NDC 24338-050 Gliadel

Carmustine

NDC Product Code 24338-050

NDC CODE: 24338-050

Proprietary Name: Gliadel What is the Proprietary Name?
The proprietary name also known as the trade name is the name of the product chosen by the medication labeler for marketing purposes.

Non-Proprietary Name: Carmustine What is the Non-Proprietary Name?
The non-proprietary name is sometimes called the generic name. The generic name usually includes the active ingredient(s) of the product.

Drug Use Information

Drug Use Information
The drug use information is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate. This information is not individual medical advice and does not substitute for the advice of a health care professional. Always ask a health care professional for complete information about this product and your specific health needs.

  • This medication is used to treat certain types of cancer (including multiple myeloma, brain tumor, Hodgkin's disease, non-Hodgkin's lymphoma). Carmustine belongs to a class of drugs known as alkylating agents. It works by slowing or stopping the growth of cancer cells.

Product Characteristics

Color(s):
WHITE (C48325)
Shape: ROUND (C48348)
Size(s):
15 MM
Score: 1

NDC Code Structure

  • 24338 - Arbor Pharmaceuticals

NDC 24338-050-08

Package Description: 8 POUCH in 1 BOX > 1 WAFER in 1 POUCH

NDC Product Information

Gliadel with NDC 24338-050 is a a human prescription drug product labeled by Arbor Pharmaceuticals. The generic name of Gliadel is carmustine. The product's dosage form is wafer and is administered via intracavitary form. The RxNorm Crosswalk for this NDC code indicates multiple RxCUI concepts are associated to this product: 212994 and 309013.

Dosage Form: Wafer - A thin slice of material containing a medicinal agent.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Gliadel Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.


Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • POLIFEPROSAN 20 (UNII: S40C40DA21)

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Intracavitary - Administration within a non-pathologic cavity, such as that of the cervix, uterus, or penis, or such as that which is formed as the result of a wound.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Alkylating Activity - [MoA] (Mechanism of Action)
  • Alkylating Drug - [EPC] (Established Pharmacologic Class)

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Arbor Pharmaceuticals
Labeler Code: 24338
FDA Application Number: NDA020637 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: NDA - A product marketed under an approved New Drug Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 12-13-2012 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2021 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N - NO What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA"s requests for correction to deficient or non-compliant submissions ("Y"), or because the listing certification is expired ("E"), or because the listing data was inactivated by FDA ("I"). Values = "Y", "N", "E", or "I".

* Please review the disclaimer below.

Information for Patients

Carmustine Implant

Carmustine Implant is pronounced as (kar mus' teen)

Why is carmustine implant medication prescribed?
Carmustine implant is used along with surgery and sometimes radiation therapy to treat malignant glioma (a certain type of cancerous brain tumor). Carmustine is in a clas...
[Read More]

* Please review the disclaimer below.

Gliadel Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

1 Indications And Usage

  • GLIADEL Wafer is indicated for the treatment of patients with:newly-diagnosed high-grade malignant glioma as an adjunct to surgery and radiation, andrecurrent glioblastoma multiforme as an adjunct to surgery.

2.1 Recommended Dose

The recommended dose of GLIADEL Wafer is eight 7.7 mg wafers for a total of 61.6 mg implanted intracranially. The safety and effectiveness of repeat administration have not been studied.

2.2 Insertion Instructions

Following maximal tumor resection, confirmation of tumor pathology and establishment of hemostasis, place up to a maximum of eight GLIADEL Wafers to cover as much of the resection cavity as possible. Should the size and shape of the resected cavity not accommodate eight wafers, place the maximum number of wafers feasible within the cavity. Slight overlapping of the wafers is acceptable. Wafers broken in half may be used, but discard wafers broken in more than two pieces. Oxidized regenerated cellulose (Surgicel®) may be placed over the wafers to secure them against the cavity surface. After placement of the wafers, irrigate the resection cavity and close the dura in a water-tight fashion.

