2.1 Recommended Dose

• For oral use only
• The recommended oral dose of reconstituted Gleolan is 20 mg / kg body weight. More than 1 vial may be required.

2.2 Reconstitution of Gleolan

Gleolan powder must be reconstituted prior to administration by a healthcare provider according to the following instructions:

• Determine the total number of vials needed to achieve the intended dose for the patient according to the equation below (rounded up to the nearest whole vial):

  # of vials =	Patient Body Weight (kg)
  	75 kg/vial

• Completely remove the white cap and aluminum crimp seal from each vial.
• Remove and retain the rubber stopper from the vial.
• Using an appropriate volumetric measuring device (e.g., flask, graduated cylinder, dosing syringe), measure 50 mL of drinking water and add to each vial containing 1,500 mg of Gleolan.
• Gently swirl the vial to completely dissolve the powder.
• The resulting reconstituted solution (30 mg of Gleolan per mL) is clear and colorless to slightly yellowish.
• If required, replace the stopper and store reconstituted solution for up to 24 hours at room temperature prior to administration.

2.3 Gleolan Administration

Gleolan is for ORAL USE ONLY. The reconstituted Gleolan solution is administered according to the following steps:

• Calculate the administration volume, in mL, to achieve the intended dose according to the following equation:

  Administration Volume (mL) =	Patient Body Weight (kg) * 20 mg/kg
  	30 mg/mL

• Transfer the entire contents of the prepared vial(s) into an appropriate dosing container (e.g., oral medicine bottle); ensure the entire contents of the vials are transferred.
• After transfer, discard the empty vial(s).
• Using a disposable volumetric syringe, remove the administration volume of reconstituted Gleolan solution from the dosing container and transfer to a separate oral dosing container.
• Discard unneeded volume of Gleolan solution.
• Administer orally 3 hours (range 2 to 4 hours) prior to induction of anesthesia.

2.4 Imaging Instructions

• Gleolan must be used with a standard surgical operating microscope adapted with a blue light emitting light source (power density 40-80 mW/cm2) and ancillary excitation and emission filters to visualize fluorescence excitation in the wavelength of 375 to 440 nm and for observation from 620 to 710 nm. Filters transmit porphyrin fluorescence as red-violet, as well as a fraction of backscattered blue excitation light necessary for distinguishing nonfluorescing tissue.
• Gleolan should only be used by neurosurgeons who have completed a training program on use of fluorescence in surgery. Training is provided by the distributor.

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.

6.1 Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of Gleolan is supported by data from 5 open label clinical studies, which included 527 patients with glioma who received ALA HCl. Adverse reactions that occurred in > 1% of patients in the week following surgery were pyrexia, hypotension, nausea, and vomiting. Adverse reactions occurring in the first 6 weeks after surgery in < 1% of patients were: chills, photosensitivity reaction, solar dermatitis, hypotension, abnormal liver function test, and diarrhea. One patient experienced respiratory failure due to drug overdose [see Overdosage (10)].

6.2 Post Marketing Experience

The following adverse reactions are among those that have been identified during post-approval use of Gleolan outside of the United States. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Immune Disorders: anaphylactic shock, angioedema, drug eruption, urticaria, erythema.

Metabolism and Nutrition Disorders: metabolic acidosis.

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.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

The safety and effectiveness of Gleolan in pediatric patients have not been established.

8.5 Geriatric Use

Of 527 subjects in clinical studies of Gleolan, 182 were 65 to < 75 years of age and 7 were ≥ 75 years of age. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. No dose adjustment is required in elderly patients.

8.6 Patients with Renal Impairment

Because approximately one third of the ALA dose is excreted in urine as parent drug, ALA clearance may be reduced in patients with renal impairment; it is not known if dose adjustment is needed [see Clinical Pharmacology (12.3)].

8.7 Patients with Hepatic Impairment

The contribution of the liver to the elimination of ALA following Gleolan dosing is unknown. ALA clearance may be reduced in patients with hepatic impairment; it is not known if dose adjustment is needed [see Clinical Pharmacology (12.3)].

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 C5H10ClNO3. Its molecular weight is 167.59 g/mol with the following structural formula:

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/cm2) 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.

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 (Tmax for 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.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

16.1 How Supplied

Gleolan (NDC 71469-231-01) 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).