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:

GLIADEL 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 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 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 ₂ in animals.

The absorption, distribution, metabolism, and excretion of the copolymer in humans is unknown. Carmustine concentrations delivered by GLIADEL 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 ² , 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 ² dose of ¹⁴ C-carmustine was excreted in the urine over 96 hours and 6% was expired as CO ₂ .

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 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 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.

CLINICAL STUDIES

In a randomized, double-blind, placebo-controlled clinical trial in adults with recurrent malignant glioma, GLIADEL prolonged survival in patients with glioblastoma multiforme (GBM). Ninety-five percent of the patients treated with GLIADEL had 7-8 wafers implanted.

In 222 patients with recurrent malignant glioma who had failed initial surgery and radiation therapy, the six-month survival rate after surgery increased from 47% (53/112) for patients receiving placebo to 60% (66/110) for patients treated with GLIADEL. Median survival increased by 33%, from 24 weeks with placebo to 32 weeks with GLIADEL treatment. In patients with GBM, the six-month survival rate increased from 36% (26/73) with placebo to 56% (40/72) with GLIADEL treatment. Median survival of GBM patients increased by 41% from 20 weeks with placebo to 28 weeks with GLIADEL treatment. In patients with pathologic diagnoses other than GBM at the time of surgery for tumor recurrence, GLIADEL produced no survival prolongation.

GLIADEL is indicated for use as an adjunct to surgery to prolong survival in patients with recurrent glioblastoma multiforme for whom surgical resection is indicated.

CONTRAINDICATIONS

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

Patients undergoing craniotomy for malignant glioma and implantation of GLIADEL 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, including one case leading to brain herniation.

Pregnancy:   There are no studies assessing the reproductive toxicity of GLIADEL. Carmustine, the active component of GLIADEL, 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 ²  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 ² basis). Embryotoxicity was characterized by increased embryo-fetal deaths, reduced numbers of litters, and reduced litter sizes.

There are no studies of GLIADEL in pregnant women. If GLIADEL is used during pregnancy, or if the patient becomes pregnant after GLIADEL 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 exists, it should be closed prior to wafer implantation.

Imaging Studies:   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 or tumor progression.

Therapeutic Interactions:   Interactions of GLIADEL with other drugs or radiotherapy have not been formally evaluated. In clinical trials, few patients have received systemic chemotherapy within 30 days of GLIADEL (6) or external beam radiation therapy (36). 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. External beam radiation therapy was initiated no sooner than three weeks after GLIADEL implantation. Of the 36 patients who received GLIADEL at initial surgery for newly diagnosed, malignant glioma followed by external beam radiation therapy, 3/15 (20%) in one study and 11/21 (52%) in the other study experienced new or worsened seizures. Patients were followed for a maximum of 24 months. The short and long-term toxicity profiles of GLIADEL when given in conjunction with radiation or chemotherapy have not been fully explored.

Carcinogenesis, Mutagenesis, Impairment of Fertility:   No carcinogenicity, mutagenicity or impairment of fertility studies have been conducted with GLIADEL. Carcinogenicity, mutagenicity and impairment of fertility studies have been conducted with carmustine, the active component of GLIADEL. 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 ² 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 ² 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 ² basis) in male rats.

Pregnancy   Pregnancy Category D: see .

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 discontinue nursing.

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

ADVERSE REACTIONS

Data in the following table are based on the experience of 222 patients with recurrent malignant glioma randomized to GLIADEL or placebo (wafer without carmustine).

The spectrum of adverse events observed in patients who received GLIADEL or placebo in clinical studies was consistent with that encountered in patients undergoing craniotomy for malignant gliomas.

GLIADEL was not reported to be the cause of death in any of the GLIADEL clinical trials.

The following post-operative adverse events were observed in 4% or more of the patients receiving GLIADEL in the placebo-controlled clinical trial. 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 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 in the randomized trial was up to 71 months.

The following adverse events were also reported in 4-9% of GLIADEL patients but were at least as frequent in the placebo group as in GLIADEL-treated patients: infection, deep thrombophlebitis, pulmonary embolism, nausea, oral moniliasis, anemia, hyponatremia, pneumonia.

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

1. Seizures: In the randomized study, the majority of seizures in the placebo and GLIADEL groups were mild or moderate in severity. The incidence of new or worsened seizures was 19% in patients treated with GLIADEL and 19% in patients receiving placebo. Of the patients with new or worsened seizures post-operatively, 12/22 (54%) of patients treated with GLIADEL 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 and 61 days in placebo patients. The occurrence of seizures did not reduce the survival benefit of GLIADEL.

2. Brain Edema: In the randomized trial, brain edema was noted in 4% of patients treated with GLIADEL and in 1% 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 wafer or its remnants.

3. Healing Abnormalities: The majority of these events were mild to moderate in severity. Healing abnormalities occurred in 14% of GLIADEL-treated patients compared to 5% of placebo recipients. These events included cerebrospinal fluid leaks, subdural fluid collections, subgaleal or wound effusions, and wound breakdown.

4. Intracranial Infection: In the randomized trial, intracranial infection (meningitis or abscess) occurred in 4% of patients treated with GLIADEL and in 1% of patients receiving placebo. In GLIADEL-treated patients, there were two cases of bacterial meningitis, one case of chemical meningitis, and one case of meningitis which was not further specified. A brain abscess developed in one placebo-treated patient. The rate of deep wound infection (infection of subgaleal space, bone, meninges, or neural parenchyma) was 6% in both GLIADEL and placebo treated patients.

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 in all studies (n=273). The events listed were either not present pre-operatively or worsened post-operatively. Whether GLIADEL 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.

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 7.7 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 1-7 :   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 wafers should be handled with care. The aluminum foil laminate pouches containing GLIADEL 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

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 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 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: 0075-9995-08

CAUTION:   FEDERAL LAW PROHIBITS DISPENSING WITHOUT PRESCRIPTION.

U.S. Patent Nos. 4,789,724 and 5,179,189.

Manufactured for

Aventis Pharmaceuticals Products Inc.

Parsippany, NJ 07054

By

Guilford Pharmaceuticals Inc.

Baltimore, MD 21224

Rev. 10/96                               IN-2250!

PRODUCT PHOTO(S):