Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2011 Publisher: Medac Gesellschaft für klinische Spezialpräparate mbH Fehlandtstraße 3 D-20354 Hamburg, 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, paresis etc.) 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 pressures, pulmonary artery systolic and diastolic pressures as well as pulmonary vascular resistance.
One case of an increased phototoxic reaction (severe sunburn lasting for 5 days) has been reported in a patient after co-administration of 5-aminolevulinic acid and a hypericin extract (a known phototoxic agent).
Patients should not be exposed to any photosensitizing agent up to 2 weeks after administration of Gliolan.
There are no adequate data from the use of this medicinal product in pregnant woman. Some limited animal studies suggest an embryotoxic acitivity of 5-ALA plus light exposure (see section 5.3). Therefore, this medicinal product should not be used during pregnancy.
It is unknown whether 5-ALA or its metabolite PPIX are excreted in human breast 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.
Gliolan has no 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:
Very common (≥ 1/10)
Common (≥ 1/100, < 1/10)
Uncommon (≥ 1/1,000, < 1/100)
Rare (≥ 1/10,000, < 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.
Uncommon: Hypotension
Uncommon: Nausea
Uncommon: Photosensitivity reaction, photodermatosis
The extent and frequency of procedure-related neurological side effects depend on the localisation of the brain tumour and the degree of resection of tumour tissue lying in eloquent brain areas (see section 4.4).
Very common: Anaemia, thrombocytopenia, leukocytosis
Common: Neurological disorders (e.g. hemiparesis, aphasia, convulsions, hemianopsia)
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
In a single-arm study 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. Possibly drug-related mild nausea was reported in 1out of 21 volunteers.
In another single-centre study, 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 study including 36 patients with malignant glioma, drug-related adverse events were reported in 4 patients (one patient: mild diarrhoea, one patient: moderate hypesthesia, one patient: moderate chills, and one patient: arterial hypotension 30 minutes after application of 5-ALA HCl). 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 (MCALS.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 study 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 HCl- 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.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
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