卡莫司汀植入膜剂(Gliadel)——全球唯一治疗脑癌的专利植入膜剂药品

About GLIADEL® Wafer
GLIADEL Wafer is a small, dime-sized wafer designed to deliver the chemotherapy drug carmustine directly to the cavity created by the surgical removal of a malignant brain tumor. Please see below for Important Safety Information about GLIADEL Wafer.

GLIADEL Wafer is approved by the U.S. Federal Food and Drug Administration (FDA) to treat patients with a new diagnosis of high grade malignant glioma in addition to surgery and radiation. GLIADEL Wafer is also intended to treat patients with recurrent glioblastoma multiforme (GBM) in addition to surgery.
Learn more about malignant gliomas and therapy with GLIADEL Wafer at About Brain Tumors.
GLIADEL Wafer Clinical Trials
A clinical study was conducted in 240 men and women undergoing surgery for a newly diagnosed high-grade malignant glioma. Each patient was randomly assigned to receive either surgery with GLIADEL Wafer implants followed by radiation or surgery with placebo wafer implants (wafers without carmustine) followed by radiotherapy. Patients who received GLIADEL Wafer in combination with radiotherapy and surgery lived an average of 13.8 months, which was 2.2 months longer than patients who did not receive GLIADEL Wafer.
A second clinical study was conducted in 222 men and women undergoing surgery for a recurrent malignant glioma. Each patient was randomly assigned to receive either surgery with GLIADEL Wafer implants or surgery with placebo wafer implants. In 145 patients with GBM who received GLIADEL Wafer in combination with surgery lived an average of 6.4 months, which was 1.8 months longer than patients who did not receive GLIADEL Wafer.
The results of these studies led to GLIADEL Wafer's FDA approvals.
GLIADEL Wafer Side Effects
Side effects that have been reported in patients receiving GLIADEL Wafer include seizures, brain swelling, healing abnormalities and intracranial infections (e.g. brain abscess and meningitis). Please see Important Safety Information below or click here for full Prescribing Information.
How GLIADEL Wafer is Used
Indications
GLIADEL® Wafer (polifeprosan 20 with carmustine implant) is indicated in patients with newly diagnosed
high-grade malignant glioma as an adjunct to surgery and radiation.
GLIADEL Wafer is also indicated in patients with recurrent glioblastoma multiforme as an adjunct to surgery.
Important Safety Information
You should not be given GLIADEL Wafer if you are allergic to carmustine or any of the components of GLIADEL Wafer.
If you are undergoing surgery for malignant glioma and implantation of GLIADEL Wafer, you should be monitored closely for known complications, including convulsions, infections, abnormal wound healing, and swelling of the brain.
If you are pregnant or are planning to become pregnant, you should understand that carmustine, the active component of GLIADEL Wafer, can cause harm to the fetus if given to a pregnant woman. It is not known if either carmustine, or other components of GLIADEL Wafer are excreted in human milk. Many drugs are excreted in human milk and there is a risk for serious side effects from carmustine in nursing infants; therefore discontinuation of nursing is recommended if you will be receiving GLIADEL Wafer.
It is possible that if GLIADEL Wafers are not implanted properly, they could block the flow of cerebrospinal fluid and might cause abnormal accumulation of fluid in the brain (obstructive hydrocephalus).

The short-term and long-term safety of GLIADEL Wafer when given together with chemotherapy is not fully known.
Following surgery to remove a brain tumor and implantation of GLIADEL Wafer, the following side effects have been reported in clinical studies:
Seizures (convulsions): In clinical studies, seizures have occurred within days or several weeks following implantation of GLIADEL Wafer. Both new seizures and worsening of seizures have been reported.
Brain Swelling: Brain swelling has occurred in clinical studies. In some cases, brain swelling may require another surgery, and removal of GLIADEL Wafers or remnants of the wafers may be required.
Abnormal wound healing: In clinical studies, abnormal healing of the surgical wound has occurred following implantation of GLIADEL Wafer. These abnormalities included reopening of the surgical area, leaking of brain or spinal fluid, delays in healing, or other abnormalities in how the wound heals.
Brain Infections: In clinical studies, brain infections, including meningitis, have occurred following implantation of GLIADEL Wafer.
Please read the full Prescribing Information and discuss it with your doctor or healthcare professional. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.FDA.gov/medwatch or call 1-800-FDA-1088.

