Polifeprosan 20 with Carmustine (Gliadel)
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Polifeprosan 20 with Carmustine (Gliadel)

GLIADEL® WAFER
(polifeprosan 20 with carmustine) Implant

DRUG DESCRIPTION

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

The structural formula for polifeprosan 20 is:

Polifeprosan 20 Structural Formula Illustration

The structural formula for carmustine is:

Carmustine Structural Formula Illustration

What are the possible side effects of carmustine (BiCNU, Gliadel)?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have a serious side effect such as:

  • new or worsening cough, fever, trouble breathing;
  • feeling short of breath on exertion;
  • chest discomfort, dry cough or hack;
  • feeling weak or tired, loss of appetite, rapid weight loss;
  • fever, chills, body aches, flu symptoms, sores in your mouth and throat;
  • easy bruising, unusual bleeding (nose,...

Read All Potential Side Effects and See Pictures of Gliadel »

What are the precautions when taking polifeprosan 20 with carmustine (Gliadel)?

Before receiving carmustine/polifeprosan 20, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

Before using this medication, tell your doctor or pharmacist your medical history.

This medication is not recommended for use during pregnancy. Consult your doctor for more details. If you become pregnant or think you may be pregnant, tell your doctor immediately.

It is not known whether this drug passes into breast milk. Because of the possible risk to the infant, breast-feeding while using this drug is not recommended. Consult your doctor before...

Read All Potential Precautions of Gliadel »

Last reviewed on RxList: 3/6/2009
This monograph has been modified to include the generic and brand name in many instances.

INDICATIONS

GLIADEL® Wafer (polifeprosan 20 with carmustine) is indicated in newly-diagnosed high-grade malignant glioma patients as an adjunct to surgery and radiation. GLIADEL® Wafer (polifeprosan 20 with carmustine) is indicated in recurrent glioblastoma multiforme patients as an adjunct to surgery.

DOSAGE AND ADMINISTRATION

Each GLIADEL® Wafer (polifeprosan 20 with carmustine) contains 7.7 mg of carmustine, resulting in a dose of 61.6 mg when eight wafers are implanted. It is recommended that eight wafers be placed in the resection cavity if the size and shape of it allows. Should the size and shape not accommodate eight wafers, the maximum number of wafers as allowed should be placed. Since there is no clinical experience, no more than eight wafers should be used per surgical procedure.

Handling and Disposal1-7

Wafers should only be handled by personnel wearing surgical gloves because exposure to carmustine can cause severe burning and hyperpigmentation of the skin. Use of double gloves is recommended and the outer gloves should be discarded into a biohazard waste container after use. A surgical instrument dedicated to the handling of the wafers should be used for wafer implantation. If repeat neurosurgical intervention is indicated, any wafer or wafer remnant should be handled as a potentially cytotoxic agent.

GLIADEL® Wafer (polifeprosan 20 with carmustine) should be handled with care. The aluminum foil laminate pouches containing GLIADEL® Wafer (polifeprosan 20 with carmustine) should be delivered to the operating room and remain unopened until ready to implant the wafers. The outside surface of the outer foil pouch is not sterile.

Instructions for Opening Pouch Containing GLIADEL® Wafer (polifeprosan 20 with carmustine)

Figure 1: To remove the sterile inner pouch from the outer pouch, locate the folded corner and slowly pull in an outward motion.

Locate the folded corner and slowly pull in an outward motion - Illustration

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.

Do NOT pull in a downward motion - Illustration

Figure 3: Remove the inner pouch by grabbing hold of the crimped edge and pulling upward.

Remove the inner pouch - Illustration

Figure 4: To open the inner pouch, gently hold the crimped edge and cut in an arc-like fashion around the wafer.

Cut in an arc-like fashion - Illustration

Figure 5: To remove the GLIADEL® Wafer (polifeprosan 20 with carmustine) , gently grasp the wafer with the aid of forceps and place it onto a designated sterile field.

Grasp the wafer with the aid of forceps - Illustration

Once the tumor is resected, tumor pathology is confirmed, and hemostasis is obtained, up to eight GLIADEL® Wafers (polifeprosan 20 with carmustine implant) may be placed to cover as much of the resection cavity as possible. Slight overlapping of the wafers is acceptable. Wafers broken in half may be used, but wafers broken in more than two pieces should be discarded in a biohazard container. Oxidized regenerated cellulose (Surgicel®) may be placed over the wafers to secure them against the cavity surface. After placement of the wafers, the resection cavity should be irrigated and the dura closed in a water tight fashion.

Unopened foil pouches may be kept at ambient room temperature for a maximum of six hours at a time.

