Gliadel

5 WARNINGS AND PRECAUTIONS Seizures: Monitor patients for seizures following implantation ( 5.1 ). Intracranial hypertension: Monitor patients for signs of increased intracranial pressure ( 5.2 ). Impaired neurosurgical wound healing: Monitor patients for complications of craniotomy ( 5.3 ). Meningitis: Monitor patients for signs of bacterial or chemical meningitis ( 5.4 ). Wafer migration: Monitor patients for signs of obstructive hydrocephalus ( 5.5 ). Embryo-fetal toxicity: Can cause fetal harm. Advise patients of the potential risk to a fetus. Advise males and females of reproductive potential to use an effective method of contraception. ( 5.6 , 8.1 , 8.3 ). 5.1 Seizures Seizures occurred in 37% of patients treated with GLIADEL Wafers for recurrent glioma in Study 2. New or worsening (treatment emergent) seizures occurred in 20% of patients; 54% of treatment emergent seizures occurred within the first 5 post-operative days [see Adverse Reactions (6.1) ]. The median time to onset of the first new or worsened post-operative seizure was four days. Institute optimal anti-seizure therapy prior to surgery. Monitor patients for seizures postoperatively. 5.2 Intracranial Hypertension Brain edema occurred in 23% of patients with newly diagnosed glioma treated with GLIADEL Wafers in Study 1. Additionally, one GLIADEL-treated patient experienced intracerebral mass effect unresponsive to corticosteroids which led to brain herniation [see Adverse Reactions (6.1) ] . Monitor patients closely for intracranial hypertension related to brain edema, inflammation, or necrosis of the brain tissue surrounding the resection. In refractory cases, consider re-operation and removal of GLIADEL Wafers or Wafer remnants. 5.3 Impaired Neurosurgical Wound Healing Impaired neurosurgical wound healing including wound dehiscence, delayed wound healing, and subdural, subgaleal, or wound effusions occur with GLIADEL Wafer treatment. In Study 1, 16% of GLIADEL Wafer-treated patients with newly diagnosed glioma experienced impaired intracranial wound healing and 5% had cerebrospinal fluid leaks. In Study 2, 14% of GLIADEL Wafer-treated patients with recurrent high-grade glioma experienced wound healing abnormalities [see Adverse Reactions (6.1) ]. Monitor patients post-operatively for impaired neurosurgical wound healing. 5.4 Meningitis Meningitis occurred in 4% of patients with recurrent glioma receiving GLIADEL Wafers in Study 2. Two cases of meningitis were bacterial; one patient required removal of the Wafers four days after implantation; the other developed meningitis following reoperation for recurrent tumor. One case was diagnosed as chemical meningitis and resolved following steroid treatment. In one case the cause was unspecified, but meningitis resolved following antibiotic treatment. Monitor postoperatively for signs of meningitis and central nervous system infection. 5.5 Wafer Migration GLIADEL Wafer migration can occur. To reduce the risk of obstructive hydrocephalus due to wafer migration into the ventricular system, close any communication larger than the diameter of a Wafer between the surgical resection cavity and the ventricular system prior to Wafer implantation. Monitor patients for signs of obstructive hydrocephalus. 5.6 Embryo-Fetal Toxicity GLIADEL Wafers can cause fetal harm when administered to a pregnant woman. Carmustine, the active component of GLIADEL Wafer, is embryotoxic and teratogenic in rats at exposures less than the exposure at the recommended human dose based on body surface area (BSA) and embryotoxic in rabbits at exposures similar to the exposure at the recommended human dose based on BSA. Advise patients of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception for 6 months after implantation of GLIADEL Wafer. Advise males with female partners of reproductive potential to use effective contraception for 3 months following implantation of GLIADEL Wafers [see Use in Specific Populations (8.1 , 8.3) , Nonclinical Toxicology (13.1) ].