GLIADEL WAFER（格立得植入剂）

Gliadel为一种白色至灰白色的一角硬币大小的薄膜，包含生物可降解聚合物聚苯丙生20和7.7mg卡莫司汀（carmustine，BCNU），卡莫司汀是治疗恶性胶质瘤的常用静脉给药的化疗药物。当手术切除脑瘤时，在经手术创建的空腔中可最多植入8片本品。在植入处，Gliadel将缓慢溶解，直接向肿瘤部位释放高浓度卡莫司汀，使扩撒到其它部位的药物减至最少。

Gliadel适应证是新诊断为高度恶性胶质瘤的患者的手术和放疗辅助药物，也可作为多形性胶质母细胞瘤（GBM）复发患者的手术辅助用药。

Polifeprosan 20 with Carmustine Implant

Gliadel Wafer格立得植入剂
 
成分及性状
Gliadel Wafer为直径1.45公分、厚约1公厘的灰白至淡黄色无菌植入製剂。每一片含可生物分解的聚酸酐polifeprosan 20 (polyanhydride
copolymer) 192.3 毫克及carmustine 7.7 毫克。Carmustine均匀分布於polifeprosan 20基质中，并由prolifeprosan 20负责控制carmustine的局部传送。
 
作用
Gliadel Wafer能够直接将carmustine释放至脑癌摘除手术后所造成的腔室内，并扩散至週边的脑组织，藉由对DNA及RNA的烷基化作用而发挥
抗惡性肿瘤作用。
 
药物动力学
Gliadel Wafer中的polifeprosan 20，在动物实验中发现，超过70%於三週内分解，分解后的单体包括carboxyphenoxypropane经由肾臟排除，而sebacic acid则经由肝臟代谢成二氧化碳排出体外。Prolifeprosan 20 在人体内的吸收、分佈、代谢及排除等特性尚不清楚。Gliadel Wafer释放至人体脑腔的carmustine浓度也尚无测量值。植入脑癌摘除手术后腔室的Gliadel Wafer能被生物分解，分解率因人而異。即使所有成分皆被充分分解，但於分解过程中，脑部影像扫瞄或再次手术皆可見到植入剂残餘物尚留在脑内。
 
适应症
作为復发性多形性神经胶母细胞瘤病人的手术辅助。
 
不良反应
1. 癲癇发作：高度惡性神经胶质瘤復发病人之再次手术臨床试验发现，兩组病人的癲癇发作率为19%，手术后五天内癲癇发作的发生率为54% (12/22，Gliadel Wafer组)及9% (2/22，安慰剂组)。手术后第一次癲癇发作时间的平均天數为Gliadel Wafer组3.5天，安慰剂组61天。
2. 脑水肿：新诊断罹患高度惡性神经胶质瘤病人之手术治療臨床试验显示，脑水肿发生率为22.5% (Gliadel Wafer组)及19.2%(安慰剂组)。脑水肿伴随肿块时(可能原因有肿瘤復发、颅内感染、坏死)，可能需要再次手术，
有些病人甚至必须取出Gliadel Wafer或其残留物。
3. 伤口癒合異常：高度惡性神经胶质瘤復发病人之再次手术臨床试验，伤口癒合異常发生率为14%(Gliadel Wafer组)及5%(安慰剂组)。
4. 颅内感染：高度惡性神经胶质瘤復发病人之再次手术臨床试验中，脑脓疡或脑膜炎的发生率为4%(Gliadel Wafer 组) 及1%( 安慰剂组)。
 
注意事项
手术摘除后的腔室应避免与脑室相通，以预防Gliadel Wafer移位至脑室，造成阻塞性水脑。如肿瘤摘除后之腔室与脑室之缺口大於Gliadel
Wafer 的直径， 应填补缺口后再植入GliadelWafer。
 
禁忌
已知对carmustine或本药品其它任一成分过敏的病人禁忌投与Gliadel Wafer。
 
交互作用
目前尚无Gliadel Wafer与其它药品交互作用的研究。化学治療併Gliadel Wafer的短期及长期毒性试验结果尚未完成。放射性治療併Gliadel
Wafer未見任何短期或慢性毒性。
 
剂量及用法
每一片Gliadel Wafer含carmustine 7.7 mg，手术植入八片等於投与剂量61.6 mg。一般建议剂量：於脑癌摘除手术后所造成的腔室内植入Gliadel Wafer八片。若空间不够植入八片，则尽可能以最大能植入的片數植入。目前尚无单次手术植入Gliadel Wafer八片以上的臨床经验，因此不建议植入八片以上。 Gliadel Wafer对儿童的安全性及有效性尚未建立。 
 