2.3 Preparation And Safe Handling

GLIADEL Wafers contain a cytotoxic drug. Follow applicable special handling and disposal procedures.1Each wafer is packaged within two nested aluminum foil laminate pouches. The inner pouch is sterile and is designed to maintain product sterility and protect the product from moisture. The outside surface of the outer laminated aluminum foil pouch is a peelable overwrap and is not sterile.Deliver GLIADEL Wafers to the operating room in their outer aluminum foil pouch, unopened. Do not open the pouch until the wafers are ready to be implanted. GLIADEL Wafers in unopened outer foil pouches are stable at room temperature for six hours at a time for up to three cycles within a 30-day period.Exposure to carmustine can cause severe burning and hyperpigmentation of the skin. Use double gloves when handling GLIADEL Wafers. Discard the outer gloves into a biohazard waste container after use. Use a dedicated surgical instrument for wafer implantation. If repeat neurosurgical intervention is indicated, handle residual wafers or wafer remnants as potential cytotoxic agents.

Other

Instructions for Opening Pouch Containing GLIADEL WaferRead all steps of the instructions prior to opening the pouch.Instructions for opening the pouch containing GLIADEL Wafer can be viewed at the following website: http://gliadel.com/hcp/pouch-opening-instructions. Illustrations are also pictured below.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: The inner pouch is a multi-layered, silver colored, foil laminate. Remove the inner pouch by grabbing hold of the crimped edge of the inner pouch using a sterile instrument 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.

Newly-Diagnosed High-Grade Malignant GliomaThe safety of GLIADEL Wafers was evaluated in a multicenter, randomized (1:1), double-blind, placebo controlled trial of 240 adult patients with newly-diagnosed high-grade malignant glioma who received up to eight GLIADEL Wafers or matched placebo implanted against the resection surfaces after maximal tumor resection (Study 1).The population in Study 1 was 67% male and 97% White, and the median age was 53 years (range: 21-72). Eighty-seven percent had a Karnofsky performance status ≥ 70 and 71% had a Karnofsky performance status of ≥ 80%. Seventy-eight percent had a histologic subtype of glioblastoma multiforme as determined by central pathology review. Thirty-eight percent of patients received 8 wafers and 78% received ≥ 6 wafers. Starting three weeks after surgery, 80% of patients received standard limited field radiation therapy (RT) described as 55-60 Gy delivered in 28 to 30 fractions over six weeks; an additional 11% received no radiotherapy and the remainder received non-standard radiotherapy or a combination of standard and non-standard radiotherapy. At the time of progression, 12% received systemic chemotherapy.Deaths occurred within 30 days of wafer implantation in 5 (4%) of patients receiving GLIADEL Wafers compared to 2 (2%) of patients receiving placebo. Deaths on the GLIADEL arm resulted from cerebral hematoma/edema (n=3), pulmonary embolism (n=1) and acute coronary event (n=1). Deaths on the placebo arm resulted from sepsis (n=1) and malignant disease (n=1).The incidence of common adverse reactions in GLIADEL Wafer-treated patients is listed in Table 1. The incidence of local adverse reactions is shown in Table 2.Table 1. Per-Patient Incidence of Adverse Reactions Occurring in Gliadel Wafer-Treated Patients with Newly-Diagnosed High Grade Malignant Glioma (Study 1) (Between Arm Difference of ≥ 4%)BODY SYSTEMGLIADEL WaferN=120PlaceboN=120%%GASTROINTESTINAL DISORDERS  Nausea2217  Vomiting2116  Constipation1912  Abdominal pain82GENERAL DISORDERS ANDADMINISTRATION SITE CONDITION  Asthenia2215  Chest pain50INJURY, POISONING AND PROCEDURALCOMPLICATIONS  Wound healing abnormalitiesIncluded (1) fluid, CDS, or subdural fluid collection; (2) CSF leak; (3) wound dehiscence, breakdown, or poor healing; and (4) subgaleal or wound effusions (including yellow discharge at the incision)1612MUSCULOSKELETAL AND CONNECTIVETISSUE DISORDERS  Back pain73PSYCHIATRIC DISORDERS  Depression1610Table 2. Incidence of Local Adverse Reactions, Study 1Not seen at baseline or worsened if present at baseline.Local Adverse ReactionsGLIADEL Wafer N=120PlaceboN=120%%Intracranial hypertension92Cerebral hemorrhage64Brain abscess64Brain cyst23Cerebral edema2319

