Gliolan

1 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 

 
 
 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Gliolan 30 mg/ml powder for oral solution. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
One bottle contains 1.17 g of 5-aminolevulinic acid (5-ALA), corresponding to 1.5 g 5-aminolevulinic 
acid hydrochloride (5-ALA HCl). 
 
One ml of reconstituted solution contains 23.4 mg of 5-ALA, corresponding to 30 mg 5-ALA HCl. 
 
 
3. PHARMACEUTICAL FORM 
 
Powder for oral solution. 
The powder is a white to off-white cake. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Gliolan is indicated in adults for visualisation of malignant tissue during surgery for malignant glioma 
(WHO grade III and IV). 
 
4.2 Posology and method of administration 
 
This medicinal product 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. 
 
Posology 
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 be 
determined according to the equation below (rounded up to the nearest whole bottle): 
 
 Patient body weight (kg) 
Number of bottles =  ——————————————

  75 kg/bottle 
 
The administration volume needed to achieve the intended dose for the individual patient can be 
calculated according to the equation below: 
 
 Patient body weight (kg) x 20 mg/kg 
Administration volume (ml) =  ———————————————————

  30 mg/ml 
 
Renal or hepatic impairment 
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.  
 
Elderly 
There are no special instructions for use in elderly patients with regular organ function. 
 



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Paediatric population 
The safety and efficacy of Gliolan in children and adolescents aged 0 to 18 years have 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 
5-ALA under conditions other than the ones used in the clinical trials entail an undetermined risk. 
 
Precautions to be taken before handling or administering 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 porphyrins. 
• Acute or chronic types of porphyria. 
• Pregnancy (see sections 4.6 and 5.3). 
 
4.4 Special warnings and precautions for use 
 
5-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) 
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. 
 
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 be 
avoided. 
 
In patients with pre-existing cardiovascular disease, this medicinal product should be used with 
caution since literature reports have shown decreased systolic and diastolic blood pressure, pulmonary 
artery systolic and diastolic pressure as well as pulmonary vascular resistance. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Patients should not be exposed to any photosensitizing agent up to 2 weeks after administration of 
Gliolan. 
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 



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There are no or limited amount of data from the use of 5-ALA in pregnant women. Some limited 
animal studies suggest an embryotoxic activity of 5-ALA plus light exposure (see section 5.3). 
Therefore, Gliolan should not be used during pregnancy.  
 
Breast-feeding 
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 be 
interrupted for 24 hours after treatment with this medicinal product. 
 
Fertility 
There are no data available regarding the influence of 5-ALA on fertility. 
 
4.7 Effects on ability to drive and use machines 
 
Not relevant, the treatment itself will have an influence on the ability to drive and use machines. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
Adverse reactions observed after the use of this medicinal product 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 5-ALA, anaesthesia, and tumour resection (= procedure-specific side effects). 
 
Most serious side effects include anaemia, thrombocytopenia, leukocytosis, neurological disorders 
and thromboembolism. 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). 
 
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 of 
the brain tumour and the degree of resection of tumour tissue lying in eloquent brain areas (see 
section 4.4). 
 
Blood and lymphatic system disorders Very common: anaemia, thrombocytopenia, 

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



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hemiparesis, aphasia, 
convulsions, hemianopsia) 

Uncommon:  brain oedema 
Very rare:  hypesthesia 

Cardiac disorders  Uncommon:  hypotension 
Vascular disorders Common:  thromboembolism 
Gastrointestinal disorders Common:  vomiting, nausea 

Very rare:  diarrhoea 
Hepatobiliary disorders Very common: blood bilirubin increased, alanine 

aminotransferase increased, 
aspartate aminotransferase 
increased, gamma 
glutamyltransferase increased, 
blood amylase increased 

 
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 
5-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 5-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, adverse drug reactions were 
reported in 4 patients (mild diarrhoea in one patient, moderate hypesthesia in another patient, 
moderate chills in 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 
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 5-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 surgery, and mild photosensitivity 
48 hours after trial surgery. 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 5-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. 
 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
Within a clinical trial, a 63-year old patient with known cardiovascular disease was accidentally given 
an overdose of 5-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 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


