DESCRIPTION

GLIADEL® Wafer (polifeprosan20 with carmustine implant) is a sterile, off-white to pale yellow wafer approximately 1.45cm in diameter and 1mm thick. Each wafer contains 192.3mg of a biodegradable polyanhydride copolymer and 7.7mg of carmustine [1,3-bis (2-chloroethyl)-1-nitrosourea, or BCNU]. Carmustine is a nitrosourea oncolytic agent. The copolymer, polifeprosan20, 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 polifeprosan20 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 threeweeks. 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 CO2 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 170mg/m2, the average terminal half-life, clearance, and steady-state volume of distribution were 22minutes, 56mL/min/kg, and 3.25L/kg, respectively. Approximately 60% of the intravenous 200mg/m2 dose of 14C-carmustine was excreted in the urine over 96hours and 6% was expired as CO2.

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 49days after implantation of GLIADEL® Wafer demonstrated that images consistent with wafers were visible to varying degrees in the scans of 11 of 18patients. Data obtained at re-operation and autopsies have demonstrated wafer remnants up to 232days after GLIADEL® Wafer implantation.

Wafer remnants removed at re-operation from two patients with recurrent malignant glioma, one at 64days and the second at 92days 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.

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 120patients and placebo wafers were implanted in 120patients. The majority of patients received 6-8wafers. 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 60Gy) typically starting 3weeks after surgery. There were 17patients (14.2%) in the GLIADEL® Wafer group and 12patients (10.0%) in the placebo group who received systemic chemotherapy during the study. All sixpatients with anaplastic oligodendroglioma received chemotherapy within 30days 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 11.6months with placebo to 13.8months 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-fivepercent of the patients treated with GLIADEL® Wafer had 7-8wafers implanted. Chemotherapy was withheld at least fourweeks (sixweeks for nitrosoureas) prior to and twoweeks after surgery in patients undergoing re-operation for malignant glioma. In 222patients 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 24weeks (5.5months) with placebo to 32weeks (7.4months) 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 20weeks (4.6months) with placebo to 28weeks (6.4months) 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 onecase 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 8mg/kg/day when given on gestation days 6 through 15. Carmustine caused fetal malformations (anophthalmia, micrognathia, omphalocele) at 1.0mg/kg/day (about 1/6 the recommended human dose (eightwafers of 7.7mg carmustine/wafer) on a mg/m2 basis). Carmustine was embryotoxic in rabbits at i.v.doses of 4.0mg/kg/day (about 1.2times the recommended human dose on a mg/m2 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 eva luated.

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 sixmonths, followed by 12months observation, to Swiss mice at i.p.doses of 2.5 and 5.0mg/kg (about 1/5 and 1/3 the recommended human dose (eightwafers of 7.7mg carmustine/wafer) on a mg/m2 basis) and to SD rats at i.p.dose of 1.5mg/kg (about 1/4 the recommended human dose on a mg/m2 basis). There were increases in tumor incidence in all treated animals, predominantly subcutaneous and lung neoplasms. Mutagenesis: Carmustine was mutagenic invitro (Ames assay, human lymphoblast HGPRT assay) and clastogenic both invitro (V79 hamster cell micronucleus assay) and invivo (SCE assay in rodent brain tumors, mouse bone marrow micronucleus assay). Impairment of Fertility: Carmustine caused testicular degeneration at i.p.doses of 8mg/kg/week for eightweeks (about 1.3times the recommended human dose on a mg/m2 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 71months.

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 5days 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 3.5days in patients treated with GLIADEL® Wafer and 61days 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%)

OVERDOSAGE

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

DOSAGE AND ADMINISTRATION

Each GLIADEL® Wafer contains 7.7mg of carmustine, resulting in a dose of 61.6mg 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 Disposal1-7: 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 (polifeprosan20 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 sixhours at a time.

HOW SUPPLIED

GLIADEL® Wafer is available in a single dose treatment box containing eight individually pouched wafers. Each wafer contains 7.7mg 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).

REFERENCES

1. Recommendations for the Safe Handling of Parenteral Antineoplastic Drugs, NIH Publication No. 83-2621. For sale by the Superintendent of Documents, U.S. Government Printing Office, Washington, DC 20402.
2. AMA Council Report, Guidelines for Handling Parenteral Antineoplastics. JAMA, 1985; 253(11):1590-1592.
3. National Study Commission on Cytotoxic Exposure -- Recommendations for Handling Cytotoxic Agents. Available from Louis P. Jeffrey, ScD., Chairman, National Study Commission on Cytotoxic Exposure, Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, Massachusetts 02115.
4. Clinical Oncological Society of Australia, Guidelines and Recommendations for Safe Handling of Antineoplastic Agents. Med J Australia, 1983; 1:426-428.
5. Jones RB, et al: Safe Handling of Chemotherapeutic Agents: A Report from the Mount Sinai Medical Center. CA -- A Cancer Journal for Clinicians, 1983; (Sept/Oct) 258-263.
6. American Society of Hospital Pharmacists Technical Assistance Bulletin on Handling Cytotoxic and Hazardous Drugs. Am J. Hosp Pharm, 1990; 47:1033-1049.
7. OSHA Work-Practice Guidelines for Personnel Dealing with Cytotoxic (Antineoplastic) Drugs. Am J Hosp Pharm, 1986; 43:1193-1204.

NDC: 62856-177-08

CAUTION: FEDERAL LAW PROHIBITS DISPENSING WITHOUT PRESCRIPTION.

Manufactured by

Eisai Inc.
Woodcliff Lake, NJ 07677

Rev. 04/2010

201241

PRINCIPAL DISPLAY PANEL

NDC 62856-177-08

Caution Card:

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