DESCRIPTION. Eisai Co., Ltd. 1. Revised: July 2016 (9th version)

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1 Eisai Co., Ltd. 1 Revised: July 2016 (9th version) Standard Commodity Classification No. of Japan Anticancer Drug- GLIADEL 7.7 mg Implant < Carmustine argent for intracerebral implant > Powerful drug and Prescription drug Storage GLIADEL should be stored under light-protected condition at or below -15 C. Expiration date GLIADEL should be used before the expiration date indicated on the package or label. Note) Caution : Use only as directed by a physician. APPROVAL NO AMX Date of listing in the NHI reimbursement price Nov 2012 Date of initial marketing in Japan Jan 2013 International birth date Sep1996 WARNINGS GLIADEL should only be administered to patients in whom implanting the product is considered appropriate, by physicians with adequate knowledge and experience regarding surgery and pharmacotherapy for malignant tumors, and in medical facilities that are able to sufficiently handle emergency situations. CONTRAINDICATIONS (GLIADEL is contraindicated in the following patients) 1. Patients with a history of hypersensitivity to any of the ingredients of GLIADEL 2. Pregnant women and women who may possibly be pregnant (see the Use during Pregnancy, Delivery or Lactation section) DESCRIPTION Brand Name GLIADEL 7.7 mg Implant Ingredient/Content (Content per Wafer) 7.7 mg as carmustine in a single wafer Inactive Ingredient mg of polifeprosan 20 Pale yellowish white to pale yellow, Dosage Form/Color disk-shaped, extended-release formulation for intracerebral implantation Size diameter, approx mm thickness, approx. 1.3 mm INDICATIONS Malignant glioma Precautions 1. GLIADEL should be implanted after histology of the tumor is confirmed by intraoperative rapid histopathological diagnosis or other examinations. 2. Intended patients should be selected after gaining full knowledge from the PHARMACOKINETICS and CLINICAL STUDIES sections, regarding the range of carmustine diffusion from GLIADEL and the rates of tumor resection, tumor histology, etc., in patients enrolled in clinical studies, and adequately understanding the efficacy and safety of GLIADEL. DOSAGE AND ADMINISTRATION The usual adult dosage for implantation is 8 wafers (61.6 mg as carmustine) or less as appropriate, depending on the size and/or shape of the tumor resection cavity. An appropriate number of wafers should be implanted so that they cover the resection surface resulting from brain tumor resection. Precaution 1. Slight overlapping of the GLIADEL wafers due to the size and/or shape of the resection cavity is acceptable. However, the wafers should not fill the space within the resection cavity that does not touch the tissue surface of the brain. 2. The efficacy and safety of GLIADEL when used after splitting the product into pieces have not been established. 3. The efficacy and safety of GLIADEL when implanted more than once have not been established. PRECAUTIONS 1. Important Precautions (1) In cases where a communication between the resection cavity and ventricular system is observed after surgical resection of the tumor, GLIADEL wafers should be implanted after taking necessary actions, such as closing the communication before using GLIADEL (as the wafers may migrate into the ventricular system and induce hydrocephalus). (2) Leakage of cerebrospinal fluid may be observed in patients receiving implantation of GLIADEL. Measures such as dural closure at the time of surgery should thus be performed properly.

2 2 Eisai Co., Ltd. (3) In cases where computed tomography and magnetic resonance imaging after implantation of GLIADEL show contrast enhancement in brain tissue around the resection cavity, conduct of appropriate measures should be considered, bearing in mind that such enhancement may be attributable to placement of GLIADEL or to tumor enlargement. (4) It has been reported that the gas accumulation is found in patients in the implantation site of GLIADEL and the neurological symptoms occurred in these patients. Patients should be closely observed for neurological symptoms such as hemiplegia, aphasia, disturbed consciousness, etc. after the implantation of GLIADEL. If any abnormality is observed, appropriate treatment must be taken. 2. Adverse Reactions <Japanese Clinical Studies> In a clinical study conducted in Japan involving 24 patients, adverse reactions (including abnormal laboratory test values) were observed in 13 patients (54.2%). The main adverse reactions were: cerebral edema, 6 patients (25.0%); fever, 3 patients (12.5%); decreased lymphocytes, 3 patients (12.5%); hemiplegia (including hemiparesis), 3 patients (12.5%); nausea, 2 patients (8.3%); vomiting, 2 patients (8.3%); decreased appetite, 2 patients (8.3%); headache, 2 patients (8.3%); and increased ALT( GPT), 2 patients (8.3%). (at the time of approval) (1) Clinically Significant Adverse Reactions 1) Convulsions and Grand Mal Convulsions (incidences unknown Note) ) Convulsions and grand mal convulsions may occur, so the patient should be observed carefully. If any abnormality is observed, appropriate treatment must be taken, such as administration of anticonvulsants. 