisation of the brain tumour and the degree of resection of tumour tissue lying in eloquent brain areas (see Section 4.4 Special Warnings and Precautions for Use). See Table 2.

Description of selected adverse reactions.

In a single-arm trial including 21 healthy male volunteers, erythema of the skin could be provoked by direct exposure to UVA light up to 24 hours after oral application of 20 mg/kg body weight ALA HCl. An adverse drug reaction of mild nausea was reported in 1 out of 21 volunteers.
In another single-centre trial, 21 patients with malignant glioma received 0.2, 2, or 20 mg/kg body weight ALA HCl followed by fluorescence-guided tumour resection. The only adverse reaction reported in this trial was one case of mild sunburn occurring in a patient treated with the highest dose.
In a single-arm trial including 36 patients with malignant glioma, drug reactions were reported in four patients (mild diarrhoea in one patient: moderate hypesthesia in another patient: moderate chills in another patient, and arterial hypotension 30 minutes after application of ALA in another patient). All patients received the medicinal product in a dose of 20 mg/kg body weight and underwent fluorescence-guided resection. Follow-up time was 28 days.
In a comparative, unblinded phase III trial (MC-ALS.3/GLI), 201 patients with malignant gliomas received ALA HCl in a dose of 20 mg/kg body weight and 176 of these patients underwent fluorescence-guided resection with subsequent radiotherapy. 173 patients received standard resection without administration of the medicinal product and subsequent radiotherapy. Follow-up time comprised at least 180 days after administration. At least possibly related adverse reactions were reported in 2/201 (1.0%) patients: mild vomiting 48 hours after trial surgery, and mild photosensitivity 48 hours after study surgery. In patients undergoing fluorescence-guided resection, the incidence of pulmonary embolism was significantly increased (7.4% cf 1.2%, p=0.006). However, the median time of onset of pulmonary embolism after study surgery was 35 days (range 1-150 days). Another patient accidentally received an overdose of the medicinal product (3000 mg instead of 1580 mg). Respiratory insufficiency, which was reported in this patient, was managed by adaptation of ventilation and resolved completely. A more pronounced transient increase of liver enzymes without clinical symptoms was observed in the ALA treated patients. Peak values occurred between 7 and 14 days after administration. Increased levels of amylase, total bilirubin, and leukocytes, but decreased levels of thrombocytes and erythrocytes were observed, however differences between treatment groups were not statistically significant.
Table 3 shows adverse events reported with a frequency of > 1% of patients in this trial.

Table 4 shows serious adverse events reported with a frequency of > 1% of patients observed in this trial up until 180 days after study surgery.

Tables 5 and 6 show the percentage of patients with laboratory parameters out of normal range observed in trial MC-ASP.3/GLI.

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 to www.tga.gov.au/reporting-problems.

4.9 Overdose

Within a clinical trial, a 63-year old patient with known cardiovascular disease was accidentally given an overdose of ALA HCl (3000 mg instead of 1580 mg). During surgery he developed respiratory insufficiency, which was managed by adaptation of ventilation. After surgery the patient also displayed facial erythema. It was stated that the patient had been exposed to more light than permitted for the trial. Respiratory insufficiency and erythema completely resolved.
In the event of overdose, supportive measures should be provided as necessary, including sufficient protection from strong light sources (e.g. direct sunlight).
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antineoplastic agents, sensitisers used in photodynamic therapy, ATC code: L01XD04.

Mechanism of action.

Aminolevulinic acid (ALA) is a natural biochemical precursor of heme that is metabolised in a series of enzymatic reactions to fluorescent porphyrins, particularly PPIX. ALA synthesis is regulated by an intracellular pool of free heme via a negative feedback mechanism. Administration of excess exogenous ALA avoids the negative feedback control, and accumulation of PPIX occurs in target tissue. In the presence of visible light, fluorescence of PPIX (photodynamic effect) in certain target tissues can be used for photodynamic diagnosis.

Pharmacodynamic effects.