6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: Seizures [ see Warnings and Precautions (5.1) ] Intracranial Hypertension [ see Warnings and Precautions (5.2) ] Impaired Neurosurgical Wound Healing [ see Warnings and Precautions (5.3) ] Meningitis [ see Warnings and Precautions (5.4) ] Newly-Diagnosed High-Grade Glioma: Most common adverse reactions (incidence >10% and between arm difference ≥4%) are cerebral edema, asthenia, nausea, vomiting, constipation, wound healing abnormalities and depression ( 6.1 ). Recurrent High-Grade Glioma: Most common adverse reactions (incidence >10% and between arm difference ≥4%) are urinary tract infection, wound healing abnormalities and fever ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Azurity Pharmaceuticals, Inc. at 1-800-461-7449 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials 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. Newly-Diagnosed High-Grade Glioma The safety of GLIADEL Wafers was evaluated in a multicenter, randomized (1:1), double-blind, placebo controlled trial of 240 adult patients with newly-diagnosed high-grade glioma who received up to eight GLIADEL Wafers or matched placebo implanted against the resection surfaces after maximal tumor resection (Study 1). The population in Study 1 was 67% male and 97% White, and the median age was 53 years (range: 21-72). Eighty-seven percent had a Karnofsky performance status ≥ 70 and 71% had a Karnofsky performance status of ≥ 80%. Seventy-eight percent had a histologic subtype of glioblastoma as determined by central pathology review. Thirty-eight percent of patients received 8 wafers and 78% received ≥ 6 wafers. Starting three weeks after surgery, 80% of patients received standard limited field radiation therapy (RT) described as 55-60 Gy delivered in 28 to 30 fractions over six weeks; an additional 11% received no radiotherapy and the remainder received non-standard radiotherapy or a combination of standard and non-standard radiotherapy. At the time of progression, 12% received systemic chemotherapy. Deaths occurred within 30 days of wafer implantation in 5 (4%) of patients receiving GLIADEL Wafers compared to 2 (2%) of patients receiving placebo. Deaths on the GLIADEL arm resulted from cerebral hematoma/edema (n=3), pulmonary embolism (n=1) and acute coronary event (n=1). Deaths on the placebo arm resulted from sepsis (n=1) and malignant disease (n=1). The incidence of common adverse reactions in GLIADEL Wafer-treated patients is listed in Table 1. The incidence of local adverse reactions is shown in Table 2. Table 1. Per-Patient Incidence of Adverse Reactions Occurring in Gliadel Wafer-Treated Patients with Newly-Diagnosed High-Grade Glioma (Study 1) (Between Arm Difference of ≥ 4%) Adverse Reaction GLIADEL Wafer N=120 Placebo N=120 % % GASTROINTESTINAL Nausea 22 17 Vomiting 21 16 Constipation 19 12 Abdominal pain 8 2 GENERAL AND ADMINISTRATION SITE CONDITION Asthenia 22 15 Chest pain 5 0 INJURY, POISONING AND PROCEDURAL COMPLICATIONS Wound healing abnormalities Included (1) fluid, CDS, or subdural fluid collection; (2) CSF leak; (3) wound dehiscence, breakdown, or poor healing; and (4) subgaleal or wound effusions (including yellow discharge at the incision) 16 12 MUSCULOSKELETAL AND CONNECTIVE TISSUE Back pain 7 3 PSYCHIATRIC Depression 16 10 Table 2. Incidence of Local Adverse Reactions, Study 1 Not seen at baseline or worsened if present at baseline. Local Adverse Reactions GLIADEL Wafer N=120 Placebo N=120 % % Cerebral edema 23 19 Intracranial hypertension 9 2 Cerebral hemorrhage 6 4 Brain abscess 6 4 Brain cyst 2 3 Recurrent High-Grade Glioma The safety of GLIADEL Wafers was evaluated in a multicenter, randomized (1:1), double-blind, placebo controlled trial of 222 patients with recurrent high-grade glioma who received up to eight GLIADEL Wafers or matched placebo implanted against the resection surfaces after maximal tumor resection (Study 2). Patients were required to have had