HOW SUPPLIED

GLIADEL® Wafer (polifeprosan 20 with carmustine) 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® Wafer (polifeprosan 20 with carmustine) must be stored at or below -20?C (-4?F).

NDC: 58063-100-01

CAUTION: FEDERAL LAW PROHIBITS DISPENSING WITHOUT PRESCRIPTION.

REFERENCES

1. Recommendations for the Safe Handling of Parenteral Antineoplastic Drugs, NIH Publication No. 83-2621. For sale by the Superintendent of Documents, U.S. Government Printing Office, Washington, DC 20402.

2. AMA Council Report, Guidelines for Handling Parenteral Antineoplastics. JAMA, 1985;253(11):1590-1592.

3. National Study Commission on Cytotoxic Exposure—Recommendations for Handling Cytotoxic Agents. Available from Louis P Jeffrey, ScD., Chairman, National Study Commission on Cytotoxic Exposure, Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, Massachusetts 02115.

4. Clinical Oncological Society of Australia, Guidelines and Recommendations for Safe Handling of Antineoplastic Agents. Med J Australia, 1983;1:426-428.

5. Jones RB, et al: Safe Handling of Chemotherapeutic Agents: A Report from the Mount Sinai Medical Center. CA— A Cancer Journal for Clinicians, 1983; (Sept/Oct) 258-263.

6. American Society of Hospital Pharmacists Technical Assistance Bulletin on Handling Cytotoxic and Hazardous Drugs. Am J. Hosp Pharm, 1990;47:1033-1049.

7. OSHA Work-Practice Guidelines for Personnel Dealing with Cytotoxic (Antineoplastic) Drugs. Am J Hosp Pharm, 1986;43: 1193-1204.

Manufactured by: MGI PHARMA, INC. Bloomington, MN 55437. Rev 12/2006.

Last reviewed on RxList: 3/6/2009
This monograph has been modified to include the generic and brand name in many instances.

SIDE EFFECTS

Adverse reactions for the trials are described in the tables below.

Primary Surgery

The following data are the most frequently occurring adverse events observed in 5% or more of the newly-diagnosed malignant glioma patients during the trial.

COMMON ADVERSE EVENTS OBSERVED IN ≥ 5% OF PATIENTS RECEIVING GLIADEL® WAFER (polifeprosan 20 with carmustine) AT INITIAL SURGERY

Body System
  Adverse event
GLIADEL® Wafer (polifeprosan 20 with carmustine)
N=120
n (%)
Placebo
N=120
n (%)
Body as a whole
  Aggravation reaction* 98 (82) 95 (79)
  Headache 33 (28) 44 (37)
  Asthenia 26 (22) 18 (15)
  Infection 22 (18) 24 (20)
  Fever 21 (18) 21 (18)
  Pain 16 (13) 18 (15)
  Abdominal pain 10 (8) 2 (2)
  Back pain 8 (7) 4 (3)
  Face edema 7 (6) 6 (5)
  Abscess 6 (5) 3 (3)
  Accidental injury 6 (5) 8 (7)
  Chest pain 6 (5) 0
  Allergic reaction 2 (2) 6 (5)
Cardiovascular system
  Deep thrombophlebitis 12 (10) 11 (9)
  Pulmonary embolus 10 (8) 10 (8)
  Hemorrhage 8 (7) 7 (6)
Digestive system
  Nausea 26 (22) 20 (17)
  Vomiting 25 (21) 19 (16)
  Constipation 23 (19) 14 (12)
  Diarrhea 6 (5) 5 (4)
  Liver function tests abnormal 1 (1) 6 (5)
Endocrine system
  Diabetes mellitus 6 (5) 5 (4)
  Cushings syndrome 4 (3) 6 (5)
Metabolic and nutritional disorders
  Healing abnormal 19 (16) 14 (12)
  Peripheral edema 11 (9) 11 (9)
Musculoskeletal system
  Myasthenia 5 (4) 6 (5)
Nervous system
  Hemiplegia 49 (41) 53 (44)
  Convulsion 40 (33) 45 (38)
  Confusion 28 (23) 25 (21)
  Brain edema 27 (23) 23 (19)
  Aphasia 21 (18) 22 (18)
  Depression 19 (16) 12 (10)
  Somnolence 13 (11) 18 (15)
  Speech disorder 13 (11) 10 (8)
  Amnesia 11 (9) 12 (10)
  Intracranial hypertension 11 (9) 2 (2)
  Personality disorder 10 (8) 9 (8)
  Anxiety 8 (7) 5 (4)
  Facial paralysis 8 (7) 5 (4)
  Neuropathy 8 (7) 12 (10)
  Ataxia 7 (6) 5 (4)
  Hypesthesia 7 (6) 6 (5)
  Paresthesia 7 (6) 10 (8)
  Thinking abnormal 7 (6) 10 (8)
  Abnormal gait 6 (5) 6 (5)
  Dizziness 6 (5) 11 (9)
  Grand mal convulsion 6 (5) 5 (4)
  Hallucinations 6 (5) 4 (3)
  Insomnia 6 (5) 7 (6)
  Tremor 6 (5) 8 (7)
  Coma 5 (4) 6 (5)
  Incoordination 3 (3) 8 (7)
  Hypokinesia 2 (2) 8 (7)
Respiratory system
  Pneumonia 10 (8) 9 (8)
  Dyspnea 4 (3) 8 (7)
Skin and appendages
  Rash 14 (12) 13 (11)
  Alopecia 12 (10) 14 (12)
Special senses
  Conjunctival edema 8 (7) 8 (7)
  Abnormal vision 7 (6) 7 (6)
  Visual field defect 6 (5) 8 (7)
  Eye disorder 3 (3) 6 (5)
  Diplopia 1 (1) 6 (5)
Urogenital system
  Urinary tract infection 10 (8) 13 (11)
  Urinary incontinence 9 (8) 9 (8)
*Adverse events coded to the COSTART term “aggravation reaction” were usually events involving tumor/disease progression or general deterioration of condition (e.g. condition/health/Karnofsky/neurological/physical deterioration).

