部份中文氨基乙酰丙酸盐酸盐处方资料（仅供参考）
中文名称：5-氨基乙酰丙酸盐酸盐
英文名称：5-Aminolevulinic acid hydrochloride
别名名称：δ-Aminolevulinic acid hydrochloride 5-Amino-4-oxopentanoic acid hydrochloride 5-Aminolaevulinic acid hydrochloride ALA
更多别名：NH2CH2C(O)CH2CH2COOH·HCl
分 子 式：C5H9NO3·HCl
分 子 量：167.59
有效成分
5-氨基乙酰丙酸（5-ALA）。
适应症
Gliolan用于外科手术切除的脑肿瘤。只用在医院。
剂量
作为粉末饮料。成年人，一般每20公斤体重每天三小时才毫克麻醉正在评论粉摄入立即之前在自来水中溶解。
更新
有时（0.1-1％），恶心。血压低。过敏光。
可以不使用
通过在腹部绞痛般的剧烈疼痛表现的遗传性疾病卟啉症，并伴有恶心，呕吐不宜使用该产品。
特别警告
明亮的光线，如操作照明和阳光直射应在手术过程中应避免此后24小时。现有的预防心血管疾病。
使用其他药品
要告诉你的医生你把所有的药是很重要的。同时使用的药物和皮肤敏感性的草本最多可以轻（如四环素和圣​​约翰草），手术后应undgåsi两个星期。
怀孕
波; r被不因无知用于
母乳喂养
不应该使用
献血者
不是。
效果
Gliolan吸收更多的癌细胞相比正常脑细胞。在癌细胞转化Gliolan到另一种物质发射紫外光时，蓝色的光照射。所以外科医生可以更好的与正常脑细胞区分肿瘤细胞，从而更彻底切除肿瘤，同时保护正常脑细胞。
剂型
粉口服。解决方法1小瓶含1.5克5- aminolevulinsyrehydrochlorid（5-ALA）
30毫克/毫升粉液
一个小瓶含有1.17克的5-氨基乙酰丙酸，对应至1.5g5-氨基乙酰丙酸
盐酸盐（5-ALA盐酸）。
一个重新构成的溶液中含有4.23毫克或5-氨基乙酰丙酸，相当于30毫克氨基乙酰丙酸5-盐酸盐（5-ALA盐酸）。

GLIOLAN (5-aminolevulinic acid hydrochloride)
CLASSIFICATION OF DISEASE:
Gliolan is used in adult patients with malignant glioma (a type of brain tumour).
Gliolan helps surgeons to see the tumour more clearly during an operation to remove it from the brain.
Because the number of patients with malignant glioma is low, the disease is considered ‘rare’, and Gliolan was designated an ‘orphan medicine’ (a medicine used in rare diseases) on 13 November 2002.

Gliolan 30mg/ml powder for oral solution
1. Name of the medicinal product
Gliolan 30 mg/ml powder for oral solution.
2. Qualitative and quantitative composition
One vial contains 1.17 g of 5-aminolevulinic acid (5-ALA), corresponding to 1.5 g 5-aminolevulinic acid hydrochloride (5-ALA HCl).
One ml of reconstituted solution contains 23.4 mg of 5-ALA, corresponding to 30 mg 5-ALA HCl.
3. Pharmaceutical form
Powder for oral solution.
The powder is a white to off-white cake.
4. Clinical particulars
4.1 Therapeutic indications
Gliolan is indicated in adult patients 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.
Patients with 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 patients
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.
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.
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 photosensitizing 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: hypesthesia
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 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. Healthcare professionals are asked to report any suspected adverse reactions (see details below).
Ireland
IMB Pharmacovigilance
Earlsfort Terrace
IRL - Dublin 2
Tel: +353 1 6764971
Fax: +353 1 6762517
Website: www.imb.ie
e-mail: imbpharmacovigilance@imb.ie
United Kingdom
Yellow Card Scheme
Website: www.mhra.gov.uk/yellowcard
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 (3000 mg instead of 1580 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).
5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antineoplastic agents, sensitisers used in photodynamic therapy, ATC code: L01XD04
Mechanism of action
5-ALA is a natural biochemical precursor of heme that is metabolised in a series of enzymatic reactions to fluorescent porphyrins, particularly PPIX. 5-ALA synthesis is regulated by an intracellular pool of free heme via a negative feedback mechanism. Administration of excess exogenous 5-ALA avoids the negative feedback control, and accumulation of PPIX occurs in target tissue. In the presence of visible light, fluorescence of PPIX (photodynamic effect) in certain target tissues can be used for photodynamic diagnosis.