储存
零下20°C以下。
 
GLIADEL WAFER IMPLANT DS 8

Generic Name: CARMUSTINE/POLIFEPROSAN 20
Class: R
Manufacture: ONCOLOGY THERAPEUTICS NET
中文名: 卡莫司汀植入膜剂
Strength: 7.7-192.3
Unit/Case: 1
Unit: UNIT

局部瘤腔植入的含卡莫司汀（BCNU）的生物可降解聚合物（Gliadel Wafer, 美国Guilford公司）在一项随机对照的III期临床试验中显示出对新诊断的恶性胶质瘤病人的生存益处（Ⅰ级证据）。由于该移植片尚未在我国上市，故还没有其对国人安全性和有效性的报道。由于尚无大规模的随机对照研究的结果支持，并且费用高,技术要求也高，目前不建议推广动脉化疗和辅助自体骨髓移植。推荐有条件的单位尽快开展MGMT蛋白的免疫组化检测或MGMT基因启动子的甲基化PCR检查，以便更好地开展恶性胶质瘤的个体化化疗。间变性少突胶质细胞瘤和间变性少突-星形细胞瘤患者，若有染色体1p 19q的联合缺失，不但对化疗敏感，而且生存期也明显延长。以贝伐单抗为代表的靶向治疗目前正在研究中。

卡莫司汀植入膜剂对恶性胶质瘤的随访和复发的治疗

强烈推荐以MRI检查为主的定期随访。放疗后2-6周行MRI检查，以后2-3年内每2-4个月MRI检查一次，三年后每3-6个月一次。对复发患者，应该根据复发部位、肿瘤大小、颅内压情况以及患者基本情况综合考虑。局部复发推荐再手术；不适合再手术的患者，可推荐放射治疗和/或化疗；如果以前接受过放疗不适合再放疗者，推荐化疗；化疗失败者，推荐改变化疗方案和/或包括分子靶向治疗的研究性治疗。弥漫或多灶复发者，推荐化疗和/或包括分子靶向治疗的研究性治疗。晚期患者，推荐给予对症支持治疗。

GLIADEL WAFER Rx only (polifeprosan 20 with carmustine implant) | Gliadel

DESCRIPTION
GLIADEL Wafer (polifeprosan 20 with carmustine implant) is a sterile, off-white to pale yellow wafer approximately 1.45 cm in diameter and 1 mm thick. Each wafer contains 192.3 mg of a biodegradable polyanhydride copolymer and 7.7 mg of carmustine [1,3-bis (2-chloroethyl)-1-nitrosourea, or BCNU]. Carmustine is a nitrosourea oncolytic agent. The copolymer, polifeprosan 20, consists of poly[bis(p-carboxyphenoxy) propane: sebacic acid] in a 20:80 molar ratio and is used to control the local delivery of carmustine. Carmustine is homogeneously distributed in the copolymer matrix.
The structural formula for polifeprosan 20 is:

The structural formula for carmustine is:

CLINICAL PHARMACOLOGY

GLIADEL Wafer is designed to deliver carmustine directly into the surgical cavity created when a brain tumor is resected. On exposure to the aqueous environment of the resection cavity, the anhydride bonds in the copolymer are hydrolyzed, releasing carmustine, carboxyphenoxypropane, and sebacic acid. The carmustine released from GLIADEL Wafer diffuses into the surrounding brain tissue and produces an antineoplastic effect by alkylating DNA and RNA.

Carmustine has been shown to degrade both spontaneously and metabolically. The production of an alkylating moiety, hypothesized to be chloroethyl carbonium ion, leads to the formation of DNA cross-links.

The tumoricidal activity of GLIADEL Wafer is dependent on release of carmustine to the tumor cavity in concentrations sufficient for effective cytotoxicity.

More than 70% of the copolymer degrades by three weeks. The metabolic disposition and excretion of the monomers differ. Carboxyphenoxypropane is eliminated by the kidney and sebacic acid, an endogenous fatty acid, is metabolized by the liver and expired as CO in animals.

The absorption, distribution, metabolism, and excretion of the copolymer in humans is unknown. Carmustine concentrations delivered by GLIADEL Wafer in human brain tissue have not been determined. Plasma levels of carmustine after GLIADEL Wafer implant were not determined. In rabbits implanted with wafers containing 3.85% carmustine, no detectible levels of carmustine were found in the plasma or cerebrospinal fluid.