Recurrent High-Grade Malignant GliomaThe safety of GLIADEL Wafers was evaluated in a multicenter, randomized (1:1), double-blind, placebo controlled trial of 222 patients with recurrent high-grade malignant glioma who received up to eight GLIADEL Wafers or matched placebo implanted against the resection surfaces after maximal tumor resection (Study 2). Patients were required to have had prior definitive external beam radiation therapy sufficient to disqualify them from additional radiation therapy. All patients were eligible to receive chemotherapy which was withheld at least four weeks (six weeks for nitrosoureas) prior to and two weeks after surgery.The population in Study 2 was 64% male, 92% White, and the median age was 49 years (range: 19-80). Sixty-five percent had a histologic subtype of glioblastoma multiforme, 26% had anaplastic astrocytoma or another anaplastic variant, 73% had a Karnofsky performance status ≥ 70, 53% had a Karnofsky performance status of ≥ 80%, 73% had only one prior surgery, and 46% had prior treatment with nitrosourea. Eighty-one percent of patients received 8 wafers and 96% received ≥ 6 wafers.Sixty-four severe adverse reactions were reported in 43(39%) patients receiving GLIADEL Wafers. Adverse reactions in GLIADEL Wafer-treated patients are shown in Table 3. Meningitis occurred in four patients receiving GLIADEL Wafers and in no patients receiving placebo. Bacterial meningitis was confirmed in two patients: the first with onset four days following GLIADEL Wafer implantation; the second following resection for tumor recurrence 155 days following GLIADEL Wafer implantation. One case, attributed to chemical meningitis resolved following steroid treatment. The cause of the fourth case was undetermined but resolved following antibiotic treatment.Table 3. Per-Patient Incidence of Adverse Reactions in Gliadel Wafer-Treated Patients with Recurrent High-Grade Malignant Glioma (Study 2) (Between Arm Difference of ≥ 4%)BODY SYSTEMGLIADEL Wafer N=110PlaceboN=112%%GENERAL  Fever128INFECTIOUS  Urinary tract infections2117INJURY, POISONING AND PROCEDURALCOMPLICATIONS  Wound healing abnormalitiesIncluded (1) fluid, CDS, or subdural fluid collection; (2) CSF leak; (3) wound dehiscence, breakdown, or poor healing; and (4) subgaleal or wound effusions (including yellow discharge at the incision)145The incidence of seizures is shown in Table 4. The incidence of hydrocephalus, cerebral edema and intracranial hypertension is shown in Table 5.Table 4. Incidence of Seizures, Study 2Adverse ReactionGLIADEL WaferN=110PlaceboN=112%%Patients with seizures  Any seizures after wafer implantation3729  New or worsening seizures2020Time to new or worsening seizures (days)Days from implantation to onset of first new or worsening seizure.  Mean (SD)26.09 (0.75)62.36 (48.66)  Median3.561.0Table 5. Hydrocephalus and Cerebral Edema, Study 2Not seen at baseline or worsened if present at baseline.Adverse ReactionGLIADEL Wafer N=110PlaceboN=112%%Hydrocephalus52Cerebral edema41

Risk SummaryGLIADEL Wafer can cause fetal harm when administered to a pregnant woman. There have been no studies with GLIADEL Wafer; however, carmustine, the active component of GLIADEL Wafer, is embryotoxic and teratogenic in rats at exposures less than the exposure at the recommended human dose on a mg/m2 basis and embryotoxic in rabbits at exposures similar to exposures at the recommended human dose on a mg/m2 basis. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

Animal DataThere are no studies assessing the reproductive toxicity of GLIADEL Wafer; however, carmustine, the active component of GLIADEL Wafer, is embryotoxic and teratogenic in rats at intraperitoneal doses of 0.5mg/kg/day or greater when given on gestation days 6 through 15. Carmustine caused fetal malformations (anophthalmia, micrognathia, omphalocele) at 1.0 mg/kg/day (about 0.12 the recommended human dose, eight wafers of 7.7 mg carmustine/wafer, on a mg/m2 basis). Carmustine was embryotoxic in rabbits at intravenous doses of 4.0 mg/kg/day (about 1.2 times 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.

Contraception

FemalesGLIADEL Wafer can cause fetal harm when administered during pregnancy (see Use in Specific Populations, 8.1). Counsel patients on pregnancy planning and prevention. Advise female patients of reproductive potential to use effective contraception after implantation of GLIADEL Wafer. Advise patients to inform their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking GLIADEL.

