GLIOLAN 30mg / ml powder for oral solution medication leaflet

Gliolan 30 mg/ml powder for oral solution.

One bottle contains 1.17 g of 5-aminolevulinic acid (5-ALA), corresponding to 1.5 g 5-aminolevulinicacid hydrochloride (5-ALA HCl).

One ml of reconstituted solution contains 23.4 mg of 5-ALA, corresponding to 30 mg 5-ALA HCl.

Powder for oral solution.

The powder is a white to off-white cake.

Gliolan is indicated in adults for visualisation of malignant tissue during surgery for malignant glioma(WHO grade III and IV).

This medicinal product should only be used by experienced neurosurgeons conversant with surgery ofmalignant gliomas and in-depth knowledge of functional brain anatomy who have completed atraining course in fluorescence-guided surgery.

The recommended dose is 20 mg 5-ALA HCl per kilogram body weight.

The total number of bottles needed to achieve the intended dose for the individual patient can bedetermined according to the equation below (rounded up to the nearest whole bottle):

Patient body weight (kg)

Number of bottles = ——————————————75 kg/b ottle

The administration volume needed to achieve the intended dose for the individual patient can becalculated according to the equation below:

Patient body weight (kg) x 20 mg/kg

Administration volume (ml) = ———————————————————30 mg/ml

No trials have been performed in patients with clinically relevant hepatic or renal impairment.

Therefore, this medicinal product should be used with caution in such patients.

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

The safety and efficacy of Gliolan in children and adolescents aged 0 to 18 years have not yet beenestablished. No data are available.

The solution should be administered orally three hours (range 2-4 hours) before anaesthesia. Use of5-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 orlater. Another dose of this medicine can be taken 2 - 4 hours before anaesthesia.

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

* Hypersensitivity to the active substance or porphyrins.

* Acute or chronic types of porphyria.

* Pregnancy (see sections 4.6 and 5.3).

5-ALA-induced fluorescence of brain tissue does not provide information about the tissue’sunderlying neurological function. Therefore, resection of fluorescing tissue should be weighed upcarefully against the neurological function of fluorescing tissue.

Special care must be taken in patients with a tumour in the immediate vicinity of an importantneurological function and pre-existing focal deficits (e.g. aphasia, vision disturbances and paresis) thatdo not improve on corticosteroid treatment. Fluorescence-guided resection in these patients has beenfound to impose a higher risk of critical neurological deficits. A safe distance to eloquent cortical areasand subcortical structures of at least 1 cm should be maintained independent of the degree offluorescence.

In all patients with a tumour in the vicinity of an important neurological function, either pre- orintraoperative measures should be used to localise that function relative to the tumour in order tomaintain safety distances.

False negative and false positive results may occur with the use of 5-ALA for intraoperativevisualisation of malignant glioma. Non-fluorescing tissue in the surgical field does not rule out thepresence of tumour in patients with glioma. On the other hand fluorescence may be seen in areas ofabnormal brain tissue (such as reactive astrocytes, atypical cells), necrotic tissue, inflammation,infections (such as fungal or bacterial infections and abscesses), CNS lymphoma or metastases fromother tumour types.

After administration of this medicinal product, 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 also section 5.3).

Within 24 hours after administration, other potentially hepatotoxic medicinal products should beavoided.

In patients with pre-existing cardiovascular disease, this medicinal product should be used withcaution since literature reports have shown decreased systolic and diastolic blood pressure, pulmonaryartery systolic and diastolic pressure as well as pulmonary vascular resistance.

Patients should not be exposed to any photosensitising agent up to 2 weeks after administration of

Gliolan.

There are no or limited amount of data from the use of 5-ALA in pregnant women. Some limitedanimal studies suggest an embryotoxic activity of 5-ALA plus light exposure (see section 5.3).

Therefore, Gliolan should not be used during pregnancy.

It is unknown whether 5-ALA or its metabolite protoporphyrin IX (PPIX) is excreted in human milk.

The excretion of 5-ALA or PPIX in milk has not been studied in animals. Breast-feeding should beinterrupted for 24 hours after treatment with this medicinal product.

There are no data available regarding the influence of 5-ALA on fertility.