Following an intravenous infusion of carmustine at doses ranging from 30 to 170 mg/m, the average terminal half-life, clearance, and steady-state volume of distribution were 22 minutes, 56 mL/min/kg, and 3.25 L/kg, respectively. Approximately 60% of the intravenous 200 mg/m dose of C-carmustine was excreted in the urine over 96 hours and 6% was expired as CO.

GLIADEL Wafers are biodegradable in human brain when implanted into the cavity after tumor resection. The rate of biodegradation is variable from patient to patient. During the biodegradation process, a wafer remnant may be observed on brain imaging scans or at re-operation even though extensive degradation of all components has occurred. Data obtained from review of CT scans obtained 49 days after implantation of GLIADEL Wafer demonstrated that images consistent with wafers were visible to varying degrees in the scans of 11 of 18 patients. Data obtained at re-operation and autopsies have demonstrated wafer remnants up to 232 days after GLIADEL Wafer implantation.

Wafer remnants removed at re-operation from two patients with recurrent malignant glioma, one at 64 days and the second at 92 days after implantation, were analyzed for content. The following table presents the results of analyses completed on these remnants.

The wafer remnants consisted mostly of water and monomeric components with minimal detectable carmustine present.

COMPOSITION OF WAFER REMNANTS REMOVED FROM TWO PATIENTS ON RE-OPERATION

Component	Patient A	Patient B
Days After GLIADEL® Wafer Implantation	64	92
Anhydride Bonds	None detected	None detected
Water Content (% of wafer remnant weight)	95-97%	74-86%
Carmustine Content (% of initial)	<0.0004%	0.034%
Carboxyphenoxypropane Content (% of initial)	9%	14%
Sebacic Acid Content (% of initial)	4%	3%

CLINICAL STUDIES

Primary Surgery

A randomized, double-blind, placebo-controlled clinical trial was conducted in adult patients with newly-diagnosed high-grade malignant glioma undergoing initial craniotomy for tumor resection. This trial determined the safety and efficacy of GLIADEL Wafer implants plus surgery and radiation therapy compared to placebo implants plus surgery and radiation therapy. Two hundred and forty patients with newly-diagnosed malignant glioma were enrolled. The most common tumor type was Glioblastoma Multiforme (GBM) (n=207), followed by anaplastic oligoastrocytoma (n=11), anaplastic oligodendroglioma (n=11), and anaplastic astrocytoma (n=2). GLIADEL Wafers were implanted at the time of the surgery in 120 patients and placebo wafers were implanted in 120 patients. The majority of patients received 6-8 wafers. The majority of patients (93/120, 77.5% in the GLIADEL Wafer group and 98/120, 81.7% in the placebo group) with newly-diagnosed malignant glioma received a standard course of radiotherapy (55 to 60 Gy) typically starting 3 weeks after surgery. There were 17 patients (14.2%) in the GLIADEL Wafer group and 12 patients (10.0%) in the placebo group who received systemic chemotherapy during the study. All six patients with anaplastic oligodendroglioma received chemotherapy within 30 days of GLIADEL Wafer implantation. Patients were followed for at least three years or until death. Only one patient was lost to follow-up. Median survival increased from 11.6 months with placebo to 13.8 months with GLIADEL Wafer (p-value <0.05, log-rank test). The hazard ratio for GLIADEL Wafer treatment was 0.73 (95% CI: 0.56-0.95).

Kaplan-Meier Overall Survival Curves for Patients Undergoing Initial Surgery for a High-Grade Malignant Glioma

When only patients with Glioblastoma multiforme were included in the analysis, the hazard ratio with GLIADEL Wafer treatment was 0.78 (95% CI: 0.59-1.03, p=0.08, log-rank test).

Surgery for Recurrent Disease

A randomized, double-blind, placebo-controlled clinical trial was conducted in adult patients with recurrent malignant glioma. This trial determined the safety and efficacy of GLIADEL Wafer implants plus surgery compared to placebo implants plus surgery.