2) Cerebral Edema, Increased Intracranial Pressure, Hydrocephalus, Encephalocele Cerebral edema (25.0%), increased intracranial pressure (incidence unknown Note) ), hydrocephalus (incidence unknown Note) ), and encephalocele (incidence unknown Note) ) may occur, so the patient should be observed carefully. If any abnormality is observed, appropriate treatment must be taken. 3) Impaired Wound Healing (incidence unknown Note) ) GLIADEL may affect wound healing. Furthermore, leakage of cerebrospinal fluid, wound dehiscence due to delayed wound healing, and wound complications may occur, so the patient should be observed carefully. If any abnormality is observed, appropriate treatment must be taken. 4) Infections (incidence unknown Note) ) Infections such as post-operative wound infection, abscess, and meningitis may occur, so the patient should be observed carefully. If any abnormality is observed, appropriate treatment must be taken. 5) Thromboembolism (incidence unknown Note) ) Thromboembolisms such as cerebral infarction, deep venous embolism, and pulmonary embolism may occur, so the patient should be observed carefully. If any abnormality is observed, appropriate treatment must be taken. 6) Hemorrhage (incidence unknown Note) ) Hemorrhagic symptoms such as tumor hemorrhage, cerebral hemorrhage, and intracranial hemorrhage may occur, so the patient should be observed carefully. If any abnormality is observed, appropriate treatment must be taken. (2) Other Adverse Reactions In cases where adverse reactions listed in the table below occur, appropriate treatment must be taken according to the symptoms. 5% 1%, <5% Systemic Fever Hypothermia, edema Neuropsychiatric Headache, hemiplegia Aphasia, hypoesthesia, memory disturbance, hemianopia, monoplegia Incidence unknown * Face edema, asthenia, malaise, swelling, phyma, cyst, pain, chest pain, weight decrease Confusional state, depression, dissociation, emotional lability, agitation, hallucination, abnormal thinking, personality disorder, anxiety, disorientation, insomnia, paranoia, dementia, somnolence, stupor, dyskinesia, paraesthesia, speech disorder, abnormal coordination, dysarthria, coma, paresthesia, unresponsive to stimuli, visual field defect, tremor, cranial nerve paralysis, dizziness, partial seizures, migraine, peripheral neuropathy, lethargy Sensory Strabismus Eye muscle paralysis, mydriasis, papilledema, visual disturbance, blindness, amblyopia, diplopia, vision blurred, photophobia, tinnitus Hematologic Lymphocyte count decreased Platelet count decreased, white blood cell count increased White blood cell count decreased, prothrombin level decreased, pancytopenia, anemia, hypovolemia

3 Eisai Co., Ltd. 3 Hepatic Renal / Urological Cardiovascular Gastrointestinal Dermatological Musculoskeletal Respiratory Metabolic / endocrine Infection Others 5% 1%, <5% ALT (GPT) increased Nausea, vomiting, decreased appetite Urinary incontinence Abdominal discomfort Irregular menstruation, CRP increased, CK (CPK) increased Incidence unknown * Liver function test abnormal, Al-P increased Urinary retention, loss of bladder sensation, pollakiuria, polyuria, sugar urinary Shock, hypertension, hypotension, cyanosis, tachycardia, electrocardiogram abnormal, cardiac output abnormal Diarrhea, constipation Pruritus, skin discoloration, urticaria, hyperhidrosis, rash Twitching, musculoskeletal rigidity, cervical pain, back pain, pain in extremities, muscle weakness Hiccup, dyspnea, aspiration pneumonia Diabetes insipidus, hyperglycemia, dehydration, hyponatremia, hypomagnesemia Sepsis, candidiasis, herpes zoster, urinary tract infection, cellulitis Post procedural hematoma, incision site pain, incision site edema incision site erythema, subgaleal hematoma, wound decomposition, inflammation of wound, cerebrospinal fluid retention, ventriculitis, cystic lymphangioma, pleocytosis *Note: Adverse reactions noted only in overseas countries are classified as incidence unknown". 3. Use during Pregnancy, Delivery or Lactation (1) GLIADEL should not be implanted in pregnant women or women who may possibly be pregnant. Women with child-bearing potential should be directed to use appropriate contraceptive methods for at least 2 weeks after implantation of GLIADEL. Men who have partners with child-bearing potential should also be directed to use appropriate contraceptive methods for at least 3 months. (Fetal toxicity and teratogenicity in pregnant animals [rabbits and rats], and decreased fertility and increased rates of embryonic death in male animals [rats] have been reported with administration of carmustine, the active ingredient of GLIADEL.) (2) Lactating women must stop breastfeeding when undergoing implantation of GLIADEL. (A study using animals [rats] has demonstrated transfer of radiation into milk with intravenous administration of 14 C-labeled carmustine.) 