Adverse reactions : תופעות לוואי

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 glutamyl transferase 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 glutamyl
transferase 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. Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form: https://sideeffects.health.gov.il/.