Ninety-five percent of the patients treated with GLIADEL Wafer had 7-8 wafers implanted. Chemotherapy was withheld at least four weeks (six weeks for nitrosoureas) prior to and two weeks after surgery in patients undergoing re-operation for malignant glioma. In 222 patients with recurrent malignant glioma who had failed initial surgery and radiation therapy, the six-month survival rate after repeat surgery increased from 47% (53/112) for patients receiving placebo to 60% (66/110) for patients treated with GLIADEL Wafer. Median survival increased by 33%, from 24 weeks (5.5 months) with placebo to 32 weeks (7.4 months) with GLIADEL Wafer treatment. In patients with GBM, the six-month survival rate increased from 36% (26/73) with placebo to 56% (40/72) with GLIADEL Wafer treatment. Median survival of GBM patients increased by 41% from 20 weeks (4.6 months) with placebo to 28 weeks (6.4 months) with GLIADEL Wafer treatment. In patients with pathologic diagnoses other than GBM at the time of surgery for tumor recurrence, GLIADEL Wafer produced no survival prolongation.

6-MONTH KAPLAN-MEIER SURVIVAL CURVES FOR PATIENTS UNDERGOING SURGERY FOR RECURRENT GBM

KAPLAN-MEIER OVERALL SURVIVAL CURVES FOR PATIENTS UNDERGOING SURGERY FOR RECURRENT GBM

INDICATIONS AND USAGE

GLIADEL Wafer is indicated in newly-diagnosed high-grade malignant glioma patients as an adjunct to surgery and radiation. GLIADEL Wafer is indicated in recurrent glioblastoma multiforme patients as an adjunct to surgery.

CONTRAINDICATIONS

GLIADEL Wafer contains carmustine. GLIADEL Wafer should not be given to individuals who have demonstrated a previous hypersensitivity to carmustine or any of the components of GLIADEL Wafer.

WARNINGS

Patients undergoing craniotomy for malignant glioma and implantation of GLIADEL Wafer should be monitored closely for known complications of craniotomy, including seizures, intracranial infections, abnormal wound healing, and brain edema. Cases of intracerebral mass effect unresponsive to corticosteroids have been described in patients treated with GLIADEL Wafer, including one case leading to brain herniation.

Pregnancy: There are no studies assessing the reproductive toxicity of GLIADEL Wafer. Carmustine, the active component of GLIADEL Wafer, can cause fetal harm when administered to a pregnant woman. Carmustine has been shown to be embryotoxic and teratogenic in rats at i.p. doses of 0.5, 1, 2, 4, or 8 mg/kg/day when given on gestation days 6 through 15. Carmustine caused fetal malformations (anophthalmia, micrognathia, omphalocele) at 1.0 mg/kg/day (about 1/6 the recommended human dose (eight wafers of 7.7 mg carmustine/wafer) on a mg/m basis). Carmustine was embryotoxic in rabbits at i.v. doses of 4.0 mg/kg/day (about 1.2 times the recommended human dose on a mg/m basis). Embryotoxicity was characterized by increased embryo-fetal deaths, reduced numbers of litters, and reduced litter sizes.

There are no studies of GLIADEL Wafer in pregnant women. If GLIADEL Wafer is used during pregnancy, or if the patient becomes pregnant after GLIADEL Wafer implantation, the patient must be warned of the potential hazard to the fetus.

PRECAUTIONS

General

Communication between the surgical resection cavity and the ventricular system should be avoided to prevent the wafers from migrating into the ventricular system and causing obstructive hydrocephalus. If a communication larger than the diameter of a wafer exists, it should be closed prior to wafer implantation.

Computed tomography and magnetic resonance imaging of the head may demonstrate enhancement in the brain tissue surrounding the resection cavity after implantation of GLIADEL Wafers. This enhancement may represent edema and inflammation caused by GLIADEL Wafer or tumor progression.

Therapeutic Interactions

Interactions of GLIADEL Wafer with other drugs have not been formally evaluated.

The short-term and long-term toxicity profiles of GLIADEL Wafer when given in conjunction with chemotherapy have not been fully explored. GLIADEL Wafer, when given in conjunction with radiotherapy does not appear to have any short-term or chronic toxicities.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity, mutagenicity or impairment of fertility studies have been conducted with GLIADEL Wafer. Carcinogenicity, mutagenicity and impairment of fertility studies have been conducted with carmustine, the active component of GLIADEL Wafer. Carmustine was given three times a week for six months, followed by 12 months observation, to Swiss mice at i.p. doses of 2.5 and 5.0 mg/kg (about 1/5 and 1/3 the recommended human dose (eight wafers of 7.7 mg carmustine/wafer) on a mg/m basis) and to SD rats at i.p. dose of 1.5 mg/kg (about 1/4 the recommended human dose on a mg/m basis). There were increases in tumor incidence in all treated animals, predominantly subcutaneous and lung neoplasms. Mutagenesis: Carmustine was mutagenic in vitro (Ames assay, human lymphoblast HGPRT assay) and clastogenic both in vitro (V79 hamster cell micronucleus assay) and in vivo (SCE assay in rodent brain tumors, mouse bone marrow micronucleus assay). Impairment of Fertility: Carmustine caused testicular degeneration at i.p. doses of 8 mg/kg/week for eight weeks (about 1.3 times the recommended human dose on a mg/m basis) in male rats.