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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). 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antineoplastic agents, sensitisers used in photodynamic therapy, 
ATC code: L01XD04 
 
Mechanism of action 
5-ALA is a natural biochemical precursor of heme that is metabolised in a series of enzymatic 
reactions to fluorescent porphyrins, particularly PPIX. 5-ALA synthesis is regulated by an 
intracellular pool of free heme via a negative feedback mechanism. Administration of excess 
exogenous 5-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 5-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 multiforme, gliosarcoma or anaplastic astrocytoma) has also been 
demonstrated to synthesise 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 tumour and normal brain may also be affected. However, 5-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. medulloblastoma, oligodendroglioma) no 
fluorescence could be observed after application of the active substance. Brain metastases revealed 
inconsistent or no fluorescence. 
 
The phenomenon of PPIX accumulation in WHO grade III and IV malignant gliomas may be 
explained by higher 5-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 5-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 (λ=400-410 nm), PPIX is strongly fluorescent (peak at λ=635 nm) 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 efficacy and safety 
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 5-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. 
 



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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 
5-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 5-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 5-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 
This medicinal product shows good solubility in aqueous solutions. After ingestion, 5-ALA itself is 
not fluorescent but is taken up by tumour tissue (see section 5.1) and is intracellularily metabolised to 
fluorescent porphyrins, predominantly PPIX. 
 
Absorption 
5-ALA as drinking solution is rapidly and completely absorbed and peak plasma levels of 5-ALA are 
reached 0.5–2 hours after oral administration of 20 mg/kg body weight. 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 this medicinal product is generally given on empty stomach 
prior to induction of anaesthesia.  
 
Distribution and biotransformation 
5-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 5-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. 5-ALA is also taken up 
and metabolised to PPIX by other tissues, e.g. liver, kidneys or skin (see section 4.4). Plasma protein 
binding of 5-ALA is unknown. 
 
Elimination 
5-ALA is eliminated quickly with a terminal half-life of 1-3 hours. Approximately 30 % of an orally 
administered dose of 20 mg/kg body weight is excreted unchanged in urine within 12 hours. 
 
Linearity/non-linearity 
There is dose proportionality between AUC0-inf. of 5-ALA values and different oral doses of this 
medicinal product. 
 



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Renal or hepatic impairment 
Pharmacokinetics of 5-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. 5-ALA administration does not influence the function of the gastrointestinal and central 
nervous 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 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 cholesterol, 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 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 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 this medicinal product.  
 
Although pivotal studies on the reproductive and developmental behaviour of 5-ALA have not been 
performed, it can be concluded that 5-ALA induced porphyrin synthesis may lead to embryotoxic 
activity in mouse, rat and chick embryos only under the condition of direct concomitant light 
exposure. 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 weeks 
after dosing. 
 
The majority of genotoxicity studies performed in the dark do not reveal a genotoxic potential of 
5-ALA. The compound potentially induces photogenotoxicity after subsequent irradiation or light 
exposure which is obviously related to the induction of porphyrin synthesis. 
Long-term in vivo carcinogenicity studies have not been conducted. However, considering the 
therapeutic indication, a single oral treatment with 5-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, this medicinal product must not be mixed with other 
medicinal products. 
 
6.3 Shelf life 
 



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Unopened bottle 
3 years. 
 
Reconstituted solution 
The reconstituted solution is physically-chemically stable for 24 hours at 25ºC. 
 
6.4 Special precautions for storage 
 
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. 
 
