HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use GLIADEL WAFER
`safely and effectively. See full prescribing information for GLIADEL WAFER.
`GLIADEL
`® WAFER (carmustine implant), for intracranial use
`Initial U.S. Approval: 1996
`------------------------------INDICATIONS AND USAGE------------------------------
`GLIADEL Wafer is an alkylating drug indicated for the treatment of:
`• newly-diagnosed high-grade glioma as an adjunct to surgery and radiation (1) and
`• recurrent glioblastoma as an adjunct to surgery (1)
`---------------------------DOSAGE AND ADMINISTRATION --------------------------
`• Recommended dose: Eight 7.7 mg wafers (61.6 mg total dose) implanted
`intracranially (2.1, 2.2)
`• Follow preparation and handling recommendations (2.3).
`--------------------------DOSAGE FORMS AND STRENGTHS-------------------------
`• Each GLIADEL Wafer contains 7.7 mg of carmustine (3).
`--------------------------------CONTRAINDICATIONS--------------------------------
` None (4)
`--------------------------WARNINGS AND PRECAUTIONS ---------------------------
`• Seizures: Monitor patients for seizures following implantation (5.1).
`• Intracranial hypertension: Monitor patients for signs of increased intracranial
`pressure (5.2).
`• Impaired neurosurgical wound healing: Monitor patients for complications
`of craniotomy (5.3).
`• Meningitis: Monitor patients for signs of bacterial or chemical meningitis (5.4).
`• Wafer migration: Monitor patients for signs of obstructive hydrocephalus (5.5).
`• Embryo-fetal toxicity: Can cause fetal harm. Advise patients of the potential risk
`to a fetus. Advise males and females of reproductive potential to use an effective
`method of contraception. (5.6, 8.1, 8.3).
`--------------------------------ADVERSE REACTIONS--------------------------------
`• Newly-Diagnosed High-Grade Glioma: Most common adverse reactions (incidence
`>10% and between arm difference ≥4%) are cerebral edema, asthenia, nausea,
`vomiting, constipation, wound healing abnormalities and depression (6.1).
`• Recurrent High-Grade Glioma: Most common adverse reactions (incidence >10%
`and between arm difference ≥4%) are urinary tract infection, wound healing
`abnormalities and fever (6.1).
`To report SUSPECTED ADVERSE REACTIONS, contact Azurity Pharmaceuticals, Inc.
`at 1-800-461-7449 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`---------------------------USE IN SPECIFIC POPULATIONS --------------------------
`• Lactation: Advise not to breastfeed (8.2).
`See 17 for PATIENT COUNSELING INFORMATION
`Revised: 05/2022
`FULL PRESCRIBING INFORMATION: CONTENTS*
`1. INDICATIONS AND USAGE
`2. DOSAGE AND ADMINISTRATION
` 2.1 Recommended Dose
` 2.2 Insertion Instructions
` 2.3 Preparation and Safe Handling
`3. DOSAGE FORMS AND STRENGTHS
`4. CONTRAINDICATIONS
`5. WARNINGS AND PRECAUTIONS
` 5.1 Seizures
` 5.2 Intracranial Hypertension
` 5.3 Impaired Neurosurgical Wound Healing
` 5.4 Meningitis
` 5.5 Wafer Migration
` 5.6 Embryo-Fetal Toxicity
`6. ADVERSE REACTIONS
` 6.1 Clinical Trials Experience
`8. USE IN SPECIFIC POPULATIONS
` 8.1 Pregnancy
` 8.2 Lactation
` 8.3 Females and Males of Reproductive Potential
` 8.4 Pediatric Use
` 8.5 Geriatric Use
`11. DESCRIPTION
`12. CLINICAL PHARMACOLOGY
` 12.1 Mechanism of Action
` 12.3 Pharmacokinetics
` 12.6 Wafer Biodegradation
`13. NONCLINICAL TOXICOLOGY
` 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14. CLINICAL STUDIES
` 14.1 Newly-Diagnosed High-Grade Glioma
` 14.2 Recurrent Glioblastoma
`15. REFERENCES
`16. HOW SUPPLIED/STORAGE AND HANDLING
`17. PATIENT COUNSELING INFORMATION
`*Sections or subsections omitted from the full prescribing information are not listed.
`FULL PRESCRIBING INFORMATION
`1 INDICATIONS AND USAGE
`GLIADEL Wafer is indicated for the treatment of patients with:
` • newly-diagnosed high-grade glioma as an adjunct to surgery and radiation, and
` • recurrent glioblastoma as an adjunct to surgery.
`2 DOSAGE AND ADMINISTRATION
`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.
`1
`Each 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.
`Instructions for Opening Pouch Containing GLIADEL Wafer
`Read 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.
`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 WARNINGS AND PRECAUTIONS
`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, subgaleal, 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 high-
`grade 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 based
`on body surface area (BSA) and embryotoxic in rabbits at exposures similar to the
`exposure at the recommended human dose based on BSA.