Pregnancy

Pregnancy Category D: see WARNINGS .

Nursing Mothers

It is not known if either carmustine, carboxyphenoxypropane, or sebacic acid is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from carmustine in nursing infants, it is recommended that patients receiving GLIADEL Wafer discontinue nursing.

Pediatric Use

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

ADVERSE REACTIONS

Adverse reactions for the trials are described in the tables below.

Primary Surgery

The following data are the most frequently occurring adverse events observed in 5% or more of the newly-diagnosed malignant glioma patients during the trial.

Surgery for Recurrent Disease

The following post-operative adverse events were observed in 4% or more of the patients receiving GLIADEL Wafer at recurrent surgery. Except for nervous system effects, where there is a possibility that the placebo wafers could have been responsible, only events more common in the GLIADEL Wafer group are listed. These adverse events were either not present pre-operatively or worsened post-operatively during the follow-up period. The follow-up period was up to 71 months.

Post-marketing experience includes spontaneous reports of cyst formation after GLIADEL wafer implantation. These occurred at varying time intervals post-implantation. Cyst formation has also been reported in patients following resection of malignant glioma who have not had Gliadel implanted.

The following four categories of adverse events are possibly related to treatment with GLIADEL Wafer. The frequency with which they occurred in the randomized trials along with descriptive detail is provided below.

1. Seizures: In the initial surgery trial, the incidence of seizures was 33.3% in patients receiving GLIADEL Wafer and 37.5% in patients receiving placebo. Grand mal seizures occurred in 5% of GLIADEL Wafer-treated patients and 4.2% of placebo treated patients. The incidence of seizures within the first 5 days after wafer implantation was 2.5% in the GLIADEL Wafer group and 4.2% in the placebo group. The time from surgery to the onset of the first post-operative seizure did not differ between the GLIADEL Wafer and placebo treated patients.

In the surgery for recurrent disease trial, the incidence of post-operative seizures was 19% in both patients receiving GLIADEL Wafer and placebo. In this study, 12/22 (54%) of patients treated with GLIADEL Wafer and 2/22 (9%) of placebo patients experienced the first new or worsened seizure within the first five post-operative days. The median time to onset of the first new or worsened post-operative seizure was 3.5 days in patients treated with GLIADEL Wafer and 61 days in placebo patients.

2. Brain Edema: In the initial surgery trial, brain edema was noted in 22.5% of patients treated with GLIADEL Wafer and in 19.2% of patients treated with placebo. Development of brain edema with mass effect (due to tumor recurrence, intracranial infection, or necrosis) may necessitate re-operation and, in some cases, removal of GLIADEL Wafer or its remnants.

3. Healing Abnormalities: The following healing abnormalities have been reported in clinical trials of GLIADEL Wafer: wound dehiscence, delayed wound healing, subdural, subgaleal or wound effusions, and cerebrospinal fluid leak. In the initial surgery trial, healing abnormalities occurred in 15.8% of GLIADEL Wafer treated patients and in 11.7% of placebo recipients. Cerebrospinal fluid leaks occurred in 5% of GLIADEL Wafer recipients and 0.8% of those given placebo. During surgery, a water-tight dural closure should be obtained to minimize the risk of cerebrospinal fluid leak.

In the surgery for recurrent disease trial, the incidence of healing abnormalities was 14% in GLIADEL Wafer treated patients and 5% in patients receiving placebo wafers.

4. Intracranial Infection: In the initial surgery trial, the incidence of brain abscess or meningitis was 5% in patients treated with GLIADEL Wafer and 6% in patients receiving placebo. In the recurrent setting, the incidence of brain abscess or meningitis was 4% in patients treated with GLIADEL Wafer and 1% in patients receiving placebo.

The following adverse events, not listed in the table above, were reported in less than 4% but at least 1% of patients treated with GLIADEL Wafer in all studies. The events listed were either not present pre-operatively or worsened post-operatively. Whether GLIADEL Wafer caused these events cannot be determined.