6.5 Nature and contents of container 
 
Colourless type I glass bottle with butyl rubber stopper containing 1.5 g powder for reconstitution in 
50 ml of drinking water. 
Pack sizes: 1, 2 and 10 bottles. 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal and other handling 
 
The oral solution is prepared by dissolving the amount of powder of one bottle in 50 ml of drinking 
water. One bottle of Gliolan 30 mg/ml powder for oral solution reconstituted in 50 ml of drinking 
water corresponds to a total dose of 1500 mg 5-aminolevulinic acid hydrochloride (5-ALA HCl). The 
reconstituted 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 local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER  
 
medac 
Gesellschaft für klinische 
Spezialpräparate mbH 
Theaterstr. 6 
22880 Wedel 
Germany 
Tel.  + 49 4103 8006 0 
Fax:  +49 4103 8006 100 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/07/413/001-003 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 07 September 2007 
Date of latest renewal: 12 September 2012 
 
 
10. DATE OF REVISION OF THE TEXT 



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Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
 
 

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


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A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer responsible for batch release 
 
medac 
Gesellschaft für klinische 
Spezialpräparate mbH 
Theaterstr. 6 
22880 Wedel 
Germany 
 
 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION 

 
• Periodic Safety Update Reports 
 
The requirements for submission of periodic safety update reports for this medicinal product 
are set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) 
of Directive 2001/83/EC and any subsequent updates published on the European medicines 
web-portal. 
 
 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT 

 
• Risk Management Plan (RMP) 
 
The MAH shall perform the required pharmacovigilance activities and interventions detailed in 
the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed 
subsequent updates of the RMP. 
 
An updated RMP should be submitted: 

• At the request of the European Medicines Agency; 
• Whenever the risk management system is modified, especially as the result of new 

information being received that may lead to a significant change to the benefit/risk profile or 
as the result of an important (pharmacovigilance or risk minimisation) milestone being 
reached. 

 
If the dates for submission of a PSUR and the update of a RMP coincide, they can be submitted at the 
same time. 
 
• Additional risk minimisation measures 
 



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Gliolan should be used only by neurosurgeons who have attended a training course in accordance with 
the standards detailed below: 
 
The Marketing Authorisation Holder in agreement with the competent authorities in the Member 
States shall implement, prior to launch: 
 
− A training course for neurosurgeons which is aimed at risk minimisation and to support safe and 

effective use for the medicinal product. The training course will take place at qualified training 
centres using qualified trainers. This course shall consist of measures aiming to minimise adverse 
events associated with the Gliolan-fluorescence-guided surgery (in particular neurological serious 
adverse events) through adequate education about: 

 
a) Theory and core principles of Gliolan-fluorescence-guided surgery and malignant glioma 

resection, including methods of eloquent sites identification; 
b) On-site instructions on the use of the fluorescence-microscope, including pitfalls and 

recognition of problems; 
c) Differentiation of fluorescence intensity, maintaining safety distances from eloquent areas; 
d) The practice of Gliolan-fluorescence-guided surgery (including participation in at least one 

case using Gliolan-fluorescence-guided surgery in the operating room with on-site 
instructions on the use of the microscope or demonstration of a fluorescence-guided resection 
by video); 

e) The current understanding of the benefits and risks of cytoreductive surgery in the 
management of patients with malignant gliomas; 

f) The theoretical base for porphyrin accumulation in malignant gliomas; 
g) The technical principles behind fluorescence-guided resections using Gliolan; 
h) How to identify suitable candidates for fluorescence-guided resections using Gliolan; 
i) How to apply Gliolan in the correct dose and timing regimen, and to understand the 

importance of concurrent corticosteroids; 
j) How to identify patients at risk for neurological deficits using fluorescence-guided resections 

with Gliolan with special focus on aphasias and other critical focal deficits; 
k) Techniques for intraoperative risk reduction (microsurgical technique, neurophysiological 

monitoring, choice of approach) and how to implement them; 
l) How to identify fluorescence for resection through using the operating microscope in a 

hands-on setting in the operating room; 
m) The benefits and risks of fluorescence-guided resections using Gliolan. 

 
Minimum requirements for a qualified trainer are: 

-  Board-certification as neurosurgeon according to local, national requirements; 
-  Previous successful participation at a training course, or equivalent course during the 

phase III trial; 
-  Experience with Gliolan-fluorescence-guided surgery in at least 20 cases. 
 

