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):

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

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.

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.

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.

4.5. Interaction with other medicinal products and other forms of interaction

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

4.6. Fertility, pregnancy and lactation

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.

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. 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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

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 (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).