Body as a Whole: peripheral edema (2%); neck pain (2%); accidental injury (1%); back pain (1%); allergic reaction (1%); asthenia (1%); chest pain (1%); sepsis (1%)

Cardiovascular System: hypertension (3%); hypotension (1%)

Digestive System: diarrhea (2%); constipation (2%); dysphagia (1%); gastrointestinal hemorrhage (1%); fecal incontinence (1%)

Hemic and Lymphatic System: thrombocytopenia (1%); leukocytosis (1%)

Metabolic and Nutritional Disorders: hyponatremia (3%); hyperglycemia (3%); hypokalemia (1%)

Musculoskeletal System: infection (1%)

Nervous System: hydrocephalus (3%); depression (3%); abnormal thinking (2%); ataxia (2%); dizziness (2%); insomnia (2%); monoplegia (2%); coma (1%); amnesia (1%); diplopia (1%); paranoid reaction (1%). In addition, cerebral hemorrhage and cerebral infarct were each reported in less than 1% of patients treated with GLIADEL Wafer.

Respiratory System: infection (2%); aspiration pneumonia (1%)

Skin and Appendages: rash (2%)

Special Senses: visual field defect (2%); eye pain (1%)

Urogenital System: urinary incontinence (2%)

COMMON ADVERSE EVENTS OBSERVED IN ≥ 5% OF PATIENTS RECEIVING GLIADEL^® WAFER AT INITIAL SURGERY

Body System    Adverse Event	GLIADEL® Wafer [N=120] n (%)	Placebo [N=120] n (%)
*Adverse events coded to the COSTART term "aggravation reaction" were usually events involving tumor/disease progression or general deterioration of condition (e.g. condition/health/Karnofsky/neurological/physical deterioration).
Body as a Whole
Aggravation reaction*	98 (82)	95 (79)
Headache	33 (28)	44 (37)
Asthenia	26 (22)	18 (15)
Infection	22 (18)	24 (20)
Fever	21 (18)	21 (18)
Pain	16 (13)	18 (15)
Abdominal pain	10 (8)	2 (2)
Back pain	8 (7)	4 (3)
Face edema	7 (6)	6 (5)
Abscess	6 (5)	3 (3)
Accidental injury	6 (5)	8 (7)
Chest pain	6 (5)	0
Allergic reaction	2 (2)	6 (5)
Cardiovascular system
Deep thrombophlebitis	12 (10)	11 (9)
Pulmonary embolus	10 (8)	10 (8)
Hemorrhage	8 (7)	7 (6)
Digestive system
Nausea	26 (22)	20 (17)
Vomiting	25 (21)	19 (16)
Constipation	23 (19)	14 (12)
Diarrhea	6 (5)	5 (4)
Liver function tests abnormal	1 (1)	6 (5)
Endocrine system
Diabetes mellitus	6 (5)	5 (4)
Cushings syndrome	4 (3)	6 (5)
Metabolic and nutritional disorders
Healing abnormal	19 (16)	14 (12)
Peripheral edema	11 (9)	11 (9)
Musculoskeletal system
Myasthenia	5 (4)	6 (5)
Nervous system
Hemiplegia	49 (41)	53 (44)
Convulsion	40 (33)	45 (38)
Confusion	28 (23)	25 (21)
Brain edema	27 (23)	23 (19)
Aphasia	21 (18)	22 (18)
Depression	19 (16)	12 (10)
Somnolence	13 (11)	18 (15)
Speech disorder	13 (11)	10 (8)
Amnesia	11 (9)	12 (10)
Intracranial hypertension	11 (9)	2 (2)
Personality disorder	10 (8)	9 (8)
Anxiety	8 (7)	5 (4)
Facial paralysis	8 (7)	5 (4)
Neuropathy	8 (7)	12 (10)
Ataxia	7 (6)	5 (4)
Hypesthesia	7 (6)	6 (5)
Paresthesia	7 (6)	10 (8)
Thinking abnormal	7 (6)	10 (8)
Abnormal gait	6 (5)	6 (5)
Dizziness	6 (5)	11 (9)
Grand mal convulsion	6 (5)	5 (4)
Hallucinations	6 (5)	4 (3)
Insomnia	6 (5)	7 (6)
Tremor	6 (5)	8 (7)
Coma	5 (4)	6 (5)
Incoordination	3 (3)	8 (7)
Hypokinesia	2 (2)	8 (7)
Respiratory system
Pneumonia	10 (8)	9 (8)
Dyspnea	4 (3)	8 (7)
Skin and appendages
Rash	14 (12)	13 (11)
Alopecia	12 (10)	14 (12)
Special senses
Conjunctival edema	8 (7)	8 (7)
Abnormal vision	7 (6)	7 (6)
Visual field defect	6 (5)	8 (7)
Eye disorder	3 (3)	6 (5)
Diplopia	1 (1)	6 (5)
Urogenital system
Urinary tract infection	10 (8)	13 (11)
Urinary incontinence	9 (8)	9 (8)