4. Pediatric Use The safety of GLIADEL in children has not been established (no clinical experience). 5. Precautions concerning Use (1) When Preparing GLIADEL 1) The product (packed in double aluminum foil laminate pouches) should be carried from storage (at or below -15 C) to the operation room while still sealed, and the pouches should not be opened until preparation for intracerebral implantation has been completed. 2) The product (when sealed) is stable for 6 h at room temperature. 3) The product (when sealed) left for 6 h or less at room temperature may be refrozen (at or below -15 C) just once, but any refrozen product should be used within 6 months. (2) Opening the Double Aluminum Foil Laminate Pouches Precautions to be taken when opening the pouches are shown in a different section, as the wafer is easily breakable. (See Illustration) (3) When Implanting GLIADEL 1) GLIADEL should be implanted after removing the tumor and obtaining sufficient hemostasis, so that the wafers cover the resection surface to the greatest possible extent. Slight overlap of the wafers due to the size and/or shape of the resection cavity is acceptable. (See Illustration) 2) In principle, GLIADEL should be discarded and not used in cases where a wafer is already broken in separate pieces at the time of pouch opening due to impacts during transportation and other reasons. (The release of carmustine was similar between a wafer broken in half and a whole wafer. However, the efficacy and safety of wafers used in separate pieces have not been established. See the <Precautions> section under DOSAGE AND ADMINISTRATION.) 6. Other Precautions Presence of genotoxicity as with other alkylating agents, and development of tumors in the lymphatic tissues, lungs, etc., of mice and rats have been reported with carmustine, the active ingredient of GLIADEL.

4 4 Eisai Co., Ltd. PHARMACOKINETICS After implantation of GLIADEL into the cavity created by resection of a tumor, it is believed that polifeprosan 20 is hydrolyzed, and that carmustine, 1,3-bis(4-carboxyphenoxy) propane (CPP), and sebacic acid (SA) are released. 1. Carmustine (1) Absorption Whole blood concentration of carmustine was measured after 7.3 (mean) wafers of GLIADEL (range, 5-8 wafers) were implanted in 6 Japanese patients with newly diagnosed malignant glioma or recurrent glioblastoma. The results showed that carmustine concentrations reached ng/ml within approximately 3 hours after GLIADEL implantation, but then remained below the lowest limit of quantitation (2.0 ng/ml) 24 hours after implantation and thereafter. Concentrations of carmustine delivered into human brain tissue after GLIADEL implantation have not been determined. 1) (Reference): Penetration region of carmustine in the animal brain tissue 2) When a polymer containing 20% 3 H-labeled carmustine (containing approximately 5 times the amount of carmustine contained in GLIADEL) was implanted into monkey brain, the penetration region of radiation in the brain tissue (defined as the region in which radioactivity concentration reached 10% of that at the polymer/tissue interface) is reportedly 6.1 mm at 1 day after implantation and 2.9 mm at 14 days after implantation. (2) Distribution 3) The human plasma protein-binding ratio of carmustine in vitro (0 degrees Celcius) has been reported as approximately 80%. (3) Metabolism 4) In an in vitro metabolism study using human hepatic microsomes and cytosol, carmustine is considered to be metabolized into 1.3-bis(2-chloroethyl) urea via denitrosation in microsomes, and also to be non-enzymatically metabolized into 2 chloroethylisocyanate, followed by formation of glutathione conjugate. (4) Excretion 5) When 14 C-labeled carmustine 200 mg/m 2 was intravenously administered in a single dose to non-japanese patients with malignant tumor, approximately 60% of the administered radioactivity was reportedly excreted in urine and less than 1% in feces within 96 hours after administration, and approximately 6% was excreted in expired breath as 14 C-CO Polifeprosan 20 The pharmacokinetics of polifeprosan 20 in humans remains unknown. (Reference): Pharmacokinetics of polifeprosan 20 in animals 6) Polifeprosan 20 (containing carmustine) synthesized with 14 C-labeled SA or CPP was placed in the brains of rats and rabbits. In rats, 11% of the radioactivity derived from 14 C-SA was excreted