Surgery for Recurrent Disease

The following post-operative adverse events were observed in 4% or more of the patients receiving GLIADEL® Wafer (polifeprosan 20 with carmustine) at recurrent surgery. Except for nervous system effects, where there is a possibility that the placebo wafers could have been responsible, only events more common in the GLIADEL® Wafer (polifeprosan 20 with carmustine) group are listed. These adverse events were either not present pre-operatively or worsened post-operatively during the follow-up period. The follow-up period was up to 71 months.

COMMON ADVERSE EVENTS OBSERVED IN ≥ 4% OF PATIENTS RECEIVING GLIADEL® WAFER (polifeprosan 20 with carmustine) AT SURGERY FOR RECURRENT DISEASE

Body System
  Adverse event
GLIADEL® Wafer (polifeprosan 20 with carmustine) with Carmustine
[N=110]
n (%)
PLACEBO Waferwithout Carmustine
[N=112]
n (%)
Body as a Whole
  Fever 13 (12) 9 (8)
  Pain* 8 (7) 1 (1)
Digestive System
  Nausea and Vomiting 9 (8) 7 (6)
Metabolic and Nutritional Disorders
  Healing Abnormal* 15 (14) 6 (5)
Nervous System
  Convulsion 21 (19) 21 (19)
  Hemiplegia 21 (19) 22 (20)
  Headache 16 (15) 14 (13)
  Somnolence 15 (14) 12 (11)
  Confusion 11 (10) 9 (8)
  Aphasia 10 (9) 12 (11)
  Stupor 7 (6) 7 (6)
  Brain Edema 4 (4) 1 (1)
  Intracranial Hypertension 4 (4) 7 (6)
  Meningitis or Abscess 4 (4) 1 (1)
Skin and Appendages
Rash 6 (5) 4 (4)
Urogenital System
  Urinary Tract Infection 23 (21) 19 (17)
*p < 0.05 for comparison of GLIADEL® Wafer versus placebo groups

Post-marketing experience includes spontaneous reports of cyst formation after GLIADEL® Wafer (polifeprosan 20 with carmustine) implantation. These occurred at varying time intervals post-implantation. Cyst formation has also been reported in patients following resection of malignant glioma who have not had Gliadel (polifeprosan 20 with carmustine) implanted.

The following four categories of adverse events are possibly related to treatment with GLIADEL® Wafer (polifeprosan 20 with carmustine) . The frequency with which they occurred in the randomized trials along with descriptive detail is provided below.