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

Adverse reactions observed after the use of this medicinal product for fluorescence-guided gliomaresection are divided into the following two categories:

- immediate reactions occurring after oral administration of the medicinal product beforeanaesthesia (= active substance-specific side effects)

- combined effects of 5-ALA, anaesthesia, and tumour resection (= procedure-specific side effects).

Most serious side effects include anaemia, thrombocytopenia, leukocytosis, neurological disorders andthromboembolism. Further frequently observed side effects are vomiting, nausea and increase of bloodbilirubin, alanine aminotransferase, aspartate aminotransferase, gamma glutamyltransferase and bloodamylase.

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).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Substance-specific side effects:

Cardiac disorders Uncommon: hypotension

Gastrointestinal disorders Uncommon: nausea

Skin and subcutaneous tissue disorders Uncommon: photosensitivity reaction,photodermatosis

Procedure-related side effects

The extent and frequency of procedure-related neurological side effects depends on the localisation ofthe brain tumour and the degree of resection of tumour tissue lying in eloquent brain areas (seesection 4.4).

Blood and lymphatic system disorders Very common: anaemia, thrombocytopenia,leukocytosis

Nervous system disorders Common: neurological disorders (e.g.

hemiparesis, aphasia, convulsions,hemianopsia)

Uncommon: brain oedema

Very rare: hypaesthesia

Cardiac disorders Uncommon: hypotension

Vascular disorders Common: thromboembolism

Gastrointestinal disorders Common: vomiting, nausea

Very rare: diarrhoea

Hepatobiliary disorders Very common: blood bilirubin increased, alanineaminotransferase increased,aspartate aminotransferaseincreased, gammaglutamyltransferase increased,blood amylase increased

In a single-arm trial including 21 healthy male volunteers, erythema of the skin could be provoked bydirect exposure to UVA light up to 24 hours after oral application of 20 mg/kg body weight5-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 bodyweight 5-ALA HCl followed by fluorescence-guided tumour resection. The only adverse reactionreported 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, adverse drug reactions were reportedin 4 patients (mild diarrhoea in one patient, moderate hypaesthesia in another patient, moderate chillsin another patient, and arterial hypotension 30 minutes after application of 5-ALA in another patient).

All patients received the medicinal product in a dose of 20 mg/kg body weight and underwentfluorescence-guided resection. Follow-up time was 28 days.

In a comparative, unblinded phase III trial (MC-ALS.3/GLI), 201 patients with malignant gliomasreceived 5-ALA HCl in a dose of 20 mg/kg body weight and 176 of these patients underwentfluorescence-guided resection with subsequent radiotherapy. 173 patients received standard resectionwithout administration of the medicinal product and subsequent radiotherapy. Follow-up timecomprised at least 180 days after administration. At least possibly related adverse reactions werereported in 2/201 (1.0 %) patients: mild vomiting 48 hours after surgery, and mild photosensitivity48 hours after trial surgery. Another patient accidentally received an overdose of the medicinalproduct (3,000 mg instead of 1,580 mg). Respiratory insufficiency, which was reported in this patient,was managed by adaptation of ventilation and resolved completely. A more pronounced transientincrease of liver enzymes without clinical symptoms was observed in the 5-ALA-treated patients. Peakvalues occurred between 7 and 14 days after administration. Increased levels of amylase, totalbilirubin, and leukocytes, but decreased levels of thrombocytes and erythrocytes were observed,however differences between treatment groups were not statistically significant.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Within a clinical trial, a 63-year old patient with known cardiovascular disease was accidentally givenan overdose of 5-ALA HCl (3,000 mg instead of 1,580 mg). During surgery he developed respiratoryinsufficiency, which was managed by adaptation of ventilation. After surgery the patient alsodisplayed facial erythema. It was stated that the patient had been exposed to more light than permittedfor the trial. Respiratory insufficiency and erythema completely resolved.

In the event of overdose, supportive measures should be provided as necessary, including sufficientprotection from strong light sources (e.g. direct sunlight).

