Gleolan

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.

• For oral use only (
  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.
  )
• Recommended reconstituted oral dose of Gleolan is 20 mg/kg. (
  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.
  )
• Administer Gleolan to patient orally 3 hours (range 2 to 4 hours) before anesthesia. (
  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.
  )
• See Full Prescribing Information for reconstitution information. (
  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.
  )
• Use appropriate visualization techniques with appropriate surgical microscopes and light source filters. (
  2.4 Imaging Instructions

  • Gleolan should 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.
  )

For oral solution: 1,500 mg aminolevulinic acid hydrochloride (ALA HCl) lyophilized powder, equivalent to 1,170 mg aminolevulinic acid (ALA) , in a 50 mL single-dose clear, colorless, glass vial with rubber stopper. After reconstitution with 50 mL drinking water, the solution contains 30 mg per mL of aminolevulinic acid hydrochloride (equivalent to 23.4 mg per mL of aminolevulinic acid) and is clear and colorless to slightly yellowish in color.

There are no available human data on Gleolan in pregnant women to inform a drug associated risk of adverse developmental outcomes. In animal reproduction studies, no adverse developmental effects were observed with oral ALA HCl administration to pregnant rabbits during organogenesis at doses 3 times the maximum recommended human oral dose

The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

• 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. Reduce exposure to sunlight or room lights for 48 hours after oral administration of Gleolan. (
  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.
  ,
  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.
  )
• Risk of misinterpretation: Non-fluorescing tissue in the surgical field does not rule out the presence of tumor. (
  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.
  ,
  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)N is Number of total (fluorescent and non-fluorescent) biopsies	Study 2 (N=370)	Study 3 (N=479)
  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
  )