Infertility

MalesCarmustine caused testicular degeneration in animals. Advise male patients of the potential risk of infertility, and to seek counseling on fertility and family planning options prior to implantation of GLIADEL Wafer. (see Nonclinical Toxicology, 13.1)

Manufactured byEisai Inc.Woodcliff Lake, NJ 07677Distributed byArbor Pharmaceuticals, LLC Atlanta, GA 30328GLIADEL® is a registered trademark of Eisai Inc.GL-PI-02

3 Dosage Forms And Strengths

GLIADEL Wafer is an off-white to pale yellow round wafer. Each GLIADEL Wafer contains 7.7 mg of carmustine.

4 Contraindications

None.

5.1 Seizures

Seizures occurred in 37% of patients treated with GLIADEL Wafers for recurrent glioma in Study 2. New or worsening (treatment emergent) seizures occurred in 20% of patients; 54% of treatment emergent seizures occurred within the first 5 post-operative days [see Adverse Reactions (6.1)]. The median time to onset of the first new or worsened post-operative seizure was four days. Institute optimal anti-seizure therapy prior to surgery. Monitor patients for seizures postoperatively.

5.2 Intracranial Hypertension

Brain edema occurred in 23% of patients with newly diagnosed glioma treated with GLIADEL Wafers in Study 1. Additionally, one GLIADEL-treated patient experienced intracerebral mass effect unresponsive to corticosteroids which led to brain herniation (see Adverse Reactions (6.1)). Monitor patients closely for intracranial hypertension related to brain edema, inflammation, or necrosis of the brain tissue surrounding the resection. In refractory cases, consider re-operation and removal of GLIADEL Wafers or Wafer remnants.

5.3 Impaired Neurosurgical Wound Healing

Impaired neurosurgical wound healing including wound dehiscence, delayed wound healing, and subdural, subgleal, or wound effusions occur with GLIADEL Wafer treatment. In Study 1, 16% of GLIADEL Wafer-treated patients with newly diagnosed glioma experienced impaired intracranial wound healing and 5% had cerebrospinal fluid leaks. In Study 2, 14% of GLIADEL Wafer-treated patients with recurrent glioma experienced wound healing abnormalities [see Adverse Reactions (6.1)]. Monitor patients post-operatively for impaired neurosurgical wound healing.

5.4 Meningitis

Meningitis occurred in 4% of patients with recurrent glioma receiving GLIADEL Wafers in Study 2. Two cases of meningitis were bacterial; one patient required removal of the Wafers four days after implantation; the other developed meningitis following reoperation for recurrent tumor. One case was diagnosed as chemical meningitis and resolved following steroid treatment. In one case the cause was unspecified, but meningitis resolved following antibiotic treatment. Monitor postoperatively for signs of meningitis and central nervous system infection.

5.5 Wafer Migration

GLIADEL Wafer migration can occur. To reduce the risk of obstructive hydrocephalus due to wafer migration into the ventricular system, close any communication larger than the diameter of a Wafer between the surgical resection cavity and the ventricular system prior to Wafer implantation. Monitor patients for signs of obstructive hydrocephalus.

5.6 Embryo-Fetal Toxicity

GLIADEL Wafers can cause fetal harm when administered to a pregnant woman. Carmustine, the active component of GLIADEL Wafer, is embryotoxic and teratogenic in rats at exposures less than the exposure at the recommended human dose on a mg/m2 basis and embryotoxic in rabbits at exposures similar to the exposure at the recommended human dose on a mg/m2 basis. Advise females of reproductive potential to avoid pregnancy after implantation of GLIADEL Wafers. If the patient becomes pregnant after GLIADEL Wafer implantation, warn the patient about the potential hazard to the fetus [see Use in Specific Populations (8.1 and 8.6)].

6 Adverse Reactions

  • The following serious adverse reactions are discussed elsewhere in the label:Seizures [(see Warnings and Precautions (5.1)]Intracranial Hypertension [(see Warnings and Precautions (5.2)]Impaired Neurosurgical Wound Healing [(see Warnings and Precautions (5.3)]Meningitis [(see Warnings and Precautions (5.4)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Teratogenic Effects

Pregnancy Category D

8.3 Nursing Mothers

It is not known if carmustine, the active component of GLIADEL Wafer, is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from carmustine, a decision should be made whether to discontinue nursing or not to administer the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

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

8.5 Geriatric Use

Clinical trials of GLIADEL Wafer did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients.

