Gliadel Dailymed

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)]

• 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 Arbor Pharmaceuticals, LLC at 1-866-516-4950 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical 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 uled 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 WaferN=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 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)	16	12
MUSCULOSKELETAL AND CONNECTIVE TISSUE
Back pain	7	3
PSYCHIATRIC
Depression	16	10

Table 2. Incidence of Local Adverse Reactions, Study 1Not seen at baseline or worsened if present at baseline.

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

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 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)	14	5

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)Days from implantation to onset of first new or worsening seizure.
Mean (SD)	26.09 (0.75)	62.36 (48.66)
Median	3.5	61.0

Table 5. Hydrocephalus and Cerebral Edema, Study 2Not seen at baseline or worsened if present at baseline.

Adverse Reaction	GLIADEL Wafer N=110	Placebo N=112
	%	%
Hydrocephalus	5	2
Cerebral edema	4	1

8 Use In Specific Populations

• Lactation: Advise not to breastfeed (8.2).

8.1Pregnancy

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.

8.2Lactation

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.

8.3Females 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)].

8.4Pediatric Use

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

8.5Geriatric 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.