COMMON ADVERSE EVENTS OBSERVED IN ≥ 4% OF PATIENTS RECEIVING GLIADEL^® WAFER AT SURGERY FOR RECURRENT DISEASE

Body System Adverse Event	GLIADEL® Wafer with Carmustine [N=110] n (%)	PLACEBO Wafer without Carmustine [N=112] n (%)
*p < 0.05 for comparison of GLIADEL® Wafer versus placebo groups
Body as a Whole
Fever	13 (12)	9 (8)
Pain*	8 (7)	1 (1)
Digestive System
Nausea and Vomiting	9 (8)	7 (6)
Metabolic and Nutritional Disorders
Healing Abnormal*	15 (14)	6 (5)
Nervous System
Convulsion	21 (19)	21 (19)
Hemiplegia	21 (19)	22 (20)
Headache	16 (15)	14 (13)
Somnolence	15 (14)	12 (11)
Confusion	11 (10)	9 (8)
Aphasia	10 (9)	12 (11)
Stupor	7 (6)	7 (6)
Brain Edema	4 (4)	1 (1)
Intracranial Hypertension	4 (4)	7 (6)
Meningitis or Abscess	4 (4)	1 (1)
Skin and Appendages
Rash	6 (5)	4 (4)
Urogenital System
Urinary Tract Infection	23 (21)	19 (17)

OVERDOSAGE

There is no clinical experience with use of more than eight GLIADEL Wafers per surgical procedure.

DOSAGE AND ADMINISTRATION

Each GLIADEL Wafer contains 7.7 mg of carmustine, resulting in a dose of 61.6 mg when eight wafers are implanted. It is recommended that eight wafers be placed in the resection cavity if the size and shape of it allows. Should the size and shape not accommodate eight wafers, the maximum number of wafers as allowed should be placed. Since there is no clinical experience, no more than eight wafers should be used per surgical procedure.

Handling and Disposal : Wafers should only be handled by personnel wearing surgical gloves because exposure to carmustine can cause severe burning and hyperpigmentation of the skin. Use of double gloves is recommended and the outer gloves should be discarded into a biohazard waste container after use. A surgical instrument dedicated to the handling of the wafers should be used for wafer implantation. If repeat neurosurgical intervention is indicated, any wafer or wafer remnant should be handled as a potentially cytotoxic agent.

GLIADEL Wafer should be handled with care. The aluminum foil laminate pouches containing GLIADEL Wafer should be delivered to the operating room and remain unopened until ready to implant the wafers. The outside surface of the outer foil pouch is not sterile.

Instructions for Opening Pouch Containing GLIADEL Wafer

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: Remove the inner pouch by grabbing hold of the crimped edge 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.

Once the tumor is resected, tumor pathology is confirmed, and hemostasis is obtained, up to eight GLIADEL Wafers (polifeprosan 20 with carmustine implant) may be placed to cover as much of the resection cavity as possible. Slight overlapping of the wafers is acceptable. Wafers broken in half may be used, but wafers broken in more than two pieces should be discarded in a biohazard container. Oxidized regenerated cellulose (Surgicel) may be placed over the wafers to secure them against the cavity surface. After placement of the wafers, the resection cavity should be irrigated and the dura closed in a water tight fashion.

Unopened foil pouches may be kept at ambient room temperature for a maximum of six hours at a time.

HOW SUPPLIED

GLIADEL Wafer is available in a single dose treatment box containing eight individually pouched wafers. Each wafer contains 7.7 mg of carmustine and is packaged in two aluminum foil laminate pouches. The inner pouch is sterile and is designed to maintain product sterility and protect the product from moisture. The outer pouch is a peelable overwrap. The outside surface of the outer pouch is not sterile.

GLIADEL Wafer must be stored at or below -20°C (-4°F).