`Advise patients of the potential risk to a fetus. Advise females of reproductive potential
`to use effective contraception for 6 months after implantation of GLIADEL Wafer. Advise
`males with female partners of reproductive potential to use effective contraception for
`3 months following implantation of GLIADEL Wafers [see Use in Specific Populations
`(8.1, 8.3), Nonclinical Toxicology (13.1)].
`6 ADVERSE REACTIONS
`The following serious adverse reactions are discussed elsewhere in the labeling:
` • 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.
`Newly-Diagnosed High-Grade Glioma
`The 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 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 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 Glioma
`(Study 1) (Between Arm Difference of ≥ 4%)
`Adverse Reaction
`GLIADEL Wafer
`N=120
`Placebo
`N=120
`% %
`GASTROINTESTINAL
`Nausea 22 17
`Vomiting 21 16
`Constipation 19 12
`Abdominal pain 8 2
`GENERAL AND ADMINISTRATION SITE CONDITION
`Asthenia 22 15
`Chest pain 5 0
`INJURY, POISONING AND PROCEDURAL COMPLICATIONS
`Wound healing abnormalities* 16 12
`MUSCULOSKELETAL AND CONNECTIVE TISSUE
`Back pain 7 3
`PSYCHIATRIC
`Depression 16 10
`*Included (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)
`Table 2. Incidence of Local Adverse Reactions, Study 1*
`Local Adverse Reactions
`GLIADEL Wafer
`N=120
`Placebo
`N=120
`% %
`Cerebral edema 23 19
`Intracranial hypertension 9 2
`Cerebral hemorrhage 6 4
`Brain abscess 6 4
`Brain cyst 2 3
`*Not seen at baseline or worsened if present at baseline.
`Recurrent High-Grade Glioma
`The safety of GLIADEL Wafers was evaluated in a multicenter, randomized (1:1),
`double-blind, placebo controlled trial of 222 patients with recurrent high-grade 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,
`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 Glioma (Study 2)
`(Between Arm Difference of ≥ 4%)
`Adverse Reaction GLIADEL Wafer
`N=110
`Placebo
`N=112
`% %
`GENERAL
`Fever 12 8
`INFECTIOUS
`Urinary tract infections 21 17
`INJURY, POISONING AND PROCEDURAL COMPLICATIONS
`Wound healing abnormalities* 14 5
`*Included (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)
`continued on reverse side
`HELSINN EXHIBIT 2013
`Azurity Pharmaceuticals, Inc. v. Helsinn Healthcare S.A.
`IPR2025-00945
`Page 1 of 2
`
`
`
`
`
`
`
`The 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 2
`Adverse Reaction GLIADEL Wafer
`N=110
`Placebo
`N=112
`Patients with seizures (%)
`Any seizures after wafer implantation 37 29
`New or worsening seizures 20 20
`Time to new or worsening seizures (days)*
`Mean (SD) 26.09 (0.75) 62.36 (48.66)
`Median 3.5 61.0
`*Days from implantation to onset of first new or worsening seizure.
`Table 5. Hydrocephalus and Cerebral Edema, Study 2*
`Adverse Reaction GLIADEL Wafer
`N=110
`Placebo
`N=112
` % %
`Hydrocephalus 5 2
`Cerebral edema 4 1
`*Not seen at baseline or worsened if present at baseline.
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`Risk Summary
`GLIADEL Wafer can cause fetal harm when administered to a pregnant woman. There
`are no available data on GLIADEL use in pregnant women. There have been no animal
`reproductive 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 based on body surface area (BSA) and
`embryotoxic in rabbits at exposures similar to exposures at the recommended human
`dose based on BSA (see Data). Advise pregnant women of the potential risk to a fetus.
`In the U.S. general population, the estimated background risk of major birth defects
`and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%,
`respectively.
`Data
`Animal Data
`There 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 0.5 mg/kg/day or greater when given on gestation days
`6 through 15. Carmustine caused fetal malformations (anophthalmia, micrognathia,
`omphalocele) at 1 mg/kg/day (about 0.12 times the recommended human dose, eight
`wafers of 7.7 mg carmustine/wafer, based on BSA). Carmustine was embryotoxic
`in rabbits at intravenous doses of 4 mg/kg/day (about 1.2 times the recommended
`human dose based on BSA). Embryotoxicity was characterized by increased embryo-
`fetal deaths, reduced numbers of litters, and reduced litter sizes.
`8.2 Lactation
`Risk Summary
`No data are available regarding the presence of carmustine, the active component of
`GLIADEL Wafer, or its metabolites in human milk or its effects on the breastfed child or
`on milk production. Because of the potential for serious adverse reactions in breastfed
`children from GLIADEL Wafers, advise women not to breastfeed following implantation
`with GLIADEL Wafers and for at least 7 days after implantation.
`8.3 Females and Males of Reproductive Potential
`Pregnancy Testing
`Verify pregnancy status of females of reproductive potential prior to implantation with
`GLIADEL Wafer [see Use in Specific Populations (8.1)].
`Contraception
`GLIADEL Wafer can cause fetal harm when administered to a pregnant woman
`[see Use in Specific Populations (8.1)].
`Females
`Advise females of reproductive potential to use effective contraception for 6 months
`after implantation of GLIADEL Wafer.