11 Description

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

12.1 Mechanism Of Action

The activity of GLIADEL Wafer is due to release of cytotoxic concentrations of carmustine, a DNA and RNA alkylating agent, into the tumor resection cavity. On exposure to the aqueous environment of the resection cavity, the anhydride bonds in the copolymer are hydrolyzed, releasing carmustine, carboxyphenoxypropane, and sebacic acid into the surrounding brain tissue.

12.3 Pharmacokinetics

Carmustine concentrations delivered by GLIADEL Wafer in human brain tissue have not been determined.Following an intravenous infusion of carmustine at doses ranging from 30 to 170 mg/m2, 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/m2 dose of 14C-carmustine was excreted in the urine over 96 hours and 6% was expired as CO2. Carmustine degrades both spontaneously and metabolically. The relevance of these data to elimination of intracranial implant-delivered carmustine are unknown.GLIADEL Wafers are biodegradable when implanted into the human brain. Wafer remnants may be observed on brain imaging scans or at re-operation. Wafer remnants were visible in 11 of 18 patients on CT scans obtained 49 days after implantation of GLIADEL Wafer. More than 70% of the copolymer degrades within three weeks. Wafer remnants have been present at re-operation and autopsy up to 232 days after GLIADEL Wafer implantation, and consisted mostly of water and monomeric components with minimal detectable carmustine present.

13.1 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 carcinogenic in rats and mice when delivered by intraperitoneal injection at doses lower than those delivered by GLIADEL Wafer at the recommended dose. There were increases in tumor incidence in all treated animals. 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).In male rats carmustine caused testicular degeneration at intraperitoneal doses of 8 mg/kg/week for eight weeks (about 1.3 times the recommended human dose on a mg/m2 basis).

14.1 Newly-Diagnosed High-Grade Malignant Glioma

Study 1 was a multicenter, double-blind, placebo-controlled, clinical trial in adult patients with newly-diagnosed high-grade malignant glioma. A total of 240 patients were randomized (1:1) to receive up to eight GLIADEL Wafers or matched placebo wafers following maximal tumor resection. Patients received post-operative radiation therapy (55-60 Gy delivered in 28 to 30 fractions over six weeks) starting three weeks after surgery. Patients with anaplastic oligodendroglioma also received systemic chemotherapy (6 cycles of PCV- lomustine 110 mg/m2 day 1, procarbazine 60 mg/m2 days 8-21, vincristine 1.4 mg/m2 days 8 and 29).The population in Study 1 was 67% male and 97% White, and the median age was 53 years (range: 21-72). Eighty-seven percent had a Karnofsky performance status ≥ 70% and 71% had a Karnofsky performance status of ≥ 80%. Seventy-eight percent had a histologic subtype of glioblastoma multiforme as determined by central pathology review. Thirty-eight percent of patients received 8 wafers and 78% received ≥ 6 wafers. Starting three weeks after surgery, 80% of patients received standard limited field radiation therapy (RT) described as 55-60 Gy delivered in 28 to 30 fractions over six weeks; 11% received no radiotherapy and the remainder received non-standard radiotherapy or a combination of standard and non-standard radiotherapy. At the time of progression, 12% received systemic chemotherapy. Patients were followed for at least three years or until death.Efficacy results for patients randomized in Study 1 are summarized in Table 6 and Figure 6. Overall survival among all patients with newly diagnosed high grade glioma, the primary outcome measure, was prolonged in the GLIADEL arm. Overall survival in the subset of patients with glioblastoma multiforme, a secondary outcome measure, was not significantly prolonged.Table 6. Overall Survival in Patients with Newly Diagnosed Glioma, Study 1.Overall Survival – ITTBased on a post-final analysis, protocol specified non-stratified log-rank test.Gliadel Wafer(n=120)Placebo Wafer(n=120)Number of deaths, n (%)111 (93%)117(98%)Median overall survival, months (95% CI)13.9 (12.1, 15.1)11.6 (10.2, 12.7)  Hazard ratio (95% CI)0.73 (0.56, 0.95)  Log-Rank test p-value<0.02p-value not adjusted for multiple comparisonsFigure 6 – Overall Survival for Patients with Newly Diagnosed High-Grade Malignant Glioma – Kaplan-Meier Curves by Treatment GroupBased on a post-final analysis, protocol specified non-stratified log-rank test; p-value not adjusted for multiple comparisons

