Aminolevulinic acid

Within 24 hours after oral administration of aminolevulinic acid, other potentially hepatotoxic medicinal products should be avoided.

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.

Oral administration

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.

Cutaneous use

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.

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

In patients with pre-existing cardiovascular disease, oral aminolevulinic acid 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.

No experience exists for the use of aminolevulinic acid in patients with inherited or acquired coagulation defects. Special care should be taken to avoid bleeding during lesion preparation in such patients.

Oral administration

There are no or limited amount of data from the use of 5-aminolevulinic acid (5-ALA) in pregnant women. Some limited animal studies suggest an embryotoxic activity of 5-ALA plus light exposure. Therefore, aminolevulinic acid should not be used during pregnancy.

Cutaneous use

There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of 5-ALA in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. As a precautionary measure, it is preferable to avoid the use of 5-ALA during pregnancy.

Oral administration

It is unknown whether 5-aminolevulinic acid or its metabolite protoporphyrin IX (PPIX) is excreted in human milk. The excretion of aminolevulinic acid or PPIX in milk has not been studied in animals. Breast-feeding should be interrupted for 24 hours after treatment with this medicinal product.

Cutaneous use

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 5-aminolaevulinic acid.

Fertility

There are no data available regarding the influence of 5-aminolevulinic acid on fertility.

Oral administration

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

Cutaneous use

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

Oral administration

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-aminolevulinic acid (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:

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.

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.

Cutaneous use

Summary of the safety profile

In clinical trials with 5-aminolevulinic acid, 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. In rare cases, adverse reactions, e.g. pain, required interruption or discontinuation of the illumination.

The study of 5-aminolevulinic acid using natural and artificial daylight showed similar types of side effects. However, intensity of some adverse reactions, particularly pain, was lower when 5-aminolevulinic acid 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 5-aminolevulinic acid 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 (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Summary of related adverse drug reactions (ADRs) reported in patients treated with photodynamic therapy with 5-aminolaevulinic acid:

^* Data from post-marketing period.
¹ This reaction also occurs before illumination.