Pharmacodynamic effects
Systemic administration of 5-ALA results in an overload of the cellular porphyrin metabolism and accumulation of PPIX in various epithelia and cancer tissues. Malignant glioma tissue (WHO-grade III and IV, e.g. glioblastoma multiforme, gliosarcoma or anaplastic astrocytoma) has also been demonstrated to synthesise and accumulate porphyrins in response to 5-ALA administration. The concentration of PPIX is significantly lower in white matter than in cortex and tumour. Tissue surrounding the tumour and normal brain may also be affected. However, 5-ALA induced PPIX formation is significantly higher in malignant tissue than in normal brain.
In contrast, in low-grade tumours (WHO-grade I and II, e.g. medulloblastoma, oligodendroglioma) no fluorescence could be observed after application of the active substance. Brain metastases revealed inconsistent or no fluorescence.
The phenomenon of PPIX accumulation in WHO grade III and IV malignant gliomas may be explained by higher 5-ALA uptake into the tumour tissue or an altered pattern of expression or activity of enzymes (e.g. ferrochelatase) involved in haemoglobin biosynthesis in tumour cells. Explanations for higher 5-ALA uptake include a disrupted blood-brain barrier, increased neo-vascularisation, and the overexpression of membrane transporters in glioma tissue.
After excitation with blue light (λ=400-410 nm), PPIX is strongly fluorescent (peak at λ=635 nm) and can be visualised after appropriate modifications to a standard neurosurgical microscope.
Fluorescence emission can be classified as intense (solid) red fluorescence (corresponds to vital, solid tumour tissue) and vague pink fluorescence (corresponds to infiltrating tumour cells), whereas normal brain tissue lacking enhanced PPIX levels reflects the violet-blue light and appears blue.
Clinical efficacy and safety
In a phase I/II trial including 21 patients, a dose-efficacy relationship between the dose levels and the extent and quality of fluorescence in the tumour core was detected: higher doses of 5-ALA enhanced the fluorescence quality and the fluorescence extent of the tumour core compared to demarcation of the tumour core under standard white illumination in a monotone, non-falling fashion. The highest dose (20 mg/kg body weight) was determined to be the most efficient.
A positive predictive value of tissue fluorescence of 84.8 % (90 % CI: 70.7 %-93.8 %) was found. This value was defined as the percentage of patients with positive tumour cell identification in all biopsies taken from areas of weak and strong fluorescence. The positive predictive value of strong fluorescence was higher (100.0 %; 90 % CI: 91.1 %-100.0 %) than of weak fluorescence (83.3 %; 90 % CI: 68.1 %-93.2 %). Results were based on a phase II trial including 33 patients receiving 5-ALA HCl in a dose of 20 mg/kg body weight.
The resulting fluorescence was used as an intraoperative marker for malignant glioma tissue with the aim of improving the surgical resection of these tumours.
In a phase III trial with 349 patients with suspected malignant glioma amenable to complete resection of contrast-enhancing tumour were randomised to fluorescence-guided resection after administration of 20 mg/kg body weight 5-ALA HCl or conventional resection under white light. Contrast-enhancing tumour was resected in 64 % of patients in the experimental group compared to 38 % in the control-group (p<0.0001).
At the visit six months after tumour resection, 20.5 % of 5-ALA-treated-patients and 11 % of patients who underwent standard surgery were alive at the six-month visit without progression. The difference was statistically significant using the chi-square test (p=0.015).
No significant increase in overall survival has been observed in this trial; however, it was not powered to detect such a difference.
5.2 Pharmacokinetic properties
General characteristics
This medicinal product shows good solubility in aqueous solutions. After ingestion, 5-ALA itself is not fluorescent but is taken up by tumour tissue (see section 5.1) and is intracellularily metabolised to fluorescent porphyrins, predominantly PPIX.
Absorption
5-ALA as drinking solution is rapidly and completely absorbed and peak plasma levels of 5-ALA are reached 0.5–2 hours after oral administration of 20 mg/kg body weight. Plasma levels return to baseline values 24 hours after administration of an oral dose of 20 mg/kg body weight. The influence of food has not been investigated because this medicinal product is generally given on empty stomach prior to induction of anaesthesia.
Distribution and biotransformation
5-ALA is preferentially taken up by the liver, kidney, endothelials and skin as well as by malignant gliomas (WHO grade III and IV) and metabolised to fluorescent PPIX. Four hours after oral administration of 20 mg/kg body weight 5-ALA HCl, the maximum PPIX plasma level is reached. PPIX plasma levels rapidly decline during the subsequent 20 hours and are not detectable anymore 48 hours after administration. At the recommended oral dose of 20 mg/kg body weight, tumour to normal brain fluorescence ratios are usually high and offer lucid contrast for visual perception of tumour tissue under violet-blue light for at least 9 hours.