prior definitive external beam radiation therapy sufficient to disqualify them from additional radiation therapy. All patients were eligible to receive chemotherapy which was withheld at least four weeks (six weeks for nitrosoureas) prior to and two weeks after surgery. The population in Study 2 was 64% male, 92% White, and the median age was 49 years (range: 19-80). Sixty-five percent had a histologic subtype of glioblastoma, 26% had anaplastic astrocytoma or another anaplastic variant, 73% had a Karnofsky performance status ≥ 70, 53% had a Karnofsky performance status of ≥ 80%, 73% had only one prior surgery, and 46% had prior treatment with nitrosourea. Eighty-one percent of patients received 8 wafers and 96% received ≥ 6 wafers. Sixty-four severe adverse reactions were reported in 43(39%) patients receiving GLIADEL Wafers. Adverse reactions in GLIADEL Wafer-treated patients are shown in Table 3. Meningitis occurred in four patients receiving GLIADEL Wafers and in no patients receiving placebo. Bacterial meningitis was confirmed in two patients: the first with onset four days following GLIADEL Wafer implantation; the second following resection for tumor recurrence 155 days following GLIADEL Wafer implantation. One case, attributed to chemical meningitis resolved following steroid treatment. The cause of the fourth case was undetermined but resolved following antibiotic treatment. Table 3. Per-Patient Incidence of Adverse Reactions in Gliadel Wafer-Treated Patients with Recurrent High-Grade Glioma (Study 2) (Between Arm Difference of ≥ 4%) Adverse Reaction GLIADEL Wafer N=110 Placebo N=112 % % GENERAL Fever 12 8 INFECTIOUS Urinary tract infections 21 17 INJURY, POISONING AND PROCEDURAL COMPLICATIONS Wound healing abnormalities Included (1) fluid, CDS, or subdural fluid collection; (2) CSF leak; (3) wound dehiscence, breakdown, or poor healing; and (4) subgaleal or wound effusions (including yellow discharge at the incision) 14 5 The incidence of seizures is shown in Table 4. The incidence of hydrocephalus, cerebral edema and intracranial hypertension is shown in Table 5. Table 4. Incidence of Seizures, Study 2 Adverse Reaction GLIADEL Wafer N=110 Placebo N=112 Patients with seizures (%) Any seizures after wafer implantation 37 29 New or worsening seizures 20 20 Time to new or worsening seizures (days) Days from implantation to onset of first new or worsening seizure. Mean (SD) 26.09 (0.75) 62.36 (48.66) Median 3.5 61.0 Table 5. Hydrocephalus and Cerebral Edema, Study 2 Not seen at baseline or worsened if present at baseline. Adverse Reaction GLIADEL Wafer N=110 Placebo N=112 % % Hydrocephalus 5 2 Cerebral edema 4 1

<table width="85%"><caption>Table 1. Per-Patient Incidence of Adverse Reactions Occurring in Gliadel Wafer-Treated Patients with Newly-Diagnosed High-Grade Glioma (Study 1) (Between Arm Difference of &#x2265; 4%)</caption><col width="64%" align="left" valign="top"/><col width="18%" align="center" valign="top"/><col width="18%" align="center" valign="top"/><thead><tr styleCode="Botrule"><th rowspan="2" styleCode="Lrule Rrule" valign="middle">Adverse Reaction</th><th styleCode="Rrule">GLIADEL Wafer N=120 </th><th styleCode="Rrule">Placebo N=120 </th></tr><tr><th align="center" styleCode="Rrule">%</th><th align="center" styleCode="Rrule">%</th></tr></thead><tbody><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule">GASTROINTESTINAL</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Nausea</td><td styleCode="Rrule">22</td><td styleCode="Rrule">17</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Vomiting</td><td styleCode="Rrule">21</td><td styleCode="Rrule">16</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Constipation</td><td styleCode="Rrule">19</td><td styleCode="Rrule">12</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Abdominal pain</td><td styleCode="Rrule">8</td><td styleCode="Rrule">2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">GENERAL AND ADMINISTRATION SITE