Carmustine (bcnu)

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.

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.

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.

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

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).