Gliadel Drug Information

• Wafer is indicated for the treatment of patients with: newly-diagnosed high-grade glioma as an adjunct to surgery and radiation, and recurrent glioblastoma as an adjunct to surgery. GLIADEL Wafer is an alkylating drug indicated for the treatment of: newly-diagnosed high-grade glioma as an adjunct to surgery and radiation and recurrent glioblastoma as an adjunct to surgery

Recommended Dose

The recommended dose of GLIADEL Wafer is eight 7.7 mg wafers for a total of 61.6 mg implanted intracranially. The safety and effectiveness of repeat administration have not been studied.

Insertion Instructions Following maximal tumor resection, confirmation of tumor pathology and establishment

of hemostasis, place up to a maximum of eight GLIADEL Wafers to cover as much of the resection cavity as possible. Should the size and shape of the resected cavity not accommodate eight wafers, place the maximum number of wafers feasible within the cavity. Slight overlapping of the wafers is acceptable.

Wafers broken in half may be used, but discard wafers broken in more than two pieces. Oxidized regenerated cellulose (Surgicel ® ) may be placed over the wafers to secure them against the cavity surface. After placement of the wafers, irrigate the resection cavity and close the dura in a water-tight fashion.

Preparation and Safe Handling

GLIADEL Wafers contain a cytotoxic drug. Follow applicable special handling and disposal procedures. 1 Each wafer is packaged within two nested aluminum foil laminate pouches. The inner pouch is sterile and is designed to maintain product sterility and protect the product from moisture.

The outside surface of the outer laminated aluminum foil pouch is a peelable overwrap and is not sterile. Deliver GLIADEL Wafers to the operating room in their outer aluminum foil pouch, unopened. Do not open the pouch until the wafers are ready to be implanted.

GLIADEL Wafers in unopened outer foil pouches are stable at room temperature for six hours at a time for up to three cycles within a 30-day period. Exposure to carmustine can cause severe burning and hyperpigmentation of the skin. Use double gloves when handling GLIADEL Wafers.

Discard the outer gloves into a biohazard waste container after use. Use a dedicated surgical instrument for wafer implantation. If repeat neurosurgical intervention is indicated, handle residual wafers or wafer remnants as potential cytotoxic agents.

Instructions for Opening Pouch Containing GLIADEL Wafer Read all steps of the instructions prior to opening the pouch. Instructions for opening the pouch containing GLIADEL Wafer can be viewed at the following website: http://gliadel.com/hcp/pouch-opening-instructions. Illustrations are also pictured below.

Figure 1: To remove the sterile inner pouch from the outer pouch, locate the folded corner and slowly pull in an outward motion. Figure 2: Do NOT pull in a downward motion rolling knuckles over the pouch. This may exert pressure on the wafer and cause it to break.

Figure 3: The inner pouch is a multi-layered, silver colored, foil laminate. Remove the inner pouch by grabbing hold of the crimped edge of the inner pouch using a sterile instrument and pulling upward. Figure 4: To open the inner pouch, gently hold the crimped edge and cut in an arc-like fashion around the wafer.

Figure 5: To remove the GLIADEL Wafer, gently grasp the wafer with the aid of forceps and place it onto a designated sterile field. Figure 1 Figure 2 Figure 3 Figure 4 Figure 5

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 fluid, CDS, or subdural fluid collection; CSF leak; wound dehiscence, breakdown, or poor healing; and 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 fluid, CDS, or subdural fluid collection; CSF leak; wound dehiscence, breakdown, or poor healing; and 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 62.36 Median 3.5

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

Pregnancy Risk Summary GLIADEL Wafer can cause fetal harm when administered to a pregnant woman. There are no available data on GLIADEL use in pregnant women. There have been no animal reproductive studies with GLIADEL Wafer; however, 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 exposures at the recommended human dose based on BSA (see Data ). Advise pregnant women of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data There are no studies assessing the reproductive toxicity of GLIADEL Wafer; however, carmustine, the active component of GLIADEL Wafer, is embryotoxic and teratogenic in rats at intraperitoneal doses of 0.5 mg/kg/day or greater when given on gestation days 6 through 15. Carmustine caused fetal malformations (anophthalmia, micrognathia, omphalocele) at 1 mg/kg/day (about 0.12 times the recommended human dose, eight wafers of 7.7 mg carmustine/wafer, based on BSA). Carmustine was embryotoxic in rabbits at intravenous doses of 4 mg/kg/day (about 1.2 times the recommended human dose based on BSA). Embryotoxicity was characterized by increased embryo-fetal deaths, reduced numbers of litters, and reduced litter sizes.

Pediatric Use The safety and effectiveness of GLIADEL Wafer in pediatric patients have not been established.