5-Aminolevulinic Acid Hydrochloride: prescribing information – dosing, contraindications, interactions, side effects

Treatment of actinic keratosis of mild to moderate severity (Olsen grade 1 to 2; see section 5.1) and of field cancerization in adults.

Treatment of superficial and/or nodular basal cell carcinoma unsuitable for surgical treatment due to possible treatment-related morbidity and/or poor cosmetic outcome in adults.

Posology in adults

For treatment of actinic keratoses (AK) of the face or scalp, one session of photodynamic therapy (with natural daylight or a red-light or artificial daylight lamp) shall be administered for single or multiple lesions or entire fields with cancerization (areas of skin where multiple AK lesions are surrounded by an area of actinic and sun-induced damage within a limited field).
For treatment of actinic keratoses (AK) in the body region trunk, neck or extremities, one session of narrow-spectrum red-light photodynamic therapy shall be administered.
Actinic keratosis lesions or fields shall be evaluated three months after treatment. Treated lesions or fields that have not completely resolved after 3 months shall be retreated.

For treatment of basal cell carcinoma (BCC), two sessions of photodynamic therapy with red-light lamp shall be administered for one or multiple lesions with an interval of about one week between sessions. Basal cell carcinoma lesions shall be evaluated three months after last treatment. Treated lesions that have not completely resolved after 3 months shall be retreated.

Paediatric population

There is no relevant use of Ameluz in the paediatric population. No data are available.

Method of administration

Ameluz is for cutaneous use.

Ameluz should be administered under the guidance of a physician, a nurse or other healthcare professional experienced in the use of photodynamic therapy. When a red-light or an artificial daylight lamp is required, the treatment should be performed by a healthcare professional.

Treatment of AK, field cancerization and BCC using a red-light lamp:

a) Preparation of the lesions: Before administration of Ameluz, all lesions should be carefully wiped with an ethanol or isopropanol-soaked cotton pad to ensure degreasing of the skin. Scales and crusts should be removed accurately and all lesion surfaces roughened gently. Care should be taken to avoid bleeding. Nodular BCC lesions are often covered by an intact epidermal keratin layer which should be removed. Exposed tumour material should be removed gently without any attempt to excise beyond the tumour margins.

b) Application of the gel: Ameluz should be applied to the lesion area or entire cancerized fields and approximately 5 mm of the surrounding area in a film of about 1 mm thickness (about 20 cm2 area per tube). The gel should be applied using glove-protected fingertips or a spatula, and it should be allowed to dry for approximately 10 minutes, before a light-tight dressing is placed over the treatment site. Following 3 hours of incubation, the dressing should be removed and the remnant gel wiped off.
The gel can be administered to healthy skin around the lesions. Direct contact of Ameluz with the eyes or mucous membranes should be avoided (keep a distance of 1 cm). In case of accidental contact, rinsing with water is recommended.

c) Illumination: After cleaning the lesions, the entire treatment area will be illuminated with a red light source, either with a narrow-spectrum around 630 nm and a light dose of approximately 37 J/cm2 or a broader and continuous spectrum in the range between 570 and 670 nm with a light dose between 75 and 200 J/cm2. It is important to ensure that the correct light dose is administered. The total light dose is determined by factors such as the irradiance (or equivalent), the size of the light field, the distance between lamp and skin surface, and the illumination time.
These factors vary with lamp type. The light dose delivered should be monitored if a suitable detector is available. During illumination the lamp should be fixed at the distance from the skin surface that is indicated in the user manual. See also section 6.6.
A narrow-spectrum lamp is recommended to achieve higher clearance rates. Symptomatic treatment of transient adverse site reactions may be considered. A broader and continuous spectrum may be used if narrow-spectrum light sources are not tolerated (see sections 4.8 and 5.1).

Note: Efficacy of Ameluz in the treatment of AK in the body regions trunk, neck and extremities has been demonstrated only in the scope of narrow-spectrum PDT. There are no data for these body regions with broader spectrum lamps PDT or with natural or artificial daylight PDT.

Lesions should be re-assessed after three months, at which point any residual lesions or fields may be retreated. It is recommended that the response of BCC lesions may be confirmed by histological examination of biopsy material, if considered necessary. Subsequently, close long-term clinical monitoring of BCC is recommended, with histology if necessary.