Systemic administration of ALA results in an overload of the cellular porphyrin metabolism and accumulation of PPIX in various epithelia and cancer tissues. Malignant glioma tissue (WHO-grade III and IV, e.g. glioblastoma, gliosarcoma or anaplastic astrocytoma) has also been demonstrated to synthesise and accumulate porphyrins in response to ALA administration. The concentration of PPIX is significantly lower in white matter than in cortex and tumour. Tissue surrounding the tumour and normal brain may also be affected. However, ALA induced PPIX formation is significantly higher in malignant tissue than in normal brain.
In contrast, in low-grade tumours (WHO-grade I and II, e.g. oligodendroglioma) no fluorescence could be observed after application of the active substance. Medulloblastoma or brain metastases revealed inconsistent results or no fluorescence.
The phenomenon of PPIX accumulation in WHO-grade III and IV malignant gliomas may be explained by higher ALA uptake into the tumour tissue or an altered pattern of expression or activity of enzymes (e.g. ferrochelatase) involved in haemoglobin biosynthesis in tumour cells.
Explanations for higher ALA uptake include a disrupted blood-brain barrier, increased neo-vascularisation, and the overexpression of membrane transporters in glioma tissue.
After excitation with blue light (lambda = 400-410 nanometre), PPIX is strongly fluorescent (peak at lambda = 635 nanometre) and can be visualised after appropriate modifications to a standard neurosurgical microscope.
Fluorescence emission can be classified as intense (solid) red fluorescence (corresponds to vital, solid tumour tissue) and vague pink fluorescence (corresponds to infiltrating tumour cells), whereas normal brain tissue lacking enhanced PPIX levels reflects the violet-blue light and appears blue.

Clinical trials.

In a phase I/II trial including 21 patients, a dose-efficacy relationship between the dose levels and the extent and quality of fluorescence in the tumour core was detected: higher doses of ALA enhanced the fluorescence quality and the fluorescence extent of the tumour core compared to demarcation of the tumour core under standard white illumination in a monotone, non-falling fashion. The highest dose (20 mg/kg body weight) was determined to be the most efficient.
A positive predictive value of tissue fluorescence of 84.8% (90% CI: 70.7%-93.8%) was found. This value was defined as the percentage of patients with positive tumour cell identification in all biopsies taken from areas of weak and strong fluorescence. The positive predictive value of strong fluorescence was higher (100.0%; 90% CI: 91.1%-100.0%) than of weak fluorescence (83.3%; 90% CI: 68.1%-93.2%). Results were based on a phase II trial including 33 patients receiving ALA HCl in a dose of 20 mg/kg body weight.
The resulting fluorescence was used as an intraoperative marker for malignant glioma tissue with the aim of improving the surgical resection of these tumours.
In a phase III trial with 349 patients with suspected malignant glioma amenable to complete resection of contrast-enhancing tumour were randomised to fluorescence-guided resection after administration of 20 mg/kg body weight ALA HCl or conventional resection under white light. Contrast-enhancing tumour was resected in 64% of patients in the experimental group compared to 38% in the control-group (p < 0.0001).
At the visit six months after tumour resection, 20.5% of ALA treated patients and 11% of patients who underwent standard surgery were alive at the six-month visit without progression. The difference was statistically significant using the chi-square test (p=0.015). No significant increase in overall survival has been observed in this trial, however, it was not powered to detect such a difference.

5.2 Pharmacokinetic Properties

General characteristics.

Gliolan shows good solubility in aqueous solutions. After ingestion, ALA itself is not fluorescent but is taken up by tumour tissue (see Section 5.1 Pharmacodynamic Properties) and is intracellularly metabolised to fluorescent porphyrins, predominantly PPIX.

Absorption.

ALA as drinking solution is rapidly and completely absorbed and peak plasma levels of ALA are reached 0.5-2 hours after oral administration of 20 mg/kg body weight. The median (range) C_max value was 20.8 (11.6 - 27.7) mg/L in normal subjects and 8.2 (7.4 - 9.7) mg/L in patients. The reason for the difference has not been established. Plasma levels return to baseline values 24 hours after administration of an oral dose of 20 mg/kg body weight. The influence of food has not been investigated because Gliolan is generally given on empty stomach prior to induction of anaesthesia.

Distribution and metabolism.

ALA is preferentially taken up by the liver, kidney, endothelials and skin as well as by malignant gliomas (WHO-grade III and IV) and metabolised to fluorescent PPIX. Four hours after oral administration of 20 mg/kg body weight ALA HCl, the maximum PPIX plasma level is reached. PPIX plasma levels rapidly decline during the subsequent 20 hours and are not detectable anymore 48 hours after administration. At the recommended oral dose of 20 mg/kg body weight, tumour to normal brain fluorescence ratios are usually high and offer lucid contrast for visual perception of tumour tissue under violet-blue light for at least 9 hours.
Besides tumour tissue, faint fluorescence of the choroid plexus was reported. ALA is also taken up and metabolised to PPIX by other tissues, e.g. liver, kidneys or skin (see Section 4.4 Special Warnings and Precautions for Use). Plasma protein binding of ALA is unknown.

Excretion.

ALA is eliminated quickly with a terminal half-life of 1-3 hours. The shorter half-life was seen in normal subjects and the longer half-life in patients. Approximately 30% of an orally administered dose of 20 mg/kg body weight is excreted unchanged in urine within 12 hours.