  1. Seizures: In the initial surgery trial, the incidence of seizures was 33.3% in patients receiving GLIADEL® Wafer (polifeprosan 20 with carmustine) and 37.5% in patients receiving placebo. Grand mal seizures occurred in 5% of GLIADEL® Wafer (polifeprosan 20 with carmustine) -treated patients and 4.2% of placebo treated patients. The incidence of seizures within the first 5 days after wafer implantation was 2.5% in the GLIADEL® Wafer (polifeprosan 20 with carmustine) group and 4.2% in the placebo group. The time from surgery to the onset of the first post-operative seizure did not differ between the GLIADEL® Wafer (polifeprosan 20 with carmustine) and placebo treated patients.
    In the surgery for recurrent disease trial, the incidence of post-operative seizures was 19% in both patients receiving GLIADEL® Wafer (polifeprosan 20 with carmustine) and placebo. In this study, 12/22 (54%) of patients treated with GLIADEL® Wafer (polifeprosan 20 with carmustine) and 2/22 (9%) of placebo patients experienced the first new or worsened seizure within the first five post-operative days. The median time to onset of the first new or worsened post-operative seizure was 3.5 days in patients treated with GLIADEL® Wafer (polifeprosan 20 with carmustine) and 61 days in placebo patients.
  2. Brain Edema: In the initial surgery trial, brain edema was noted in 22.5% of patients treated with GLIADEL® Wafer (polifeprosan 20 with carmustine) and in 19.2% of patients treated with placebo. Development of brain edema with mass effect (due to tumor recurrence, intracranial infection, or necrosis) may necessitate re-operation and, in some cases, removal of GLIADEL® Wafer (polifeprosan 20 with carmustine) or its remnants.
  3. Healing Abnormalities: The following healing abnormalities have been reported in clinical trials of GLIADEL® Wafer (polifeprosan 20 with carmustine) : wound dehiscence, delayed wound healing, subdural, subgaleal or wound effusions, and cerebrospinal fluid leak. In the initial surgery trial, healing abnormalities occurred in 15.8% of GLIADEL® Wafer (polifeprosan 20 with carmustine) treated patients and in 11.7% of placebo recipients. Cerebrospinal fluid leaks occurred in 5% of GLIADEL® Wafer (polifeprosan 20 with carmustine) recipients and 0.8% of those given placebo. During surgery, a water-tight dural closure should be obtained to minimize the risk of cerebrospinal fluid leak. In the surgery for recurrent disease trial, the incidence of healing abnormalities was 14% in GLIADEL® Wafer (polifeprosan 20 with carmustine) treated patients and 5% in patients receiving placebo wafers.
  4. Intracranial Infection: In the initial surgery trial, the incidence of brain abscess or meningitis was 5% in patients treated with GLIADEL (polifeprosan 20 with carmustine) ® Wafer and 6% in patients receiving placebo. In the recurrent setting, the incidence of brain abscess or meningitis was 4% in patients treated with GLIADEL (polifeprosan 20 with carmustine) ® Wafer and 1% in patients receiving placebo.

The following adverse events, not listed in the table above, were reported in less than 4% but at least 1% of patients treated with GLIADEL® Wafer (polifeprosan 20 with carmustine) in all studies. The events listed were either not present pre-operatively or worsened post-operatively. Whether GLIADEL® Wafer (polifeprosan 20 with carmustine) caused these events cannot be determined.

Body as a Whole: peripheral edema (2%); neck pain (2%); accidental injury (1%); back pain (1%); allergic reaction (1%); asthenia (1%); chest pain (1%); sepsis (1%)

Cardiovascular System: hypertension (3%); hypotension (1%)

Digestive System: diarrhea (2%); constipation (2%); dysphagia (1%); gastrointestinal hemorrhage (1%); fecal incontinence (1%)

Hemic and Lymphatic System: thrombocytopenia (1%); leukocytosis (1%)

Metabolic and Nutritional Disorders: hyponatremia (3%); hyperglycemia (3%); hypokalemia (1%)

Musculoskeletal System: infection (1%)

Nervous System: hydrocephalus (3%); depression (3%); abnormal thinking (2%); ataxia (2%); dizziness (2%); insomnia (2%); monoplegia (2%); coma (1%); amnesia (1%); diplopia (1%); paranoid reaction (1%). In addition, cerebral hemorrhage and cerebral infarct were each reported in less than 1% of patients treated with GLIADEL® Wafer (polifeprosan 20 with carmustine) .

Respiratory System: infection (2%); aspiration pneumonia (1%)

Skin and Appendages: rash (2%)

Special Senses: visual field defect (2%); eye pain (1%)

Urogenital System: urinary incontinence (2%)

Read the Gliadel (polifeprosan 20 with carmustine) Side Effects Center for a complete guide to possible side effects »

DRUG INTERACTIONS

No information provided.

Last reviewed on RxList: 3/6/2009
This monograph has been modified to include the generic and brand name in many instances.

WARNINGS

Patients undergoing craniotomy for malignant glioma and implantation of GLIADEL® Wafer (polifeprosan 20 with carmustine) should be monitored closely for known complications of craniotomy, including seizures, intracranial infections, abnormal wound healing, and brain edema. Cases of intracerebral mass effect unresponsive to corticosteroids have been described in patients treated with GLIADEL® Wafer (polifeprosan 20 with carmustine) , including one case leading to brain herniation.