Besides tumour tissue, faint fluorescence of the choroid plexus was reported. 5-ALA is also taken up and metabolised to PPIX by other tissues, e.g. liver, kidneys or skin (see section 4.4). Plasma protein binding of 5-ALA is unknown.
Elimination
5-ALA is eliminated quickly with a terminal half-life of 1-3 hours. Approximately 30 % of an orally administered dose of 20 mg/kg body weight is excreted unchanged in urine within 12 hours.
Linearity/non-linearity
There is dose proportionality between AUC0-inf. of 5-ALA values and different oral doses of this medicinal product.
Renal or hepatic impairment
Pharmacokinetics of 5-ALA in patients with renal or liver impairment has not been investigated.
5.3 Preclinical safety data
Standard safety pharmacology experiments were performed under light protection in the mouse, rat and dog. 5-ALA administration does not influence the function of the gastrointestinal and central nervous system. A slight increase in saluresis cannot be excluded.
Single administration of high doses of 5-ALA to mice or rats leads to unspecific findings of intolerance without macroscopic abnormalities or signs of delayed toxicity. Repeat-dose toxicity studies performed in rats and dogs demonstrate dose-dependent adverse reactions affecting changes in bile duct histology (non-reversible within a 14 day recovery period), transient increase in transaminases, LDH, total bilirubin, total cholesterin, creatinine, urea and vomiting (only in dogs). Signs of systemic toxicity (cardiovascular and respiratory parameters) occurred at higher doses in the anaesthetised dog: at 45 mg/kg body weight intravenously a slight decrease in peripheral arterial blood pressure and systolic left ventricular pressure was recorded. Five minutes after administration, the baseline values had been reached again. The cardiovascular effects seen are considered to be related to the intravenous route of administration.
Phototoxicity observed after 5-ALA treatment in vitro and in vivo is obviously closely related to dose- and time-dependent induction of PPIX synthesis in the irradiated cells or tissues. Destruction of sebaceous cells, focal epidermal necrosis with a transient acute inflammation and diffuse reactive changes in the keratinocytes as well as transient secondary oedema and inflammation of dermis are observed. Light exposed skin recovered completely except for a persistent reduction in the number of hair follicles. Accordingly, general light protective measures of eyes and skin are recommended for at least 24 hours after administration of this medicinal product.
Although pivotal studies on the reproductive and developmental behaviour of 5-ALA have not been performed, it can be concluded that 5-ALA induced porphyrin synthesis may lead to embryotoxic activity in mouse, rat and chick embryos only under the condition of direct concomitant light exposure. This medicinal product should, therefore, not be administered to pregnant women. Excessive single dose treatment of rats with 5-ALA reversibly impaired male fertility for two weeks after dosing.
The majority of genotoxicity studies performed in the dark do not reveal a genotoxic potential of 5-ALA. The compound potentially induces photogenotoxicity after subsequent irradiation or light exposure which is obviously related to the induction of porphyrin synthesis.
Long-term in vivo carcinogenicity studies have not been conducted. However, considering the therapeutic indication, a single oral treatment with 5-ALA might not be related to any serious potential carcinogenic risk.
6. Pharmaceutical particulars
6.1 List of excipients
None.
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
6.3 Shelf life
Unopened vial
3 years.
Reconstituted solution
The reconstituted solution is physically-chemically stable for 24 hours at 25°C.
6.4 Special precautions for storage
Keep the vial in the outer carton in order to protect from light.
For storage conditions after reconstitution of the medicinal product, see section 6.3.
6.5 Nature and contents of container
Colourless type II glass vial with butyl rubber stopper containing 1.5 g powder for reconstitution in 50 ml of drinking water.
Pack sizes: 1, 2 and 10 vials.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
The oral solution is prepared by dissolving the amount of powder of one vial in 50 ml of drinking water. The reconstituted solution is a clear and colourless to slightly yellowish fluid.
Gliolan is for single use only and any content remaining after first use must be discarded.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7. Marketing authorisation holder
medac
Gesellschaft für klinische
Spezialpräparate mbH
Theaterstr. 6
22880 Wedel
Germany
Tel. + 49 4103 8006 0
Fax: +49 4103 8006 100
8. Marketing authorisation number(s)
EU/1/07/413/001-003
9. Date of first authorisation/renewal of the authorisation
Date of first authorisation: 07 September 2007
Date of latest renewal: 12 September 2012
10. Date of revision of the text
02/2014
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.