Minimum requirements for a qualified training centre are: 
-  Microscope modified for fluorescence-guided resection; 
-  Sufficient case load (at least 10 patients per year) of malignant gliomas (WHO grade III 

and IV); 
-  Neurophysiological monitoring techniques for surgery in eloquent brain regions. 

 



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ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 



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A. LABELLING 



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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Gliolan 30 mg/ml powder for oral solution 
5-aminolevulinic acid hydrochloride 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
One bottle contains 1.17 g of 5-aminolevulinic acid, corresponding to 1.5 g 5-aminolevulinic acid 
hydrochloride (5-ALA HCl). 
 
One ml of reconstituted solution contains 23.4 mg of 5-aminolevulinic acid, corresponding to 30 mg 
5-aminolevulinic acid hydrochloride (5-ALA HCl). 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder for oral solution 
 
1 bottle 
2 bottles 
10 bottles 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For oral use after reconstitution. 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
Shelf life of the reconstituted solution: 24 hours at 25 °C. 
 



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9. SPECIAL STORAGE CONDITIONS 
 
Keep the bottle in the outer carton in order to protect from light. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 
 
Single use bottle – discard any content remaining after first use. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
medac GmbH 
Theaterstr. 6 
22880 Wedel 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/07/413/001 
EU/1/07/413/002 
EU/1/07/413/003 
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
<2D barcode carrying the unique identifier included.> 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  



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SN:  
NN: 



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PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING 
 
BOTTLE LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Gliolan 30 mg/ml powder for oral solution 
5-aminolevulinic acid hydrochloride 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
One bottle contains 1.17 g of 5-aminolevulinic acid, corresponding to 1.5 g 5-aminolevulinic acid 
hydrochloride (5-ALA HCl). 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder for oral solution 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For oral use after reconstitution. 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Keep the bottle in the outer carton in order to protect from light. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 



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Single use bottle – discard any content remaining after first use. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
medac GmbH 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 



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B. PACKAGE LEAFLET



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Package leaflet: Information for the user 
 

Gliolan 30 mg/ml powder for oral solution 
5-aminolevulinic acid hydrochloride 

 
 

Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
• Keep this leaflet. You may need to read it again. 
• If you have any further questions, ask your doctor or pharmacist. 
• If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
 
1. What Gliolan is and what it is used for 
2. What you need to know before you take Gliolan 
3. How to take Gliolan 
4. Possible side effects 
5. How to store Gliolan 
6. Contents of the pack and other information 
 
 
1. What Gliolan is and what it is used for 
 
Gliolan is used for the visualisation of certain brain tumours (called malignant glioma) during tumour 
surgery. 
 
Gliolan contains a substance called aminolevulinic acid (5-ALA). 5-ALA 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 to better see what is normal tissue 
and what is tumour tissue. This helps the surgeon to remove the tumour while sparing healthy tissue. 
 
 
2. What you need to know before you take Gliolan 
 
Do not take Gliolan 
• if you are allergic to 5-ALA or porphyrins. 
• in case of known or suspected acute or chronic types of porphyria (i.e. inherited or acquired 

disorders of certain enzymes in the synthesis pathway of red blood pigment). 
• in case of known or suspected pregnancy. 
 
Warnings and precautions 
Talk to your doctor or pharmacist before taking Gliolan. 
• For 24 hours after administration of this medicine, protect your eyes and skin from strong 

light (for example direct sunlight or brightly focused indoor light). 
• If you have a heart disease or had heart disease in the past, you should tell your doctor. In this 

case, this medicine should be used with caution because your blood pressure may be decreased. 
 
Renal or hepatic impairment 
No trials have been performed in patients with poor liver or kidney function. Therefore, this medicine 
should be used with caution in such patients.  
 
Elderly 
There are no special instructions for use in elderly patients with normal organ function. 
 



 22 

Children and adolescents (< 18 years) 
There is no experience with Gliolan in children and adolescents. Therefore this medicine is not 
recommended in this age group. 
 
Other medicines and Gliolan 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines, particularly medicines that may cause skin problems when the skin comes under strong 
light (for example some types of medicines called antibiotics), but also medicines obtained without 
prescription (for example hypericin or Saint John’s wort extracts). 
 