Pregnancy

There are no studies assessing the reproductive toxicity of GLIADEL® Wafer (polifeprosan 20 with carmustine) . Carmustine, the active component of GLIADEL® Wafer (polifeprosan 20 with carmustine) , can cause fetal harm when administered to a pregnant woman. Carmustine has been shown to be embryotoxic and teratogenic in rats at i.p. doses of 0.5, 1, 2, 4, or 8 mg/kg/day when given on gestation days 6 through 15. Carmustine caused fetal malformations (anophthalmia, micrognathia, omphalocele) at 1.0 mg/kg/day (about 1/6 the recommended human dose [eight wafers of 7.7 mg carmustine/wafer] on a mg/m2 basis). Carmustine was embryotoxic in rabbits at i.v. 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.

There are no studies of GLIADEL® Wafer (polifeprosan 20 with carmustine) in pregnant women. If GLIADEL® Wafer (polifeprosan 20 with carmustine) is used during pregnancy, or if the patient becomes pregnant after GLIADEL® Wafer (polifeprosan 20 with carmustine) implantation, the patient must be warned of the potential hazard to the fetus.

PRECAUTIONS

General

Communication between the surgical resection cavity and the ventricular system should be avoided to prevent the wafers from migrating into the ventricular system and causing obstructive hydrocephalus. If a communication larger than the diameter of a wafer exists, it should be closed prior to wafer implantation.

Computed tomography and magnetic resonance imaging of the head may demonstrate enhancement in the brain tissue surrounding the resection cavity after implantation of GLIADEL® Wafer (polifeprosan 20 with carmustine) s. This enhancement may represent edema and inflammation caused by GLIADEL® Wafer (polifeprosan 20 with carmustine) or tumor progression.

Therapeutic Interactions

Interactions of GLIADEL® Wafer (polifeprosan 20 with carmustine) with other drugs have not been formally evaluated.

The short-term and long-term toxicity profiles of GLIADEL® Wafer (polifeprosan 20 with carmustine) when given in conjunction with chemotherapy have not been fully explored. GLIADEL® Wafer (polifeprosan 20 with carmustine) , when given in conjunction with radiotherapy does not appear to have any short-term or chronic toxicities.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity, mutagenicity or impairment of fertility studies have been conducted with GLIADEL® Wafer (polifeprosan 20 with carmustine) . Carcinogenicity, mutagenicity and impairment of fertility studies have been conducted with carmustine, the active component of GLIADEL® Wafer (polifeprosan 20 with carmustine) . Carmustine was given three times a week for six months, followed by 12 months observation, to Swiss mice at i.p. doses of 2.5 and 5.0 mg/kg (about 1/5 and 1/3 the recommended human dose [eight wafers of 7.7 mg carmustine/wafer] on a mg/m2 basis) and to SD rats at i.p. dose of 1.5 mg/kg (about 1/4 the recommended human dose on a mg/m2 basis). There were increases in tumor incidence in all treated animals, predominantly subcutaneous and lung neoplasms. Mutagenesis: 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). Impairment of Fertility: Carmustine caused testicular degeneration at i.p. doses of 8 mg/kg/week for eight weeks (about 1.3 times the recommended human dose on a mg/m2 basis) in male rats.

Pregnancy

Pregnancy Category D: see WARNINGS.

Nursing Mothers

It is not known if either carmustine, carboxyphenoxypropane, or sebacic acid is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from carmustine in nursing infants, it is recommended that patients receiving GLIADEL® Wafer (polifeprosan 20 with carmustine) discontinue nursing.

Pediatric Use

The safety and effectiveness of GLIADEL® Wafer (polifeprosan 20 with carmustine) in pediatric patients have not been established.

Last reviewed on RxList: 3/6/2009
This monograph has been modified to include the generic and brand name in many instances.

OVERDOSE

There is no clinical experience with use of more than eight GLIADEL® Wafer (polifeprosan 20 with carmustine) s per surgical procedure.

CONTRAINDICATIONS

GLIADEL® Wafer (polifeprosan 20 with carmustine) contains carmustine. GLIADEL® Wafer (polifeprosan 20 with carmustine) should not be given to individuals who have demonstrated a previous hypersensitivity to carmustine or any of the components of GLIADEL® Wafer (polifeprosan 20 with carmustine) .

Last reviewed on RxList: 3/6/2009
This monograph has been modified to include the generic and brand name in many instances.

CLINICAL PHARMACOLOGY

GLIADEL® Wafer (polifeprosan 20 with carmustine) 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® Wafer (polifeprosan 20 with carmustine) 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® Wafer (polifeprosan 20 with carmustine) 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 CO2 in animals.

The absorption, distribution, metabolism, and excretion of the copolymer in humans is unknown. Carmustine concentrations delivered by GLIADEL® Wafer (polifeprosan 20 with carmustine) in human brain tissue have not been determined. Plasma levels of carmustine after GLIADEL® Wafer (polifeprosan 20 with carmustine) 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/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.