Treatment of AK and field cancerization of the face and scalp with natural or artificial daylight:

a) Considerations before treatment:
Natural daylight PDT should only be used if the conditions are suitable to stay comfortably outdoors for two hours (with temperatures > 10 °C). If the weather is rainy, or is likely to become so, natural daylight treatment should not be used.
For natural daylight PDT, sunscreen should be applied 15 min prior to lesion pretreatment in order to protect sun exposed skin. Only sunscreen with chemical filters and SPF 30 or higher

should be used. Sunscreens with physical filters such as titanium dioxide, zinc oxide, etc. should not be used, as these inhibit light absorption and may therefore impact efficacy.
For artificial daylight PDT, sunscreen is not needed, as patients are not exposed to ultraviolet light during illumination.

b) Preparation of the lesions: Before administration of Ameluz, all lesions should be carefully wiped with an ethanol or isopropanol-soaked cotton pad to ensure degreasing of the skin. Scales and crusts should be removed accurately and all lesion surfaces roughened gently. Care should be taken to avoid bleeding.

c) Application of the gel: A thin layer of Ameluz should be applied to the lesion area or entire cancerized fields and approximately 5 mm of the surrounding area using glove-protected fingertips or a spatula. No occlusive dressing is necessary during incubation. It can be used optionally for artificial daylight PDT, but it should be removed before illumination at the latest.
The gel can be administered to healthy skin around the lesions. Direct contact of Ameluz with the eyes or mucous membrane should be avoided (keep a distance of 1 cm). In case of accidental contact, rinsing with water is recommended. The gel should not be wiped off during the entire daylight PDT.

d) Incubation and illumination using daylight for AK treatment:
Natural daylight PDT:
If conditions are suitable (see section a. Considerations before treatment), patients shall go outside within 30 minutes after application of the gel and stay for 2 continuous hours in full daylight.
Taking shelter in the shade in hot weather is acceptable. Interruption of the time outdoors should be compensated by a longer illumination time. Remaining gel should be removed after completion of light exposure.
Artificial daylight PDT:
To ensure sufficient protoporphyrin IX (PpIX) synthesis, the total treatment time (covering incubation and illumination) should be 2 hours and should not exceed 2.5 hours. However, illumination should start within 0.5 to 1 hour after gel application to avoid excessive PpIX accumulation, which might lead to increased pain sensation. The illumination time may vary due to different characteristics (e.g. irradiance and light spectrum) of the CE marked medical devices for artificial daylight PDT. The devices should have either a continuous or an intermittent spectrum covering one or more of the PpIX absorption peaks/bands in the range between 400 and 750 nm. All studied artificial daylight devices with proven PpIX activating activity at least addressed the red PpIX absorption peak at about 631 nm. In order to ensure that the correct light dose is administered, light dose and illumination conditions recommended in the user manuals of the artificial daylight devices should be considered. However, the minimal applied dose at the lesions surface should not be less than ~14 J/cm². Patient and operator should adhere to safety instructions provided with the light source. Remaining gel should be removed after completion of light exposure.

Lesions should be re-assessed after three months, at which point any residual lesions or fields may be retreated.

• Hypersensitivity to the active substance, to porphyrins, to soya or peanuts, or to any of the excipients listed in section 6.1.

• Porphyria.

• Known photodermatoses of varying pathology and frequency, e.g. metabolic disorders such as aminoaciduria, idiopathic or immunological disorders such as polymorphic light reaction, genetic disorders such as xeroderma pigmentosum, and diseases precipitated or aggravated by exposure to sun light such as lupus erythematosus or pemphigus erythematosus.

Summary of the safety profile

In clinical trials with Ameluz, local skin reactions at the application site were observed in most of the subjects treated for actinic keratosis and basal cell carcinoma. This is to be expected as the therapeutic principle of photodynamic therapy is based on phototoxic effects of protoporphyrin IX which is synthesized from the active ingredient 5-aminolaevulinic acid.
The most common signs and symptoms are application site irritation, erythema, pain, and oedema. The intensity of these effects is dependent on the type of illumination used for photodynamic therapy. The increased effects correlate with the higher clearance rate of red-light narrow spectrum lamps (see section 5.1). In rare cases, adverse reactions, e.g. pain, required interruption or discontinuation of the illumination.
The study of Ameluz using natural and artificial daylight showed similar types of side effects.
However, intensity of some adverse reactions, particularly pain, was lower when Ameluz was used in combination with daylight PDT.
Most adverse reactions occur during illumination or shortly afterwards. The symptoms are usually of mild or moderate intensity (investigator’s assessment on a 4-point scale), and last for 1 to 4 days in most cases; in some cases, however, they may persist for 1 to 2 weeks or even longer.