CONDITION</td><td/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Asthenia</td><td styleCode="Rrule">22</td><td styleCode="Rrule">15</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Chest pain</td><td styleCode="Rrule">5</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">INJURY, POISONING AND PROCEDURAL COMPLICATIONS</td><td/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Wound healing abnormalities <footnote ID="K1035">Included (1) fluid, CDS, or subdural fluid collection; (2) CSF leak; (3) wound dehiscence, breakdown, or poor healing; and (4) subgaleal or wound effusions (including yellow discharge at the incision)</footnote></td><td styleCode="Rrule">16</td><td styleCode="Rrule">12</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">MUSCULOSKELETAL AND CONNECTIVE TISSUE</td><td/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Back pain</td><td styleCode="Rrule">7</td><td styleCode="Rrule">3</td></tr><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule">PSYCHIATRIC</td></tr><tr><td styleCode="Lrule Rrule">Depression</td><td styleCode="Rrule">16</td><td styleCode="Rrule">10</td></tr></tbody></table>

<table width="85%"><caption>Table 2. Incidence of Local Adverse Reactions, Study 1 <footnote ID="K1082">Not seen at baseline or worsened if present at baseline.</footnote></caption><col width="64%" align="left" valign="top"/><col width="18%" align="center" valign="top"/><col width="18%" align="center" valign="top"/><thead><tr styleCode="Botrule"><th rowspan="2" styleCode="Lrule Rrule" valign="middle">Local Adverse Reactions</th><th styleCode="Rrule">GLIADEL Wafer N=120 </th><th styleCode="Rrule">Placebo N=120 </th></tr><tr><th align="center" styleCode="Rrule">%</th><th align="center" styleCode="Rrule">%</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Cerebral edema</td><td styleCode="Rrule">23</td><td styleCode="Rrule">19</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Intracranial hypertension</td><td styleCode="Rrule">9</td><td styleCode="Rrule">2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Cerebral hemorrhage</td><td styleCode="Rrule">6</td><td styleCode="Rrule">4</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Brain abscess</td><td styleCode="Rrule">6</td><td styleCode="Rrule">4</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Brain cyst</td><td styleCode="Rrule">2</td><td styleCode="Rrule">3</td></tr></tbody></table>

<table width="85%"><caption>Table 3. Per-Patient Incidence of Adverse Reactions in Gliadel Wafer-Treated Patients with Recurrent High-Grade Glioma (Study 2) (Between Arm Difference of &#x2265; 4%)</caption><col width="64%" align="left" valign="top"/><col width="18%" align="center" valign="top"/><col width="18%" align="center" valign="top"/><thead><tr styleCode="Botrule"><th rowspan="2" styleCode="Lrule Rrule" valign="middle">Adverse Reaction</th><th styleCode="Rrule">GLIADEL Wafer N=110 </th><th styleCode="Rrule">Placebo N=112 </th></tr><tr><th align="center" styleCode="Rrule">%</th><th align="center" styleCode="Rrule">%</th></tr></thead><tbody><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule">GENERAL</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Fever</td><td styleCode="Rrule">12</td><td styleCode="Rrule">8</td></tr><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule">INFECTIOUS</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Urinary tract infections</td><td styleCode="Rrule">21</td><td styleCode="Rrule">17</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">INJURY, POISONING AND PROCEDURAL COMPLICATIONS</td><td/><td styleCode="Rrule"/></tr><tr><td styleCode="Lrule Rrule">Wound healing abnormalities <footnote ID="K1290">Included (1) fluid, CDS, or subdural fluid collection; (2) CSF leak; (3) wound dehiscence, breakdown, or poor healing; and (4) subgaleal or wound effusions (including yellow discharge at the incision)</footnote></td><td styleCode="Rrule">14</td><td styleCode="Rrule">5</td></tr></tbody></table>