GLIADEL® Wafer (polifeprosan 20 with carmustine) s 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® Wafer (polifeprosan 20 with carmustine) 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® Wafer (polifeprosan 20 with carmustine) 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.

COMPOSITION OF WAFER REMNANTS REMOVED FROM TWO PATIENTS ON RE-OPERATION

Component Patient A Patient B
Days After GLIADEL® Wafer Implantation 64 92
Anhydride Bonds None detected None detected
Water Content (% of wafer remnant weight) 95-97% 74-86%
Carmustine Content (% of initial) < 0.0004% 0.034%
Carboxyphenoxypropane Content (% of initial) 9% 14%
Sebacic Acid Content (% of initial) 4% 3%

The wafer remnants consisted mostly of water and monomeric components with minimal detectable carmustine present.

Clinical Studies

Primary Surgery

A randomized, double-blind, placebo-controlled clinical trial was conducted in adult patients with newly-diagnosed high-grade malignant glioma undergoing initial craniotomy for tumor resection. This trial determined the safety and efficacy of GLIADEL® Wafer (polifeprosan 20 with carmustine) implants plus surgery and radiation therapy compared to placebo implants plus surgery and radiation therapy. Two hundred and forty patients with newly-diagnosed malignant glioma were enrolled. The most common tumor type was Glioblastoma Multiforme (GBM) (n=207), followed by anaplastic oligoastrocytoma (n=11), anaplastic oligodendroglioma (n=11), and anaplastic astrocytoma (n=2). GLIADEL® Wafer (polifeprosan 20 with carmustine) s were implanted at the time of the surgery in 120 patients and placebo wafers were implanted in 120 patients. The majority of patients received 6-8 wafers. The majority of patients (93/120, 77.5% in the GLIADEL® Wafer (polifeprosan 20 with carmustine) group and 98/120, 81.7% in the placebo group) with newly-diagnosed malignant glioma received a standard course of radiotherapy (55 to 60 Gy) typically starting 3 weeks after surgery. There were 17 patients (14.2%) in the GLIADEL® Wafer (polifeprosan 20 with carmustine) group and 12 patients (10.0%) in the placebo group who received systemic chemotherapy during the study. All six patients with anaplastic oligodendroglioma received chemotherapy within 30 days of GLIADEL® Wafer (polifeprosan 20 with carmustine) implantation. Patients were followed for at least three years or until death. Only one patient was lost to follow-up. Median survival increased from 11.6 months with placebo to 13.8 months with GLIADEL® Wafer (polifeprosan 20 with carmustine) (p-value < 0.05, log-rank test). The hazard ratio for GLIADEL® Wafer (polifeprosan 20 with carmustine) treatment was 0.73 (95% CI: 0.56-0.95).

Kaplan-Meier Overall Survival Curves for Patients Undergoing Initial Surgery for a High-Grade Malignant Glioma

Kaplan-Meier Overall Survival Curves - Illustration

When only patients with glioblastoma multiforme were included in the analysis, the hazard ratio with GLIADEL® Wafer (polifeprosan 20 with carmustine) treatment was 0.78 (95% CI: 0.59-1.03, p=0.08, log-rank test).

Surgery for Recurrent Disease

A randomized, double-blind, placebo-controlled clinical trial was conducted in adult patients with recurrent malignant glioma. This trial determined the safety and efficacy of GLIADEL® Wafer (polifeprosan 20 with carmustine) implants plus surgery compared to placebo implants plus surgery.

Ninety-five percent of the patients treated with GLIADEL® Wafer (polifeprosan 20 with carmustine) had 7-8 wafers implanted. Chemotherapy was withheld at least four weeks (six weeks for nitrosoureas) prior to and two weeks after surgery in patients undergoing re-operation for malignant glioma. In 222 patients with recurrent malignant glioma who had failed initial surgery and radiation therapy, the six-month survival rate after repeat surgery increased from 47% (53/112) for patients receiving placebo to 60% (66/110) for patients treated with GLIADEL® Wafer (polifeprosan 20 with carmustine) Median survival increased by 33%, from 24 weeks (5.5 months) with placebo to 32 weeks (7.4 months) with GLIADEL® Wafer (polifeprosan 20 with carmustine) treatment. In patients with GBM, the six-month survival rate increased from 36% (26/73) with placebo to 56% (40/72) with GLIADEL® Wafer (polifeprosan 20 with carmustine) treatment. Median survival of GBM patients increased by 41% from 20 weeks (4.6 months) with placebo to 28 weeks (6.4 months) with GLIADEL® Wafer (polifeprosan 20 with carmustine) treatment. In patients with pathologic diagnoses other than GBM at the time of surgery for tumor recurrence, GLIADEL® Wafer (polifeprosan 20 with carmustine) produced no survival prolongation.