Pharmacotherapeutic group: Antineoplastic agents, sensitisers used in photodynamic therapy,

ATC code: L01XD04

Mechanism of action5-ALA is a natural biochemical precursor of heme that is metabolised in a series of enzymaticreactions to fluorescent porphyrins, particularly PPIX. 5-ALA synthesis is regulated by an intracellularpool of free heme via a negative feedback mechanism. Administration of excess exogenous 5-ALAavoids the negative feedback control, and accumulation of PPIX occurs in target tissue. In thepresence of visible light, fluorescence of PPIX (photodynamic effect) in certain target tissues can beused for photodynamic diagnosis.

Systemic administration of 5-ALA results in an overload of the cellular porphyrin metabolism andaccumulation of PPIX in various epithelia and cancer tissues. Malignant glioma tissue (WHO-grade IIIand IV, e.g. glioblastoma, gliosarcoma or anaplastic astrocytoma) has also been demonstrated tosynthesise and accumulate porphyrins in response to 5-ALA administration. The concentration of

PPIX is significantly lower in white matter than in cortex and tumour. Tissue surrounding the tumourand normal brain may also be affected. However, 5-ALA induced PPIX formation is significantlyhigher in malignant tissue than in normal brain.

In contrast, in low-grade tumours (WHO-grade I and II, e.g. oligodendroglioma) no fluorescencecould be observed after application of the active substance. Medulloblastomas or brain metastasesrevealed inconsistent results or no fluorescence.

The phenomenon of PPIX accumulation in WHO-grade III and IV malignant gliomas may beexplained by higher 5-ALA uptake into the tumour tissue or an altered pattern of expression or activityof enzymes (e.g. ferrochelatase) involved in haemoglobin biosynthesis in tumour cells. Explanationsfor higher 5-ALA uptake include a disrupted blood-brain barrier, increased neo-vascularisation, andthe overexpression of membrane transporters in glioma tissue.

After excitation with blue light (λ=400-410 nm), PPIX is strongly fluorescent (peak at λ=635 nm) andcan be visualised after appropriate modifications to a standard neurosurgical microscope.

Fluorescence emission can be classified as intense (solid) red fluorescence (corresponds to vital, solidtumour tissue) and vague pink fluorescence (corresponds to infiltrating tumour cells), whereas normalbrain tissue lacking enhanced PPIX levels reflects the violet-blue light and appears blue.

In a phase I/II trial including 21 patients, a dose-efficacy relationship between the dose levels and theextent and quality of fluorescence in the tumour core was detected: higher doses of 5-ALA enhancedthe fluorescence quality and the fluorescence extent of the tumour core compared to demarcation ofthe tumour core under standard white illumination in a monotone, non-falling fashion. The highestdose (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 allbiopsies taken from areas of weak and strong fluorescence. The positive predictive value of strongfluorescence 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 receiving5-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 theaim of improving the surgical resection of these tumours.

In a phase III trial with 349 patients with suspected malignant glioma amenable to complete resectionof contrast-enhancing tumour were randomised to fluorescence-guided resection after administrationof 20 mg/kg body weight 5-ALA HCl or conventional resection under white light. Contrast-enhancingtumour 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 5-ALA-treated-patients and 11 % of patientswho underwent standard surgery were alive at the six-month visit without progression. The differencewas 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 poweredto detect such a difference.

General characteristics

This medicinal product shows good solubility in aqueous solutions. After ingestion, 5-ALA itself isnot fluorescent but is taken up by tumour tissue (see section 5.1) and is intracellularly metabolised tofluorescent porphyrins, predominantly PPIX.

Absorption5-ALA as drinking solution is rapidly and completely absorbed and peak plasma levels of 5-ALA arereached 0.5-2 hours after oral administration of 20 mg/kg body weight. Plasma levels return tobaseline values 24 hours after administration of an oral dose of 20 mg/kg body weight. The influenceof food has not been investigated because this medicinal product is generally given on empty stomachprior to induction of anaesthesia.

Distribution and biotransformation5-ALA is preferentially taken up by the liver, kidney, endothelials and skin as well as by malignantgliomas (WHO grade III and IV) and metabolised to fluorescent PPIX. Four hours after oraladministration of 20 mg/kg body weight 5-ALA HCl, the maximum PPIX plasma level is reached.