Linearity/nonlinearity.

By regression analysis, the AUC_0-inf of ALA plasma levels versus dose was linear over the dose range (0.2, 2, and 20 mg/kg) studied (R² = 0.9998). Dose proportionality was not found for the active metabolite, PPIX, within 12 hours in normal patients.

Renal or hepatic impairment.

Pharmacokinetics of ALA in patients with renal or liver impairment has not been investigated.

5.3 Preclinical Safety Data

Standard safety pharmacology experiments were performed under light protection in the mouse, rat and dog. ALA administration does not influence the function of the gastro-intestinal and central nervous system. A slight increase in saluresis cannot be excluded.
Single administration of high doses of ALA to mice or rats leads to unspecific findings of intolerance without macroscopic abnormalities or signs of delayed toxicity. Repeat-dose toxicity studies performed in rats and dogs demonstrate dose-dependent adverse reactions affecting changes in bile duct histology (non-reversible within a 14 day recovery period), transient increase in transaminases, LDH, total bilirubin, total cholesterin, creatinine, urea and vomiting (only in dogs). Signs of systemic toxicity (cardiovascular and respiratory parameters) occurred at higher doses in the anaesthetised dog: at 45 mg/kg body weight intravenously a slight decrease in peripheral arterial blood pressure and systolic left ventricular pressure was recorded. Five minutes after administration, the baseline values had been reached again. The cardiovascular effects seen are considered to be related to the intravenous route of administration.
Phototoxicity observed after ALA treatment in vitro and in vivo is obviously closely related to dose- and time-dependent induction of PPIX synthesis in the irradiated cells or tissues. Destruction of sebaceous cells, focal epidermal necrosis with a transient acute inflammation and diffuse reactive changes in the keratinocytes as well as transient secondary oedema and inflammation of dermis are observed. Light exposed skin recovered completely except for a persistent reduction in the number of hair follicles. Accordingly, general light protective measures of eyes and skin are recommended for at least 24 hours after administration of Gliolan.
Although pivotal studies on the reproductive and developmental behaviour of ALA have not been performed, it can be concluded that ALA induced porphyrin synthesis may lead to embryotoxic activity in mouse, rat and chick embryos only under the condition of direct concomitant light exposure. Gliolan should, therefore, not be administered to pregnant women. Excessive single dose treatment of rats with ALA reversibly impaired male fertility for two weeks after dosing.

Genotoxicity.

The majority of genotoxicity studies performed in the dark do not reveal a genotoxic potential of ALA. The compound potentially induces photogenotoxicity after subsequent irradiation or light exposure, which is obviously related to the induction of porphyrin synthesis.

Carcinogenicity.

Long-term in vivo carcinogenicity studies have not been conducted. However, considering the therapeutic indication, a single oral treatment with ALA might not be related to any serious potential carcinogenic risk.

6 Pharmaceutical Particulars

6.1 List of Excipients

None.

6.2 Incompatibilities

In the absence of compatibility studies, Gliolan must not be mixed with other medicines except those mentioned in Special Precautions for Disposal).

6.3 Shelf Life

Unopened vial.

36 months.

Storage conditions after reconstitution.

The reconstituted solution is physically-chemically stable for 24 hours at 25°C.
Use within 4 hours of reconstitution.

6.4 Special Precautions for Storage

Store the vials in original cartons below 25°C. Protect from light.
For storage conditions after reconstitution of the medicine, see Section 6.3 Shelf Life.

6.5 Nature and Contents of Container

Clear type I 50 mL glass vial with butyl rubber stopper and secured with aluminium 'push tear-off' cap. Contains 1.5 g powder for reconstitution in 50 mL of drinking water.

Pack sizes.

1, 2 and 10 vials of powder in a carton. Not all pack sizes may be marketed.

6.6 Special Precautions for Disposal

Reconstitution.

The oral solution is prepared by dissolving the amount of powder of one vial in 50 mL of drinking water. The reconstituted solution is a clear and colourless to slightly yellowish fluid.
In the absence of compatibility studies, Gliolan must not be mixed with other medicinal products.

Disposal.

Any unused product or waste material should be disposed of in accordance with local requirements. Gliolan is for single use only and any content remaining after first use must be discarded.

6.7 Physicochemical Properties

Chemical structure.

Chemical Formula: C₅H₉NO₃.HCl.

CAS number.

5451-09-2.
Molecular Weight: 167.59 g/mol. Freely soluble in water. pKa1: 3.90. pKa2: 8.05. The reconstituted solution has a pH of approximately 2.2 - 2.8.

7 Medicine Schedule (Poisons Standard)

Australia: S4.

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