6-MONTH KAPLAN-MEIER SURVIVAL CURVES FOR PATIENTS UNDERGOING SURGERY FOR RECURRENT GBM

6-Month Kaplan-Meier Survival Curves - Illustration

KAPLAN-MEIER OVERALL SURVIVAL CURVES FOR PATIENTS UNDERGOING SURGERY FOR RECURRENT GBM

Kaplan-Meier Overall Survival Curves For Patients Undergoing Surgery For Recurrent Gbm - Illustration

Last reviewed on RxList: 3/6/2009
This monograph has been modified to include the generic and brand name in many instances.

PATIENT INFORMATION

No information provided. Please refer to the WARNINGS and PRECAUTIONS sections.

Last reviewed on RxList: 3/6/2009
This monograph has been modified to include the generic and brand name in many instances.

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PATIENT INFORMATION

No information provided. Please refer to the WARNINGS and PRECAUTIONS sections.

Last reviewed on RxList: 3/6/2009
This monograph has been modified to include the generic and brand name in many instances.

Disclaimer

Gliadel Consumer

IMPORTANT: HOW TO USE THIS INFORMATION: This 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 for you. This information is not individual medical advice and does not substitute for the advice of your health care professional. Always ask your health care professional for complete information about this product and your specific health needs.

CARMUSTINE/POLIFEPROSAN 20 - IMPLANT

(kar-MUS-teen/POL-ee-FEP-roe-san)

COMMON BRAND NAME(S): Gliadel

USES: This medication is used with brain surgery and radiation to treat a certain type of brain tumor ( malignant glioma). It is also used with surgery to treat a type of malignant glioma (glioblastoma multiforme) that comes back.

Carmustine works by stopping the growth of tumor cells. It helps to kill any leftover tumor cells that are not taken out by the surgery. Polifeprosan 20 works by controlling the release of carmustine into the area where the brain tumor was taken out.

HOW TO USE: This medication is placed by a surgeon during brain surgery into the area where the brain tumor was taken out. The implant will dissolve slowly, releasing the medication to the surrounding area. Follow all your doctor's instructions on what to do before and after surgery.

The number of implants placed is based on the size of the area to cover. The maximum recommended dose is 8 implants placed at each surgery.

Since this drug can be absorbed through the skin, women who are pregnant or who may become pregnant should not handle this medication.

Disclaimer

Gliadel Consumer (continued)

SIDE EFFECTS: Constipation, stomach/abdominal/back pain, nausea, or vomiting may occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

Many people using this medication have serious side effects. However, your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Careful monitoring by your doctor may decrease your risk.

Tell your doctor immediately if any of these unlikely but serious side effects occur: swelling/redness/warmth at surgery site, wound at surgery site that is opening or not healing properly, signs of an infection (e.g., fever), chest pain, mental/mood changes (e.g., depression, anxiety).

Seek immediate medical attention if any of these unlikely but very serious side effects occur: seizures, severe headache, extreme tiredness/weakness, confusion, weakness on one side of the body, slurred speech, stiff neck, fainting.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice any other effects not listed above, contact your doctor or pharmacist.

In the US -

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

Read the Gliadel (polifeprosan 20 with carmustine) Side Effects Center for a complete guide to possible side effects »

PRECAUTIONS: Before receiving carmustine/polifeprosan 20, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

Before using this medication, tell your doctor or pharmacist your medical history.

This medication is not recommended for use during pregnancy. Consult your doctor for more details. If you become pregnant or think you may be pregnant, tell your doctor immediately.

It is not known whether this drug passes into breast milk. Because of the possible risk to the infant, breast-feeding while using this drug is not recommended. Consult your doctor before breast-feeding.

Disclaimer

Gliadel Consumer (continued)

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor or pharmacist first.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use.

Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center.

NOTES: Keep all regular medical and laboratory appointments.

Laboratory and/or medical tests (e.g., wound exams) should be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

MISSED DOSE: Not applicable.

STORAGE: Store in a freezer at or below -4 degrees F (-20 degrees C). Unopened foil pouches may be kept at room temperature for up to 6 hours. Consult your pharmacist for details. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised May 2010. Copyright(c) 2010 First Databank, Inc.

Gliadel Patient Information Including Side Effects

Brand Names: BiCNU, Gliadel

Generic Name: carmustine (Pronunciation: kar MUS teen)

What is carmustine (Gliadel)?

Carmustine is a cancer medication that interferes with the growth and spread of cancer cells in the body.

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

Carmustine is sometimes given with other cancer medications.

Carmustine may also be used for other purposes not listed in this medication guide.