`Males
`Based on its mechanism of action, advise males with female partners of reproductive
`potential to use effective contraception for 3 months following implantation of GLIADEL
`Wafer [see Clinical Pharmacology (12.1), Nonclinical Toxicology (13.1)].
`Infertility
`Males
`Carmustine caused testicular degeneration in animals. Advise male patients of the
`potential risk of infertility [see Nonclinical Toxicology (13.1)].
`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 CLINICAL PHARMACOLOGY
`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 wafer insertion, the mean whole blood Cmax (± SD) is
`10.2 ng/mL ± 4.8 ng/mL.
`Absorption
`Systemic absorption of carmustine is measurable for approximately 24 hours after
`wafer insertion. Carmustine C
`max was reached approximately 3 hours after wafer
`insertion.
`Elimination
`Metabolism
`Carmustine degrades both spontaneously and metabolically.
`12.6 Wafer Biodegradation
`GLIADEL Wafers are biodegradable when implanted into the human brain. Wafer
`remnants were visible 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 7.8 months after GLIADEL Wafer
`implantation and consisted mostly of water and monomeric components with minimal
`detectable carmustine present.
`13 NONCLINICAL TOXICOLOGY
`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 based
`on body surface area).
`14 CLINICAL STUDIES
`14.1 Newly-Diagnosed High-Grade Glioma
`Study 1 was a multicenter, double-blind, placebo-controlled, clinical trial in adult
`patients with newly-diagnosed high-grade 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/m
`2 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 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, a secondary outcome measure, was not
`significantly prolonged.
`Table 6. Overall Survival in Patients with Newly-Diagnosed
`High-Grade Glioma, Study 1.
`Overall Survival – ITT*
`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)
`Log-Rank test p-value
`0.73 (0.56, 0.95)
`<0.02**
`*Based on a post-final analysis, protocol specified non-stratified log-rank test.
`**p-value not adjusted for multiple comparisons
`Figure 6: Kaplan-Meier Curves of Overall Survival in Patients with Newly
`Diagnosed High-Grade Glioma, Study 1.*
`GLIADEL Wafer
`Placebo
`*Based on a post-final analysis, protocol specified non-stratified log-rank test;
` p-value not adjusted for multiple comparisons
`14.2 Recurrent Glioblastoma
`Study 2 was a multicenter, double-blind, placebo controlled, clinical trial in adult
`patients with recurrent high-grade 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 high-grade
`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,
`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, 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.
`Table 7. Main Efficacy Outcome Measures in Patients with
`Recurrent Glioblastoma, Study 2.
`GLIADEL Wafer Placebo Wafer
`GLIOBLASTOMA n=72 n=73
`6-Month Survival
`Number of deaths, n (%) 32 47
`6-month survival rate (%) 56% 36%
`Log-Rank test p-value
`Gehan’s generalized Wilcoxon Test p-value
`0.013**
`0.015**
`Overall Survival
`Number 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-value
`0.181**
`0.021**
`**p-value not adjusted for multiple comparisons
`Figure 7: Kaplan-Meier Curves of 6-Month Survival for Patients with Recurrent
`Glioblastoma, Study 2.
`Log-Rank
`p=0.01
`Months from Implant Surgery
`Survival %
`100
`90
`80
`70
`60
`50
`40
`30
`20
`10
`0
`0 1 2 3 4 5 6
`GLIADEL Wafer
`Placebo
`Figure 8: Kaplan-Meier Curves of Overall Survival for Patients with Recurrent
`Glioblastoma, Study 2.
`Months from Implant Surgery
`Survival Rate x 100
`100
`90
`80
`70
`60
`50
`40
`30
`20
`10
`0
`LOG–RANK P=0.18
`WILCOXON P=0.021
`0 6 12 18 24 30 36 42 48 54
`GLIADEL
`Placebo
`15 REFERENCES
`1. “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
`Store GLIADEL Wafer at or below -20°C (-4°F).
`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
`Advise patients of the potential risk to a fetus. Advise women to inform their healthcare
`provider of a known or suspected pregnancy [see Warnings and Precautions (5.6),
`Use in Specific Populations (8.1)].
`Advise females of reproductive potential to use effective contraception for at least
`6 months after implantation of GLIADEL Wafer [see Use in Specific Populations (8.3)].
`Advise males with female partners of reproductive potential to use effective
`contraception for 3 months following implantation of GLIADEL Wafer [see Use in
`Specific Populations (8.3), Nonclinical Toxicology (13.1)].
`Lactation
`Advise women not to breastfeed following implantation with GLIADEL Wafers and for at
`least 7 days after implantation [see Use in Specific Populations (8.2)].
`Infertility
`Advise males of reproductive potential that GLIADEL Wafer may impair fertility
`[see Use in Specific Populations (8.3), Nonclinical Toxicology (13.1)].
`Manufactured by
`Eisai Inc.
`Nutley, NJ 07110
`Distributed by
`Azurity Pharmaceuticals, Inc.
`Woburn, MA 01801
`Patent: https://azurity.com/patents
`GLIADEL
`® is a registered trademark of Eisai Inc.
`GL-PI-05
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