Gliadel

Less serious, more common side effects include:

• nausea
• vomiting
• headache
• loss of balance or coordination
• pale skin
• flushing
• fainting
• dizziness
• fast or irregular heartbeat
• chest pain
• darkened skin

Tell your doctor right away if you experience any of these symptoms:

• swelling, pain, redness, burning, or leakage of fluid at the injection site
• rash
• itching
• swelling of the face, lips, or throat
• difficulty breathing
• fever
• sore throat
• chills
• aches and pains
• unusual bleeding or bruising
• black and tarry stools
• red blood in stools
• bloody vomit
• vomited material that looks like coffee grounds
• extreme tiredness
• paleness
• lack of energy
• loss of appetite
• pain in the upper right part of the stomach
• yellowing of the skin or eyes
• decreased urination
• swelling of the hands, feet, ankles, or lower legs
• changes in vision

Tell your doctor about any side effect that is bothersome or doesn't go away.

See "Drug Precautions" for serious side effects.

This is not a complete list of carmustine drug interactions. Ask your doctor or pharmacist for more information.

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements. Especially tell your doctor if you take:

• cimetidine (Tagamet)
• phenytoin (Dilantin)
• digoxin (Lanoxin)

Other medications may interact with carmustine. It is possible that medications that suppress the immune system could increase the risk of low blood cell counts and infections associated with carmustine. Be sure to discuss all of your medications with your doctor and pharmacist.

Tell your doctor if you are breastfeeding or plan to breastfeed. It is not known if carmustine is excreted in human breast milk or if it will harm your nursing baby. It is generally recommended that women receiving carmustine treatments should not breastfeed.

Injectable:

• Carmustine comes in powder form. Liquid is added to carmustine and then it is injected slowly, over at least 2 hours, intravenously (into a vein) by a healthcare professional in a medical facility (hospital or clinic). It is usually given once every 6 weeks. The dose is sometimes divided into two doses and is given 2 days in a row, every 6 weeks.
• Your doctor will order weekly blood tests to measure certain cells in your blood. If your blood cell counts are too low, your doctor may order a delay in treatment.

Topical:

• This medication also comes in a wafer form that is implanted within the cranium (skull) via surgical procedure.

Carmustine is used to treat brain tumors, Hodgkin's disease, multiple myeloma, and non-Hodgkin's lymphoma.

Carmustine can lower blood cells that help your body fight infections and help your blood to clot. You may get an infection or bleed more easily. Call your doctor if you have unusual bruising or bleeding, or signs of infection (fever, chills, body aches).

Carmustine can cause nausea and vomiting that may last up to 6 hours after your injection.

You should not receive this medication if you are allergic to it.

To make sure carmustine is safe for you, tell your doctor if you have:

• bone marrow suppression;

• liver disease;

• kidney disease; or

• a history of lung or breathing problems.

Do not use carmustine if you are pregnant. It could harm the unborn baby. Use effective birth control, and tell your doctor if you become pregnant during treatment.

It is not known whether carmustine passes into breast milk or if it could harm a nursing baby. You should not breast-feed while using this medicine.

In the U.S.

• Gliadel

Available Dosage Forms:

• Implant

Therapeutic Class: Antineoplastic Agent

Pharmacologic Class: Alkylating Agent

Chemical Class: Nitrosourea

It is important that your doctor check your progress closely while you are receiving this medicine. This will allow your doctor to see if the medicine is working properly and to check for unwanted effects.

Using this medicine while you are pregnant can harm your unborn baby. Use an effective form of birth control to keep from getting pregnant after receiving the medicine. If you think you have become pregnant while using this medicine, tell your doctor right away.

This medicine may cause seizures after the surgical procedure. Call your doctor if you have symptoms of seizures after receiving this medicine.

This medicine may cause increased pressure in the head (intracranial hypertension). Tell your doctor right away if you have a severe headache, nausea, vomiting, blurred vision, or any change in vision after receiving the implant.

This medicine may cause a brain infection called meningitis. Tell your doctor right away if you have a severe headache, confusion, drowsiness, nausea, a general feeling of illness, or a stiff neck.

Some men using this medicine have become infertile (unable to have children). If you plan to have children, talk to your doctor before receiving this medicine.

• If you have an allergy to carmustine or any other part of Gliadel (carmustine intracranial implant).
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you are breast-feeding. Do not breast-feed while you take this medicine.

This medicine may interact with other drugs or health problems.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take Gliadel with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

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)]

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 Malignant 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 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.

Recurrent High-Grade Malignant 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 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.

The incidence of seizures is shown in Table 4. The incidence of hydrocephalus, cerebral edema and intracranial hypertension is shown in Table 5.

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.

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.

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)].

Manufactured by
Eisai Inc.
Woodcliff Lake, NJ 07677

Distributed by
Arbor Pharmaceuticals, LLC
Atlanta, GA 30328

Gliadel® is a registered trademark of Eisai Inc.

GL-PI-02