What are the possible side effects of carmustine (Gliadel)?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have a serious side effect such as:

  • new or worsening cough, fever, trouble breathing;
  • feeling short of breath on exertion;
  • chest discomfort, dry cough or hack;
  • feeling weak or tired, loss of appetite, rapid weight loss;
  • fever, chills, body aches, flu symptoms, sores in your mouth and throat;
  • easy bruising, unusual bleeding (nose, mouth, vagina, or rectum), purple or red pinpoint spots under your skin;
  • pale skin, feeling light-headed, rapid heart rate, trouble concentrating;
  • urinating less than usual or not at all;
  • drowsiness, confusion, mood changes, increased thirst, swelling, weight gain, feeling short of breath;
  • severe burning, irritation, or skin changes where the injection was given; or
  • redness of your eyes or skin and severe warmth or tingling under your skin (within 2 to 4 hours after your carmustine injection).

Less serious side effects may include:

  • nausea, vomiting;
  • headache; or
  • mild pain, swelling, redness, or darkened skin color where the injection was given.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Read the Gliadel (polifeprosan 20 with carmustine) Side Effects Center for a complete guide to possible side effects »

What is the most important information I should know about carmustine (Gliadel)?

You should not use this medication if you are allergic to carmustine.

Before receiving carmustine, tell your doctor if you have bone marrow suppression, liver or kidney disease, or a history of lung or breathing problems.

Carmustine is usually given once every 6 weeks. You may be given either a single injection or multiple injections over a 2-day period. Follow your doctor's dosing instructions very carefully.

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

Carmustine can lower blood cells that help your body fight infections. Your blood will need to be tested weekly for at least 6 weeks after you receive a dose of carmustine. Your kidneys, liver, and lung function may also need to be tested. Do not miss any follow-up visits to your doctor.

Side Effects Centers

Gliadel Patient Information including How Should I Take

What should I discuss with my healthcare provider before receiving carmustine (Gliadel)?

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

To make sure you can safely receive carmustine, tell your doctor if you have any of these other conditions:

  • bone marrow suppression;
  • liver disease;
  • kidney disease; or
  • a history of lung or breathing problems.

FDA pregnancy category D. 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 you are being treated with carmustine.

How is carmustine given (Gliadel)?

Carmustine is injected into a vein through an IV. You will receive this injection in a clinic or hospital setting. Carmustine must be given slowly, and the IV infusion can take at least 2 hours to complete.

Carmustine is usually given once every 6 weeks. You may be given either a single injection or multiple injections over a 2-day period. Follow your doctor's dosing instructions very carefully.

Tell your caregivers if you feel any burning or pain around the IV needle when carmustine is injected.

Carmustine can cause nausea and vomiting that may last up to 6 hours after your injection. You may be given anti-nausea medications to help prevent these side effects.

Carmustine can lower blood cells that help your body fight infections. Your blood will need to be tested often. Your cancer treatments may be delayed based on the results of these tests. Visit your doctor regularly.

To be sure your blood cells do not get too low, your blood will need to be tested weekly for at least 6 weeks after you receive a dose of carmustine. This medication can have long-lasting effects on your body. Your kidneys, liver, and lung function may also need to be tested. Do not miss any follow-up visits to your doctor for blood or urine tests.

Side Effects Centers

Gliadel Patient Information including If I Miss a Dose

What happens if I miss a dose (Gliadel)?

Call your doctor for instructions if you miss an appointment for your carmustine injection.

What happens if I overdose (Gliadel)?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include severe forms of the serious side effects listed in this medication guide.

What should I avoid while receiving carmustine (Gliadel)?

Avoid being near people who are sick or have infections. Tell your doctor at once if you develop signs of infection.

What other drugs will affect carmustine (Gliadel)?

Tell your doctor about all other medications you use, especially cimetidine (Tagamet).

There may be other drugs that can interact with carmustine. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

Where can I get more information?

Your doctor or pharmacist can provide more information about carmustine.


Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

Every effort has been made to ensure that the information provided by Cerner Multum, Inc. ('Multum') is accurate, up-to-date, and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. Multum information has been compiled for use by healthcare practitioners and consumers in the United States and therefore Multum does not warrant that uses outside of the United States are appropriate, unless specifically indicated otherwise. Multum's drug information does not endorse drugs, diagnose patients or recommend therapy. Multum's drug information is an informational resource designed to assist licensed healthcare practitioners in caring for their patients and/or to serve consumers viewing this service as a supplement to, and not a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. Multum does not assume any responsibility for any aspect of healthcare administered with the aid of information Multum provides. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse or pharmacist.

Copyright 1996-2012 Cerner Multum, Inc. Version: 4.01. Revision date: 10/14/2011.

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Side Effects Centers

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