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 up to 2 weeks after you have 
taken Gliolan. 
 
Within 24 hours after having taken Gliolan, avoid any other medicines that may harm the liver. 
 
Gliolan with food and drink 
This medicine is generally used once only, namely 2-4 hours before anaesthesia for surgery for certain 
brain tumours called glioma. You should not drink or eat for at least 6 hours before anaesthesia. 
 
Pregnancy and breast-feeding 
Pregnancy 
It is not known whether Gliolan will harm an unborn baby. Do not use this medicine if you are 
pregnant.  
 
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. 
 
Driving and using machines 
This medicine itself has no influence on the ability to drive and use machines. 
 
 
3. How to take Gliolan 
 
This medicine is a powder that must be first mixed with drinking water before use. This is always 
done by a pharmacist or a nurse and not by yourself. The usual dose is 20 mg 5-ALA HCl per 
kilogram body weight. The pharmacist or nurse will calculate the exact dose you need and the amount 
of the solution (in ml) you have to drink. You have to drink the prepared solution 2-4 hours before 
anaesthesia. 
 
If the anaesthesia/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 anaesthesia. 
 
If you take more Gliolan than you should 
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). 
 
If you forget to take Gliolan 
This medicine is given once only at the day of surgery, 2 – 4 hours before start of anaesthesia. If you 
have forgotten to take this medicine during this time period, it is not advisable to take it just before 
start of anaesthesia. In this case, anaesthesia and surgery must be postponed for at least 2 hours, if 
possible. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 



 23 

 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Most serious side effects include mild alterations of blood cell counts (red and white cells, platelets), 
disorders that affect the nervous system (neurological disorders) like partial paralysis of one side of 
the body (hemiparesis) and blood clots that may obstruct blood vessels (thromboembolism). Further 
frequently observed side effects are being sick (vomiting), feeling sick (nausea) and 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.  
 
Tell your doctor immediately if you experience any complaints. 
 
Side effects are divided into the following two categories: 
• immediate side effects after having taken Gliolan and before anaesthesia 
• combined side effects of Gliolan, anaesthesia, and tumour resection. 
 
After having taken Gliolan and before start of anaesthesia, the following side effects may occur:  
 

Uncommon side effects (may affect up to 1 in 100 people): 
Feeling sick (nausea), decrease of blood pressure (hypotension), skin reactions (for example rash, 
looking like sunburn). 

 
In combination with anaesthesia and tumour resection further side effects may occur:  

Very common side effects (may affect more than 1 in 10 people): 
Mild alterations of blood cell counts (red and white cells, platelets), and 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 changes peak between 7 and 14 days after 
surgery. The changes will completely resolve within a few weeks. Usually you will not 
experience any symptoms when these changes occur. 
 
Common side effects (may affect up to 1 in 10 people): 
Feeling sick (nausea), being sick (vomiting), disorders that affect the nervous system 
(neurological disorders) like partial paralysis of one side of the body (hemiparesis), total or 
partial loss of ability to use or understand language (aphasia), seizures (convulsions) and 
blindness for half the field of vision in one or both eyes (hemianopsia), and blood clots that may 
obstruct blood vessels (thromboembolism). 
 
Uncommon side effects (may affect up to 1 in 100 people): 
Decrease of blood pressure (hypotension), brain swelling (brain oedema). 
 
Very rare side effects (may affect up to 1 in 10,000 people) or not known (frequency cannot 
be estimated from the available data): 
Decrease of your sense of touch (hypaesthesia), and loose or watery stools (diarrhoea).  
 

 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety 
of this medicine. 
 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


 24 

5. How to store Gliolan 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the carton after EXP. The expiry date 
refers to the last day of that month. 
 
Keep the bottle in the outer carton in order to protect from light. 
 
The reconstituted solution is physically-chemically stable for 24 hours at 25 °C. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Gliolan contains 
The active substance is 5-aminolevulinic acid hydrochloride (5-ALA HCl). One bottle contains 1.17 g 
of 5-aminolevulinic acid (5-ALA), corresponding to 1.5 g 5-ALA HCl. 
One ml of reconstituted solution contains 23.4 mg of 5-ALA, corresponding to 30 mg 5-ALA HCl. 
 