in urine, 1% in feces, and 46% in expired breath (as 14 C-CO 2 ) within 7 days after administration, while 8% remained in wafer remnants in the brain. In rabbits, 62% of the radioactivity derived from 14 C-CPP was excreted in urine and 2% in feces within 21 days after administration, and 29% remained in wafer remnants in the brain. CLINICAL STUDIES 1. Results from Japanese clinical studies 1) An uncontrolled open-label clinical study was conducted in 16 patients with newly diagnosed malignant glioma and 8 patients with recurrent glioblastoma, and the safety and efficacy of GLIADEL implanted following tumor resection were evaluated. Histopathological types of the 24 patients were determined by central pathological diagnosis, showing the following findings: glioblastoma in 9 patients and non-glioblastoma in 7 patients (anaplastic oligodendroglioma in 3 patients, oligodendroglioma in 2 patients, anaplastic ganglioglioma and oligo-astrocytoma in 1 patient each) for the newly diagnosed patients, and glioblastoma in 4 patients and non-glioblastoma in 4 patients (anaplastic oligodendroglioma, anaplastic oligo-astrocytoma, anaplastic astrocytoma, and high-grade glioma in 1 patient each) for patients with recurrence. The mean rate (± standard deviation) of patients undergoing tumor resection when GLI- ADEL was implanted was 91.9 ± 8.5% among newly diagnosed patients, 87.3 ± 17.0% in patients with recurrence, and 90.3 ± 11.8% overall. In newly diagnosed patients, combination therapy consisting of temozolomide and radiation was performed after GLIADEL implantation. Eight wafers were implanted in 21 of the 24 patients, with 5, 6, and 7 wafers in one each of the remaining 3 patients. The results showed the 12-month survival rate obtained with Kaplan-Meier analysis was 100.0% in the newly diagnosed patients, and 6- and 12-month survival rates were 87.5% and 62.5%, respectively, among patients with recurrence. The median survival period at 12 months was impossible to calculate for both newly diagnosed patients and patients with recurrence. Among newly diagnosed patients, the progression-free survival rate was 75.0% (95% confidence interval [CI], %) at 6 months and 62.5% (95%CI, %) at 12 months. The median duration of progression-free survival was impossible to calculate at 12 months. In patients with recurrence, the progression-free survival rate was 37.5% (95%CI, %) at 6 months, and 25.0% (95%CI, %) at 12 months. The median duration of progression-free survival was 170 days. PHARMACOLOGY 1. Anti-tumor effect 7) Carmustine has been proved to prolong the survival of mice in which the U-87 MG cell line derived from human glioblastoma had been transplanted. 2. Mechanism of action 8-11) Carmustine is considered to induce cell-cycle arrest and apoptosis by alkylating DNA and inhibiting nucleic acid synthesis.

5 Eisai Co., Ltd. 5 PHYSICOCHEMISTRY Nonproprietary name: Carmustine Chemical name: 1,3-bis(2-chloroethyl)-1-nitrosourea Molecular formula: C 5 H 9 Cl 2 N 3 O 2 Molecular weight: Structural formula: REQUESTS FOR LITERATURE AND PRODUCT INFORMATION SHOULD BE MADE TO: Customer Drug Information Service Free Dial: Eisai Co., Ltd. Nobelpharma Co., Ltd. Customer Center 12-10, Nihonbashi Kobuna-cho, Chuo-ku, Tokyo, , Japan TEL: Description: Carmustine occurs as a light-yellow powder. It is very soluble in dimethylsulfoxide, ethanol (95), dichloromethane, or acetonitrile, soluble in propylene glycol, methanol, or anhydrous diethyl ether, and slightly soluble in water. Melting point: Approximately 31 C PRECAUTIONS FOR HANDLING Carmustine may cause severe burns and pigmentation if it comes into contact with the skin. GLIADEL should be handled with caution. Manufactured and marketed by: Eisai Co., Ltd. 6-10, Koishikawa 4-chome, Bunkyo-ku, Tokyo, Co-promoted by: Nobelpharma Co., Ltd , Nihonbashi Kobuna-cho, Chuo-ku, Tokyo, PACKAGING GLIADEL 7.7 mg Implant: 8 wafers (8 pouches that contain one wafer each), 4 wafers (4 pouches that contain one wafer each), 1 wafer (1 pouch that contain one wafer) REFERENCES 1) Aoki T, et al.: Neurol Med Chir (Tokyo) 2014; 54: ) Fung LK, et al.: Cancer Res. 1998; 58: ) Loo TL, et al.: J Pharma Sci 1966; 55: ) Company data: Metabolism study of carmustine using human hepatic microsome and human hepatic cytosole 5) DeVita VT, et al.: Clin Pharmacol Ther 1967;8: ) Company data: Pharmacokinetics of polyfeprosan 20 in rats and rabbits 7) Company data: Anti-tumor effect of carmustine on intracranial transplant model of human glioblastoma cell line (U-87MG) 8) Chabner BA, et al.: Goodman & Gilman s The pharmacological basis of therapeutics 11 th ed. 2006; ) Tashima M, et al.: Biochem Pharmacol 1979; 28: ) Batista LFZ, et al.: Cancer Res 2007; 67; ) Xu GW, et al.: Int J Cancer 2005; 116:

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