PPIX plasma levels rapidly decline during the subsequent 20 hours and are not detectable anymore48 hours after administration. At the recommended oral dose of 20 mg/kg body weight, tumour tonormal brain fluorescence ratios are usually high and offer lucid contrast for visual perception oftumour tissue under violet-blue light for at least 9 hours.

Besides tumour tissue, faint fluorescence of the choroid plexus was reported. 5-ALA is also taken upand metabolised to PPIX by other tissues, e.g. liver, kidneys or skin (see section 4.4). Plasma proteinbinding of 5-ALA is unknown.

Elimination5-ALA is eliminated quickly with a terminal half-life of 1-3 hours. Approximately 30 % of an orallyadministered dose of 20 mg/kg body weight is excreted unchanged in urine within 12 hours.

There is dose proportionality between AUC0-inf. of 5-ALA values and different oral doses of thismedicinal product.

Pharmacokinetics of 5-ALA in patients with renal or liver impairment has not been investigated.

Standard safety pharmacology experiments were performed under light protection in the mouse, ratand dog. 5-ALA administration does not influence the function of the gastrointestinal and centralnervous system. A slight increase in saluresis cannot be excluded.

Single administration of high doses of 5-ALA to mice or rats leads to unspecific findings ofintolerance without macroscopic abnormalities or signs of delayed toxicity. Repeat-dose toxicitystudies performed in rats and dogs demonstrate dose-dependent adverse reactions affecting changes inbile duct histology (non-reversible within a 14 day recovery period), transient increase intransaminases, LDH, total bilirubin, total cholesterol, creatinine, urea and vomiting (only in dogs).

Signs of systemic toxicity (cardiovascular and respiratory parameters) occurred at higher doses in theanaesthetised dog: at 45 mg/kg body weight intravenously a slight decrease in peripheral arterial bloodpressure and systolic left ventricular pressure was recorded. Five minutes after administration, thebaseline values had been reached again. The cardiovascular effects seen are considered to be related tothe intravenous route of administration.

Phototoxicity observed after 5-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 ofsebaceous cells, focal epidermal necrosis with a transient acute inflammation and diffuse reactivechanges in the keratinocytes as well as transient secondary oedema and inflammation of dermis areobserved. Light-exposed skin recovered completely except for a persistent reduction in the number ofhair follicles. Accordingly, general light protective measures of eyes and skin are recommended for atleast 24 hours after administration of this medicinal product.

Although pivotal studies on the reproductive and developmental behaviour of 5-ALA have not beenperformed, it can be concluded that 5-ALA induced porphyrin synthesis may lead to embryotoxicactivity in mouse, rat and chick embryos only under the condition of direct concomitant lightexposure. This medicinal product should, therefore, not be administered to pregnant women.

Excessive single dose treatment of rats with 5-ALA reversibly impaired male fertility for two weeksafter dosing.

The majority of genotoxicity studies performed in the dark do not reveal a genotoxic potential of5-ALA. The compound potentially induces photogenotoxicity after subsequent irradiation or lightexposure which is obviously related to the induction of porphyrin synthesis.

Long-term in vivo carcinogenicity studies have not been conducted. However, considering thetherapeutic indication, a single oral treatment with 5-ALA might not be related to any serious potentialcarcinogenic risk.

None.

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.

Unopened bottle4 years.

The reconstituted solution is physically-chemically stable for 24 hours at 25ºC.

Keep the bottle in the outer carton in order to protect from light.

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

Colourless type I glass bottle with butyl rubber stopper containing 1.5 g powder for reconstitution in50 ml of drinking water.

Pack sizes: 1, 2 and 10 bottles.

Not all pack sizes may be marketed.

The oral solution is prepared by dissolving the amount of powder of one bottle in 50 ml of drinkingwater. One bottle of Gliolan 30 mg/ml powder for oral solution reconstituted in 50 ml of drinkingwater corresponds to a total dose of 1,500 mg 5-aminolevulinic acid hydrochloride (5-ALA HCl). Thereconstituted solution is a clear and colourless to slightly yellowish fluid.

Gliolan is for single use only and any content remaining after first use must be discarded.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

photonamic GmbH & Co. KG

Eggerstedter Weg 1225421 Pinneberg

Germany

EU/1/07/413/001-003

Date of first authorisation: 07 September 2007

Date of latest renewal: 30 August 2012

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.