PRINCIPAL DISPLAY PANEL - 1,500 mg Vial Carton

NDC 59137-231-01
Rx only

Gleolan ®
(aminolevulinic
acid hydrochloride)

for oral solution

1,500 mg

Reconstitute Prior To Use.

For Oral Use Only

SINGLE-DOSE VIAL.

Discard Unused Portion

One Vial

MEDEXUS
PHARMA

1 INDICATIONS AND USAGE

Gleolan is indicated in patients with glioma [suspected World Health Organization (WHO) Grades III or IV on preoperative imaging] as an adjunct for the visualization of malignant tissue during surgery.

5 WARNINGS AND PRECAUTIONS

5.1 Risk of Phototoxic Reaction

Due to the risk of phototoxic reactions, do not administer phototoxic drugs (St. John's wort, griseofulvin, thiazide diuretics, sulfonylureas, phenothiazines, sulphonamides, quinolones and tetracyclines), and topical preparations containing ALA for 24 hours during the perioperative period [see Drug Interactions (7)] . Reduce exposure to sunlight or room lights for 48 hours after administration of Gleolan.

5.2 Risk of Misinterpretation

Errors may occur with the use of Gleolan for intraoperative visualization of malignant glioma, including false negatives and false positives. Non- fluorescing tissue in the surgical field does not rule out the presence of tumor in patients with glioma [see Clinical Studies (14)] . Fluorescence may be seen in areas of inflammation or metastases from other tumor types.

5.3 Hypersensitivity Reactions

Hypersensitivity reactions, including serious hypersensitivity reactions have occurred; these reactions include anaphylactic shock, swelling, and urticaria [see Contraindications (4), Adverse Reactions (6.2)] . Always have cardiopulmonary resuscitation personnel and equipment readily available and monitor all patients for hypersensitivity reactions.

7 DRUG INTERACTIONS

Phototoxic Drugs

Patients exposed to a photosensitizing agent may experience a phototoxic skin reaction (severe sunburn). Due to the risk of possible phototoxic reactions, avoid administering phototoxic drugs such as St. John's wort, griseofulvin, thiazide diuretics, sulfonylureas, phenothiazines, sulphonamides, quinolones and tetracyclines, and topical preparations containing ALA for 24 hours before and after administration of Gleolan.

11 DESCRIPTION

11.1 Chemical Properties

Gleolan (aminolevulinic acid hydrochloride) is an optical imaging agent for oral solution. The 50-mL, clear vial contains 1,500 mg of lyophilized aminolevulinic acid hydrochloride powder (equivalent to 1,170 mg aminolevulinic acid). After reconstitution, the product has a concentration of 30 mg aminolevulinic acid hydrochloride per mL (equivalent to 23.4 mg aminolevulinic acid per mL). The chemical name is 5-amino-4-oxo-pentanoic acid hydrochloride. The chemical formula for aminolevulinic acid hydrochloride is C 5H 10ClNO 3. Its molecular weight is 167.59 g/mol with the following structural formula:

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

ALA occurs endogenously as a metabolite that is formed in the mitochondria from succinyl-CoA and glycine. Exogenous administration of ALA leads to accumulation of the ALA metabolite PpIX in tumor cells. The reason for the accumulation of PpIX in neoplastic brain tissue is not known.

During glioma surgery, Gleolan is used with an operating microscope adapted with a blue emitting light source (power density 40-80 mW/cm 2) and filters for excitation light of wavelength 375 to 440 nm, and observation at wavelengths of 620 to 710 nm. This allows tumor tissue to be visualized as red fluorescence. Tissue lacking sufficient PpIX concentrations appears blue.

12.2 Pharmacodynamics

The effect of the timing of the Gleolan dosing on fluorescence intensity in brain tissue is unknown. The relationship between systemic ALA plasma concentrations at the time of visualization and fluorescence intensity in brain is also unknown. The dose of 20 mg / kg provided stronger ALA-induced fluorescence in glioma tissue by both visual and spectrophotometric assessment compared to lower doses tested.

Cardiac Electrophysiology

Administration of the approved recommended dose of Gleolan did not prolong the QT interval to any clinically relevant extent.