14.2 Recurrent Glioblastoma Multiforme

Study 2 was a multicenter, double-blind, placebo controlled, clinical trial in adult patients with recurrent malignant glioma. Patients were required to have had prior definitive external beam radiation therapy sufficient to disqualify them from additional radiation therapy. Following maximal tumor resection and confirmation of malignant glioma, a total of 222 patients were randomized (1:1) to receive a maximum of eight GLIADEL Wafers (n=110) or matched placebo wafers (n=112) positioned to cover the entire resection surface. All patients were eligible to receive chemotherapy which was withheld at least four weeks (six weeks for nitrosoureas) prior to and two weeks after surgery. Patients were followed for up to 71 months.The population in Study 2 was 64% male and 92% White, and the median age was 49 years (range: 19-80). Sixty-five percent had a histologic subtype of glioblastoma multiforme, 26% had anaplastic astrocytoma or another anaplastic variant, 73% had a Karnofsky performance status ≥ 70, 53% had a Karnofsky performance status of ≥ 80%, 73% had only one prior surgery, and 46% had prior treatment with nitrosourea. Eighty-one percent of patients received 8 wafers and 96% received ≥ 6 wafers.Survival and 6-month mortality rate in the subgroup of patients with recurrent glioblastoma multiforme, were exploratory outcome measures and are summarized in Table 7 and Figures 7 and 8. No survival prolongation was observed in patients with pathologic diagnoses other than glioblastoma multiforme.Table 7. Main Efficacy Outcome Measures in Patients with Recurrent Gliomablastoma Multiforme, Study 2.Gliadel WaferPlacebo WaferGLIOBLASTOMA MULTIFORMEn=72n=736-Month SurvivalNumber of deaths, n (%)32476-month survival rate (%)56%36%   Log-Rank test p-value   Gehan's generalized Wilcoxon Test p-value0.013p-value not adjusted for multiple comparisons0.015Overall SurvivalNumber of deaths, n (%)71 (99%)72 (99%)Median overall survival (95% CI (months)6.51 (5.32, 7.49)4.63 (3.78, 5.52)   Log-Rank test p-value  Gehan's generalized Wilcoxon Test p-value0.1810.021Figure 7: 6-Month Survival for Patients with Recurrent Glioblastoma Multiforme– Kaplan-Meier Curves by Treatment GroupFigure 8: Overall Survival (months) for Patients with Recurrent Glioblastoma Multiforme– Kaplan-Meier Curves by Treatment Group

15 References

  • "OSHA Hazardous Drugs". OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html

16 How Supplied/Storage And Handling

GLIADEL Wafer is supplied 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.NDC for single dose treatment box: 24338-050-08

Storage And Handling

Store GLIADEL Wafer at or below -20ºC (-4ºF).Do not keep unopened foil pouches at ambient room temperature for more than six hours at a time for up to three cycles within a 30-day period.GLIADEL Wafer is a cytotoxic drug and special handling and disposal procedures should be considered.1

17 Patient Counseling Information

Seizures: Advise patients to report any new or change in their seizure activity [(see Warnings and Precautions (5.1)].Intracranial Hypertension: Advise patients to report severe headaches, nausea, vomiting or new onset visual disturbances [(see Warnings and Precautions (5.2)].Impaired Neurosurgical Wound Healing: Advise patients to report any evidence of wound dehiscence, fever or cerebrospinal fluid leak [see Warnings and Precautions (5.3)].Meningitis: Advise patients to report symptoms of meningitis such as fever or stiff neck [see Warnings and Precautions (5.4)].Embryo-Fetal Toxicity: Counsel patients on pregnancy planning and prevention. Advise females of reproductive potential to use effective contraception during treatment with GLIADEL [see Warnings and Precautions (5.6)].Nursing Infants: Advise nursing mothers to discontinue nursing after GLIADEL WAFER implantation [see Use in Specific Populations (8.3)].

* Please review the disclaimer below.