Tabulated list of adverse reactions

The incidence of adverse reactions in 624 subjects exposed to photodynamic therapy with Ameluz in pivotal clinical trials is listed below. All these adverse reactions were non serious. The table additionally includes serious adverse reactions reported post-marketing. Frequencies are defined as 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), and not known (frequency cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 1: Summary of related adverse drug reactions (ADRs) reported in patients treated with photodynamic therapy with 5-aminolaevulinic acid System organ class Frequency Adverse reaction Infections and infestations Uncommon At application site: Pustules Not at application site: Rash pustular Psychiatric disorders Uncommon Nervousness Nervous system disorders Common Headache Uncommon Transient global amnesia (incl. confusion and disorientation)*, Dysaesthesia

Eye disorders
Uncommon
Eyelid oedema, vision blurred, visual impairment
Vascular disorders
Uncommon
Hot flush
Skin and subcutaneous tissue disorders
Uncommon
Blister, dry skin, petechiae, skin tightness
Musculoskeletal and connective tissue disorders
Uncommon
Back pain
General disorders and administration site conditions
Very common
At application site: Erythema, pain (incl. burning pain), irritation, pruritus, oedema, scab, exfoliation, induration, paraesthesia Common At application site: Vesicles, discharge, erosion, reaction, discomfort, hyperalgesia, haemorrhage, warmth Uncommon At application site: Discoloration, ulcer, swelling, inflammation, eczema infected, hypersensitivity*1 Not at application site: Chills, feeling hot, pyrexia, pain, fatigue, ulcer, swelling Injury, poisoning and procedural complications Uncommon Wound secretion * Data from post-marketing period.
1 This reaction also occurs before illumination.

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.

Risk of Transient Global Amnesia (TGA)
Photodynamic therapy (PDT) may be a precipitating factor for transient global amnesia in very rare instances. Although the exact mechanism is not known, stress and pain associated with PDT may increase the risk to develop transient amnesia. If amnesia is observed, the PDT must be discontinued immediately (see section 4.8).

Use of immunosupressants
As inflammatory response is important for the effect of PDT, the trials investigating the efficacy and safety of Ameluz excluded patients who were undergoing treatment with immunosuppression therapy.
No experience exists for the use of Ameluz in patients taking immunosuppressants. Therefore, the use of immunosuppressants during treatment with Ameluz is not recommended.

Ameluz should not be used on bleeding lesions
Any bleeding must be stopped before application of the gel. No experience exists for the use of Ameluz in patients with inherited or acquired coagulation defects. Special care should be taken to avoid bleeding during lesion preparation in such patients (see section 4.2).

Risk of mucous membrane and eye irritation
Ameluz can cause mucous membrane or eye irritation. The excipient sodium benzoate may be mildly irritant to the skin, eyes, and mucous membranes.
Special care should be taken to avoid applying Ameluz into eyes or to mucous membranes. In case of accidental contact, the site must be rinsed with water.

Ameluz should not be used on skin areas affected by other diseases or tattoos.
The success and assessment of treatment may be impaired if the treated area is affected by the presence of skin diseases (e.g. skin inflammation, located infection, psoriasis, eczema, and malignant skin cancers other than indicated) as well as tattoos. No experience exists with these situations.

Intensive lesion preparation might lead to increased pain
Some intensive lesion preparation protocols (e.g. chemical peel followed by ablative laser) might increase the frequency and intensity of pain sensation during PDT. This was noticed in the scope of artificial daylight PDT but should also be considered for red-light PDT and natural daylight PDT.

Ameluz transiently increases phototoxicity
Any UV-therapy should be discontinued before treatment. As a general precaution, sun exposure on the treated lesion sites and surrounding skin should be avoided for approximately 48 hours following treatment. Concomitant use of medicinal products with known phototoxic or photoallergic potential such as St. John’s wort, griseofulvin, thiazide diuretics, sulfonylureas, phenothiazines, sulphonamides, quinolones and tetracyclines may enhance the phototoxic reaction to photodynamic therapy.

Risk of allergic reaction
Ameluz contains soybean phosphatidylcholine and should not be applied to patients known to be allergic to peanut or soya (see section 4.3).

Ameluz does not significantly increase the natural plasma levels of 5-aminolaevulinic acid or protoporphyrin IX following topical application (see section 5.2).
No interaction studies have been performed.

Pregnancy
There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of 5-aminolaevulinic acid in pregnant women. Animal studies do not indicate direct or indirect harmful

effects with respect to reproductive toxicity (see section 5.3). As a precautionary measure, it is preferable to avoid the use of Ameluz during pregnancy.