12.3 Pharmacokinetics

In 12 healthy subjects, the mean half-life of ALA following the recommended dose of Gleolan solution was 0.9 ± 1.2 hours (mean ± std dev) with a range of 0.8 to 1.3 hours. Maximum concentrations of the PpIX metabolite (T maxfor PpIX) occurred with a median of 4 hours and a range of 1.2 to 7.8 hours. The elimination half-life of PpIX was 3.6 ± 1.8 hours (mean ± std dev) with a range of 1.2 to 7.8 hours.

Absorption

In 12 healthy subjects, the absolute bioavailability of ALA following the recommended dose of Gleolan solution was 100.0% ± 1.1 with a range of 78.5% to 131.2%. Maximum ALA plasma concentrations were reached with a median of 0.8 hour (range 0.5 – 1.0 hour).

Distribution

In in vitro experiments using ALA concentrations up to approximately 25% of the maximal concentration that occurs in plasma following the recommended dose of Gleolan solution, the mean protein binding of ALA was 12%.

Elimination

Metabolism

Exogenous ALA is metabolized to PpIX, but the fraction of administered ALA that is metabolized to PpIX is unknown. The average plasma AUC of PpIX is less than 6% of that of ALA.

Excretion

In 12 healthy subjects, excretion of parent ALA in urine in the 12 hours following administration of the recommended dose of Gleolan solution was 34 ± 8% (mean ± std dev) with a range of 27% to 57%.

Specific Populations

The effect of renal or hepatic impairment on the pharmacokinetics of ALA following Gleolan administration is unknown.

Drug Interaction Studies

In vitro studies suggest that phenytoin and other anti-convulsants may decrease cellular PpIX accumulation following Gleolan dosing.

ALA is not an inhibitor of CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A.

14 CLINICAL STUDIES

The efficacy of 20 mg / kg ALA HCl was evaluated in 3 clinical studies (Study 1-3) involving patients, ages 18 to 75 years old, who had a preoperative MRI compatible with high-grade glioma (WHO Grade III or IV) and were undergoing surgical resection.

Study 1 was an open-label study of 33 patients with newly diagnosed high-grade glioma and Study 2 was an open-label study of 36 patients with recurrent high- grade glioma. In Studies 1 and 2, after initial debulking was carried out under white light, biopsies were obtained under fluorescent light from fluorescent and nonfluorescent sites. Presence of fluorescence (positive/negative) was compared to tumor status (true/false) using histopathology as the reference standard. True positives and false positives among fluorescent biopsies and true negatives and false negatives among nonfluorescent biopsies are provided in Table 1.

Study 3 was a randomized, multicenter study in 415 patients with a preoperative diagnosis of high-grade glioma by MRI. Patients were randomized in 1:1 ratio to ALA fluorescence arm or to white light control arm. Biopsies were obtained from tumor-core, tumor-margin and regions just distant to the tumor margins. In 349 patients high grade glioma was confirmed by a blinded central read and histopathology. The remaining patients were diagnosed with metastatic disease, abscess, low-grade glioma or other conditions.

In patients with confirmed high-grade glioma randomized to the ALA fluorescence arm, presence of fluorescence at a biopsy level was compared to tumor status using histopathology as the reference standard (Table 1). In 4 patients with low-grade glioma (WHO Grade I or II) who received ALA HCl, 9 out of 10 biopsies were false negative.

The extent of resection among patients with confirmed high-grade glioma in the ALA fluorescence arm was compared to that among patient in the control arm, with the "completeness" of resection being determined by a central blinded read of early post-surgical MRI. Percentage of patients who had "completeness" of resection was 64% in the ALA arm and 38% in the control arm, with the difference of 26% [95% CI: (16%, 36%)].

Table 1. Presence of Fluorescence Compared to Histopathology (biopsy level)

	Study 1 (N=297) *	Study 2 (N=370) *	Study 3 (N=479) *
N is Number of total (fluorescent and non-fluorescent) biopsies
Number of Fluorescent Biopsies	185	354	319
True Positive	178	342	312
False Positive	7	12	7
Number of Nonfluorescent Biopsies	112	16	160
True Negative	27	3	30
False Negative	85	13	130

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

Gleolan (NDC 59137-231-01) is supplied as 1,500 mg of lyophilized aminolevulinic acid hydrochloride powder (equivalent to 1,170 mg aminolevulinic acid), for oral solution in a 50-mL clear, colorless, glass vial with a rubber stopper and an aluminum crimp seal.

16.2 Storage and Handling

Store at 25 °C (77 °F); excursions permitted to 15-30 °C (59-86 °F).