What Gliolan looks like and contents of the pack 
This medicine is a powder for oral solution. The powder is a white to off-white cake. The 
reconstituted solution is a clear and colourless to slightly yellowish fluid.  
Gliolan is provided in a glass bottle and presented in packs of 1, 2 and 10 bottles. Not all pack sizes 
may be marketed.  
 
Marketing Authorisation Holder and Manufacturer 
medac 
Gesellschaft für klinische 
Spezialpräparate mbH 
Theaterstr. 6 
22880 Wedel 
Germany 
Tel.  +49 4103 8006-0 
Fax: +49 4103 8006-100 
 
 
This leaflet was last revised in  
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. 
 
This leaflet is available in all EU/EEA languages on the European Medicines Agency website. 

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


 25 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX 
 

CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE 
OF THE MEDICINAL PRODUCT TO BE IMPLEMENTED BY THE MEMBER STATES 

 
 
 



 26 

CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT TO BE IMPLEMENTED BY THE 
MEMBER STATES 
 
The Member States should ensure that all conditions or restrictions with regard to the safe and 
effective use of the medicinal product described below are implemented: 
 
Gliolan should be used only by neurosurgeons who have attended a training course in accordance with 
the standards detailed below:  
 
The Member States shall agree with the Marketing Authorisation Holder, prior to launch, measures 
for the implementation of the following: 
 
− A training course for neurosurgeons which is aimed at risk minimisation and to support safe and 

effective use for the medicinal product. The training course will take place at qualified training 
centres using qualified trainers. This course shall consist of measures aiming to minimise adverse 
events associated with the Gliolan-fluorescence-guided surgery (in particular neurological serious 
adverse events) through adequate education about: 

 
a) Theory and core principles of Gliolan-fluorescence-guided surgery and malignant glioma 

resection, including methods of eloquent sites identification;  
b) On-site instructions on the use of the fluorescence-microscope, including pitfalls and 

recognition of problems;  
c) Differentiation of fluorescence intensity, maintaining safety distances from eloquent areas; 
d) The practice of Gliolan-fluorescence-guided surgery (including participation in at least one 

case using Gliolan-fluorescence-guided surgery in the operating room with on-site 
instructions on the use of the microscope or demonstration of a fluorescence-guided resection 
by video);  

e) The current understanding of the benefits and risks of cytoreductive surgery in the 
management of patients with malignant gliomas;  

f) The theoretical base for porphyrin accumulation in malignant gliomas;  
g) The technical principles behind fluorescence-guided resections using Gliolan;  
h) How to identify suitable candidates for fluorescence-guided resections using Gliolan;  
i) How to apply Gliolan in the correct dose and timing regimen, and to understand the 

importance of concurrent corticosteroids;  
j) How to identify patients at risk for neurological deficits using fluorescence-guided resections 

with Gliolan with special focus on aphasias and other critical focal deficits;  
k) Techniques for intraoperative risk reduction (microsurgical technique, neurophysiological 

monitoring, choice of approach) and how to implement them;  
l) How to identify fluorescence for resection through using the operating microscope in a hands-

on setting in the operating room;  
m) The benefits and risks of fluorescence-guided resections using Gliolan. 

 
Minimum requirements for a qualified trainer are:  

- Board-certification as neurosurgeon according to local, national requirements;  
- Previous successful participation at a training course, or equivalent course during the 

phase III trial;  
- Experience with Gliolan-fluorescence-guided surgery in at least 20 cases.  
 

Minimum requirements for a qualified training centre are:  
- Microscope modified for fluorescence-guided resection;  
- Sufficient case load (at least 10 patients per year) of malignant gliomas (WHO grade III 

and IV);  
- Neurophysiological monitoring techniques for surgery in eloquent brain regions.  

 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET
	CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT TO BE IMPLEMENTED BY THE MEMBER STATES