Carmustine (Implantation-Local)


VA CLASSIFICATION
Primary: AN100

Commonly used brand name(s): Gliadel Wafer.

Another commonly used name is
BCNU .
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antineoplastic—

Indications

Accepted

Tumors, brain (treatment)—Carmustine implants are indicated, by insertion into the surgical resection cavity, to prolong survival of patients who require surgery for recurrent glioblastoma multiforme {01}.


Pharmacology/Pharmacokinetics

Note: Pharmacokinetic studies of carmustine and the biodegradable polyanhydride copolymer with which it is formulated into the implant dosage form have not been done in patients following implantation into brain tissue {01}. However, in animal studies, carmustine was not detected in the plasma or cerebrospinal fluid of rabbits implanted with the medication {01}.


Mechanism of action/Effect:

Carmustine is an alkylating agent of the nitrosourea type {01}. Carmustine's antineoplastic effect involves alkylation of DNA and RNA and cross-linking of DNA by carmustine and/or an active metabolite {01}.

Biotransformation:

Biotransformation of carmustine occurs spontaneously and/or metabolically {01}. A metabolite, thought to be chloroethyl carbonium ion, is an active alkylating agent {01}.

Note: The anhydride bonds of the copolymer with which carmustine is formulated into the implantable dosage form are hydrolyzed upon exposure to the aqueous environment of the tumor resection cavity, yielding carboxyphenoxypropane and sebacic acid and releasing carmustine {01}. More than 70% of the copolymer is degraded within 3 weeks after implantation {01}.



Precautions to Consider

Tumorigenicity

Carmustine caused an increase in the incidence of tumors, predominantly subcutaneous and lung tumors, in all treated animals (mice given 2.5 or 5 mg per kg of body weight [mg/kg] and rats given 1.5 mg/kg intraperitoneally three times a week for 6 months) {01}. These doses are equivalent to one fifth, one third, and one fourth, respectively, of the recommended human dose of eight 7.7-mg implants on a mg per square meter of body surface area (mg/m 2) basis {01}.

Mutagenicity

Carmustine is mutagenic in vitro (in the Ames test and the human lymphoblast HGPRT assay) and clastogenic both in vitro (in the micronucleus assay in V79 hamster cells) and in vivo (in the SCE assay in rodent brain tumors and the mouse bone marrow micronucleus assay) {01}.

Pregnancy/Reproduction
Fertility—
Intraperitoneal administration of 8 mg/kg of carmustine (equivalent to approximately 1.3 times the recommended human dose on a mg/m 2 basis) per week for 8 weeks caused testicular degeneration in male rats {01}.

Pregnancy—
Adequate and well-controlled studies have not been done in humans {01}.

Reproductive studies with implanted carmustine have not been done in animals {01}. However, carmustine was teratogenic in rats, causing anophthalmia, micrognathia, and omphalocele, when administered intraperitoneally on days 6 through 15 of gestation in doses of 1 mg/kg (equivalent to approximately one sixth of the recommended human dose on a mg/m 2 basis) or higher {01}. Also, carmustine was embryotoxic in rabbits, causing increased embryo and fetal deaths, reduced numbers of litters, and reduced litter sizes, at a dose of 4 mg/kg per day intravenously (approximately 1.2 times the recommended human dose on a mg/m 2 basis) {01}.

FDA Pregnancy Category D {01}.

Breast-feeding

It is not known whether carmustine or the breakdown products of the copolymer with which it is formulated into the implant are distributed into breast milk {01}. However, because of the potential for severe carmustine-induced adverse effects in nursing infants, it is recommended that breast-feeding be discontinued after insertion of the implants {01}.

Pediatrics

Appropriate studies on the relationship of age to the effects of carmustine implants have not been performed in pediatric patients {01}. Safety and efficacy have not been established {01}.


Geriatrics


No information is available on the relationship of age to the effects of carmustine implants in geriatric patients.

Diagnostic interference
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results
Tumor progression assessment    (implant-induced edema and inflammation in brain tissue surrounding the resection cavity may produce enhancement similar to that produced by tumor progression in computerized tomographic or magnetic resonance imaging studies {01})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problem exists:
» Hypersensitivity to carmustine or other components of the implant, history of{01}
Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» Abnormal wound healing and
» Brain edema and
» Convulsions and
» Intracranial infections and
» Other complications of craniotomy    (patients should be monitored for the occurrence of such complications following implantation {01})




Side/Adverse Effects

Note: In general, adverse effects reported following implantation of carmustine are typical of those occurring in patients undergoing craniotomy for resection of malignant gliomas {01}. In clinical trials, most of the reported adverse effects did not occur significantly more often in treated patients than in controls (recipients of implants containing only the biodegradable copolymer) {01}.
Although a causal relationship has not been established, the following adverse effects were also reported in clinical trials (frequencies of occurrence varying from less than 1 to 3%): allergic reaction; asthenia; back, chest, eye, or neck pain; central nervous system (CNS) effects, including ataxia, cerebral hemorrhage, cerebral infarct, coma, diplopia, dizziness, hydrocephalus, and monoplegia; gastrointestinal tract effects, including constipation, diarrhea, dysphagia, fecal incontinence, and gastrointestinal hemorrhage; hematologic abnormalities, including leukocytosis and thrombocytopenia; hypertension or hypotension; metabolic abnormalities, including hyperglycemia, hypokalemia, and hyponatremia; musculoskeletal system infection; peripheral edema; psychological changes, including abnormal thinking, amnesia, insomnia, mental depression, and paranoid reaction; respiratory infection or aspiration pneumonia; sepsis; visual field defects; and urinary incontinence {01}.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent (> 10%)
    
