Source: European Medicines Agency (EU) Revision Year: 2018 Publisher: medac, Gesellschaft für klinische, Spezialpräparate mbH, Theaterstr. 6, 22880 Wedel, Germany, Tel. + 49 4103 8006 0, Fax: +49 4103 8006 100
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.
Patients should not be exposed to any photosensitizing agent up to 2 weeks after administration of Gliolan.
There are no or limited amount of data from the use of 5-ALA in pregnant women. Some 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.
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.
There are no data available regarding the influence of 5-ALA on fertility.
Not relevant, the treatment itself will have an influence on the ability to drive and use machines.
Adverse reactions observed after the use of this medicinal product for fluorescence-guided glioma resection are divided into the following two categories:
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.
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:
Uncommon: hypotension
Uncommon: nausea
Uncommon: photosensitivity reaction, photodermatosis
Procedure-related side effects:
Very common: anaemia, thrombocytopenia, leukocytosis
Common: neurological disorders (e.g. hemiparesis, aphasia, convulsions, hemianopsia)
Uncommon: brain oedema
Very rare: hypesthesia
Uncommon: hypotension
Common: thromboembolism
Common: vomiting, nausea
Very rare: diarrhoea
Very common: blood bilirubin increased, alanine aminotransferase increased, aspartate aminotransferase increased, gamma glutamyltransferase increased, blood amylase increased
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).
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 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.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
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