Breast-feeding
It is unknown whether 5-aminolaevulinic acid/metabolites are excreted in human milk. A risk to the suckling child cannot be excluded. Breast-feeding should be discontinued for 12 hours after treatment with Ameluz.

Fertility
There are no data available on the effect of 5-aminolaevulinic acid on fertility.

Ameluz has no or negligible influence on the ability to drive and use machines.

Overdose following topical administration is unlikely and has not been reported in clinical studies. If Ameluz is accidentally ingested, systemic toxicity is unlikely. Protection from sun light exposure for 48 hours and observation are nevertheless recommended.

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Antineoplastic agents, sensitizers used in photodynamic/radiation therapy, ATC code: L01XD04

Mechanism of action

Following topical application of 5-aminolaevulinic acid (ALA), the substance is metabolized to protoporphyrin IX (PpIX), a photoactive compound which accumulates intracellularly in the treated lesions. PpIX is activated by illumination with light of a suitable wavelength and energy. In the presence of oxygen, reactive oxygen species are formed. The latter causes damage of cellular components and eventually destroys the target cells.

When Ameluz is used with the red-light PDT protocol, PpIX accumulates intracellularly in the target cells during incubation under light-tight dressing. The subsequent illumination activates the accumulated porphyrins and thus leads to phototoxicity for the light-exposed target cells.

When Ameluz is used with natural or artificial daylight PDT protocols, PpIX is continuously produced and activated within the target cells during light exposure, resulting in a constant micro-phototoxic effect. No occlusive dressing is necessary, but it can be used optionally during incubation for artificial daylight PDT.

PDT with artificial daylight devices showed comparable results to PDT with natural daylight.
Artificial daylight PDT devices may vary in terms of specific light spectrum, irradiance and illumination time. The analysis of exemplary artificial daylight devices (i.e. MultiLite®, Medisun® PDT 9000, and indoorLux®) indicated sufficient PpIX activation by all tested devices.

Clinical efficacy and safety

Treatment of actinic keratosis (AK) and field cancerization:

Efficacy and safety of Ameluz for the treatment of actinic keratosis (AK) has been evaluated in 746 patients enrolled in clinical trials. In clinical phase III, a total of 486 patients were treated with Ameluz. All patients had at least 4 mild to moderate actinic keratosis lesions. The application site preparation and duration of incubation followed the description under section 4.2. If not completely cleared 12 weeks after initial treatment, lesions or cancerized fields were treated a second time with an identical regimen.

A) Photodynamic therapy with red-light for AK of face and scalp

Absorption

In vitro dermal absorption into human skin was studied using Ameluz containing radiolabelled 5-aminolaevulinic acid (ALA). After 24 hours, the mean cumulative absorption (including accumulation in the dermis) through human skin was 0.2% of the administered dose. Corresponding studies in human skin with actinic keratosis lesions and/or roughened surface were not performed.

Distribution

In a phase II clinical trial, 5-aminolaevulinic acid and protoporphyrin IX serum levels and ALA urine levels were measured before, 3 and 24 hours after administration of Ameluz for photodynamic treatment. None of the post-dose levels were increased in comparison to the naturally occurring pre- dose levels, showing absence of a relevant systemic absorption after topical administration.

A maximal use PK study was conducted in 12 patients bearing at least 10 mild to moderate AKs on the face or forehead. An entire tube of placebo and Ameluz followed by PDT was applied in a fixed sequence design with a washout period of 7 days to evaluate baseline and Ameluz dependent plasma concentrations of ALA and PpIX. In most patients an up to 2.5-fold increase of basic ALA plasma concentrations was observed during the first 3 hours after Ameluz application, which is still within the normal range of previously reported and published endogenous ALA concentrations. The plasma concentrations of metabolite PpIX were generally low in all patients and in none of the patients, an obvious increase of PpIX plasma concentrations was observed after Ameluz application.

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 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.

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.

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.

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.

• Hypersensitivity to the active substance or porphyrins.
• Acute or chronic types of porphyria.
• Pregnancy (see sections 4.6 and 5.3).

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.
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, 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 hypaesthesia 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 (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 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.

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.

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 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.

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

Pregnancy
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.

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

Within a clinical trial, a 63-year old patient with known cardiovascular disease was accidentally given an overdose of 5-ALA HCl (3,000 mg instead of 1,580 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).

5.
PHARMACOLOGICAL 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, 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. oligodendroglioma) no fluorescence could be observed after application of the active substance. Medulloblastomas 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 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

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 intracellularly 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.

Renal or hepatic impairment