GLEOLAN

5 WARNINGS AND PRECAUTIONS 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 , 7 ) Risk of misinterpretation: Non-fluorescing tissue in the surgical field does not rule out the presence of tumor. ( 5.2 , 14 ) 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 ADVERSE REACTIONS Adverse reactions occurring in >1% of patients in the week following surgery were pyrexia, hypotension, nausea, and vomiting. ( 6.1 ) Adverse reactions occurring in < 1% of patients in the first 6 weeks after surgery were: chills, photosensitivity reaction, solar dermatitis, hypotension, abnormal liver function test, and diarrhea. ( 6.1 ) Neurologic events related to the surgical procedure occurred in 29% of patients and included: aphasia, hemiparesis, hemianopia, headache, seizure, hemiplegia, monoparesis, hypoesthesia, and brain edema. ( 6.1 ) Elevated liver enzymes occurred in clinical studies. There were no cases of liver failure. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact NXDC toll-free at (844) 517-5252 and adverseevents@nxdevcorp.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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) ] . Neurologic Events Nervous system disorders occurred in 29% of patients within the first week after surgery. Events occurring in > 1% of patients included aphasia (8%), hemiparesis (7.8%), hemianopsia (3.2%), headache (2.7%), seizure (1.9%), hemiplegia (1.9%), monoparesis (1.3%) and hypoesthesia (1.1%). Brain edema occurred in < 1 % of patients in the first 6 weeks after surgery. In a randomized clinical trial (Study 3), the numbers of serious neurologic adverse events in the post operative period were higher in patients randomized to ALA fluorescence arm compared to the control arm. An imbalance was notable for the adverse events aphasia, ataxia, convulsion and hemianopsia, and is likely related to the higher amount of brain resection performed in the ALA arm. At longer follow up periods, the numbers between the two arms appeared similar [see Clinical Trials (14) ] . Elevated Liver Enzymes Worsening of ≥ 2 Common Toxicity Criteria (CTC) grades in alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT) occurred in (15.8% and 11.6%, respectively) within the first week after surgery. Absolute levels ranged from 2 times to greater than 10 times the upper limit of normal (ULN) for each parameter. At 6 weeks, ALT remained elevated in 2.9% of patients (range 2 to greater than 5 X ULN), and GGT was elevated in 7.5% of patients (range 2 to greater than 10 X ULN). No cases of liver failure occurred. 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.