Convulsions{01}
    
fever{01}
    
hemiplegia{01} (inability to move legs or arms)
    
surgical site healing abnormalities{01}
    
urinary tract infection{01} (blood in urine; burning, painful, or difficult urination; lower back or side pain)

Note: In clinical trials, new or worsened convulsions, usually mild to moderate in severity, occurred as frequently in control patients as in treated patients {01}. The first new or worsened convulsion occurred within the first 5 days postoperatively in 54% of the treated patients and 9% of the controls who experienced this complication; the median time to onset in the two groups was 3.5 days and 61 days, respectively {01}. The beneficial effect of the active treatment on survival was not affected {01}.
Reported surgical site healing abnormalities included cerebrospinal fluid (CSF) leaks, subdural fluid accumulation, subgaleal effusions, wound breakdown, and wound effusions {01}.


Incidence less frequent (4 to 10%)
    
Aphasia{01} (problems in speaking)
    
brain edema{01}
    
infection, including abscess{01} or meningitis{01} (confusion; fever; headache; stiff neck)
    
intracranial hypertension{01} (headache; nausea and vomiting; papilledema)
    
pain{01}
    
rash{01}
    
stupor{01} (extremely severe sleepiness)

Note: Brain edema may result in a mass effect (characterized by bradycardia, hypertension, pupillary enlargement, slow breathing, and stupor) that is unresponsive to corticosteroid treatment {01}. In some cases, reoperation and removal of the implant or its remnants may be necessary {01}.




Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent (³ 10%)
    
Confusion{01} —without other symptoms of infection
    
drowsiness{01}
    
headache{01} —without other symptoms of infection or intracranial hypertension
    
nausea or vomiting{01} —without other symptoms of intracranial hypertension





Overdose
There is no experience with overdose of the carmustine implants {01}.


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Carmustine (Implantation-Local) .

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before receiving this medication
»   Conditions affecting use, especially:
Hypersensitivity to carmustine or other components of the implant, history of

Pregnancy—Potential risk because carmustine is tumorigenic, embryotoxic, and teratogenic in animals; informing physician immediately if pregnancy is suspected





Breast-feeding—Not recommended because of potential for carmustine-induced serious adverse effects in the infant

Precautions after receiving this medication
» Importance of close monitoring by the physician


Side/adverse effects
Signs of potential side effects, especially convulsions, fever, hemiplegia, urinary tract infection, aphasia, brain edema, infection, intracranial hypertension, pain, rash, or stupor


General Dosing Information
Carmustine implants are inserted into the surgical resection cavity after the tumor has been resected, tumor pathology has been confirmed, and hemostasis has been achieved {01}. Prior to implantation, communication between the surgical resection cavity and the ventricular system, if present, should be closed {01}. This measure is needed to prevent the implants from migrating into the ventricular system and causing obstructive hydrocephalus {01}.

After the implants are in place, a layer of oxidized regenerated cellulose may be placed over the implants to secure them against the surface of the surgical resection cavity {01}. The resection cavity should be irrigated prior to closing the dura in a watertight fashion {01}.

Safety considerations for handling this medication
The packets containing the implants should be handled carefully {01}. They should be brought into the operating room unopened and remain sealed until the time of implantation {01}.

The implants should be handled only by individuals wearing surgical gloves; contact with carmustine may cause severe burning and hyperpigmentation of the skin {01}. It is recommended that two pairs of gloves be worn {01}. The outer pair should be discarded into a biohazard container after use {01}.

It is recommended that the implantation be performed using a surgical instrument dedicated to the handling of the implants {01}.

If a repeat procedure is performed in an implanted area, any implant or remnant remaining in the surgical field should be treated as a potentially cytotoxic agent {01}.


Implantation Dosage Forms

CARMUSTINE IMPLANTS{02}

Usual adult dose
Tumors, brain
Implantation, into the surgical resection cavity, up to 8 implants, depending on the capacity of the cavity {01}. As much of the cavity as possible should be covered {01}. Slight overlapping is acceptable {01}.


Note: Implants that have been broken in half may be used, but any that have been broken into more than two pieces should be discarded into a biohazard container {01}.


Usual adult prescribing limits
Up to 8 implants per procedure {01}.

Usual pediatric dose
Safety and efficacy have not been established {01}.

Strength(s) usually available
U.S.—


7.7 mg (Rx) [Gliadel Wafer (polifeprosan 20 [biodegradable polyanhydride copolymer] 192.3 mg)]

Packaging and storage:
Store at or below -20 °C (-4 °F) {01}. However, unopened foil packets may be kept at room temperature for no longer than 6 hours at a time {01}.

Note: Carmustine implants are packaged in two aluminum foil pouches. The sterile inner packet is designed to protect the implant from moisture as well as to maintain sterility. The outer surface of the overwrap is not sterile {01}.




Developed: 08/12/1998



References
  1. Gliadel Wafer package insert (Rhône-Poulenc Rorer—US), Rev 10/96, Rec 12/96.
  1. USP Nomenclature Committee Meeting, Rockville, MD, Jan. 9-10, 1997.
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