BCNU
BiCNU(r), GLIADEL(r) Wafer
alkylating agent, cytotoxic
Special pediatric considerations are noted when applicable, otherwise adult provisions apply.
Carmustine is a highly lipid-soluble nitrosurea compound. Carmustine, a bifunctional alkylating agent,3 alkylates DNA and RNA, can cross-link DNA, and inhibits several enzymes by carbamoylation.1 It is cell-cycle phase nonspecific.4 Carmustine is generally not cross-resistant with other alkylating agents,5 however, cross-resistance between carmustine and lomustine has occurred.1
Table refers to intravenous (IV) dosing. Pharmacokinetic properties of the implantable carmustine-impregnated wafer have not been evaluated.6 High-dose5 is defined here as >200 mg/m2.
| Oral Absorption | not known 7 | |
| Distribution | highly lipid soluble 8 (e.g., enters breast milk, brain) | |
| cross blood brain barrier? | passes readily 1 (15-70% of concurrent plasma concentrations) children 9 : >90% | |
| volume of distribution | 3.25 L/kg (5.1 L/kg, high dose) 10 children 9 : 90 L/m 2 | |
| plasma protein binding | 80% children 9 : 65-75% | |
| Metabolism | rapid spontaneous decomposition 3 ; significant hepatic metabolism 3,8 | |
| active metabolite(s) | yes 1 | |
| inactive metabolite(s) | yes 7 | |
| Excretion | predominately renal; respiratory 6-10% 8 as CO 2 | |
| urine 8 | 60-70% within 96 h | |
| feces 1 | <1% | |
| terminal half life | 0.25-0.75 h, non-linear dose-related | |
| clearance | 56 mL/min/kg (78 mL/min/kg, high dose) 10 children 9 : 1,500-2,000 mL/min/m 2 | |
Adapted from standard reference5 unless specified otherwise.
Table refers to intravenous (IV) dosing except where specified.
| Primary uses: | Other uses: |
| *Brain tumours | Glioblastoma 11 (implantable carmustine-impregnated wafer) |
| *Glioma (implantable carmustine-impregnated wafer) | Lymphoma, cutaneous T-cell 1 (topical carmustine) |
| *Lymphoma, Hodgkin's disease | |
| *Lymphoma, non-Hodgkin's | |
| *Multiple myeloma | |
| *Melanoma | |
| *Gastrointestinal cancer | |
*Health Canada approved indication
Caution:
Dose-related pulmonary toxicity may occur with carmustine injection; patients receiving cumulative doses
>1,400 mg/m2 are at higher risk.8 Single doses of >450 mg/m2 may be associated with the development of acute lung injury in approximately 20% of patients. For more information, see paragraph following Side Effects table.
Special populations: children 5
Carmustine injection should be used with extreme caution in
due to the high risk of pulmonary toxicity.
Carcinogenicity: 5
Carmustine is carcinogenic in rats and mice, producing a marked increase in tumour incidence with therapeutic doses.
Mutagenicity: Mutagenic in Ames test and mammalian in vitro mutation test.12Carmustine is clastogenic in mammalian in vitro and in vivo chromosome tests.
Fertility: 5
Carmustine affects fertility in male rats at doses somewhat higher than human doses.
Pregnancy: FDA Pregnancy Category D.8 There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).
Breastfeeding 8
is contraindicated as carmustine injection is detected in human breast milk.
The table includes adverse events that presented during drug treatment but may not necessarily have a causal relationship with the drug. Because clinical trials are conducted under very specific conditions, the adverse event rates observed may not reflect the rates observed in clinical practice. Adverse events are generally included if they were reported in more than 1% of patients in the product monograph or pivotal trials, and/or determined to be clinically important. When placebo-controlled trials are available, adverse events are included if the incidence is > 5% higher in the treatment group.
CARMUSTINE INJECTION:
High-dose5 is defined here as >200 mg/m2.
| ORGAN SITE | SIDE EFFECT |
| Clinically important side effects are in bold, italics 13 | |
| blood/bone marrow/ febrile neutropenia | anemia (1-10%) 8 |
| myelosuppression (>10%) 8 ; onset 7-14 days, nadir 21-35 days, recovery 42-56 days; cumulative, dose related, delayed and often biphasic 11 ; see paragraph following Side Effects table | |
| cardiovascular (general) | hypotension, due to alcohol content of diluent (high-dose therapy >10%) 8 |
| dermatology/skin | extravasation hazard: vesicant 14 |
| alopecia 7 (1-10%) 8 | |
| dermatitis with topical use (50%) 10 improves with reduced concentration of compounded product | |
| flushing, due to alcohol content of diluent (1-10%) 8 ; increased with administration times <1-2 h 15 | |
| hyperpigmentation, transient, 4 with accidental skin contact (>10%) 8 | |
| injection site reaction; see paragraph following Side Effects table | |
| ORGAN SITE | SIDE EFFECT |
| Clinically important side effects are in bold, italics 13 | |
| gastrointestinal | emetogenic potential 16 : >250 mg/m 2 high; < 250 mg/m 2 high-moderate |
| anorexia (1-10%) 8 | |
| constipation (1-10%) 8 | |
| diarrhea (1-10%) 8 | |
| nausea and vomiting, severe (>10%) 8 ; begins within 2-4 h of administration and lasts for 4-6 h | |
| stomatitis (1-10%) | |
| hepatobiliary/pancreas | hepatotoxicity, reversible, delayed up to 60 days after administration (<1%, 1 high-dose therapy 1-10 % and dose-limiting 11 ) |
| metabolic/laboratory | alkaline phosphatase, reversible increase (>20-25%) 8 |
| bilirubin, reversible increase (>20-25%) 8 | |
| SGOT, reversible increase (>20-25%) 8 | |
| neurology | ataxia (>10%) 8 |
| dizziness (>10%) 8 | |
| encephalopathy (<1%, high-dose therapy 1-10% and dose-limiting 11 ) | |
| ocular/visual | ocular toxicities, transient conjunctival flushing and blurred vision; retinal hemorrhages (>10%) 8 |
| pain | headache 1 |
| muscular pain (<1%) | |
| pulmonary | pulmonary toxicity (up to 30%); see paragraph following Side Effects table |
| BCNU pneumonitis 17 (20% for doses >450 mg/m 2 ) 17 ; see paragraph following Side Effects table | |
| interstitial fibrosis (<1%, up to 50% for cumulative doses >1,400 mg/m 2 ) 8 | |
| renal/genitourinary | renal toxicity 7,11 (<1% for cumulative doses <1,000 mg/m 2 ) |
| secondary malignancy | acute leukemias, bone marrow dysplasias 5 ; following long-term use |
| sexual/reproductive function | gynecomastia (<1%) |
| infertility 7 | |
| teratogenesis 7 | |
| vascular | phlebitis (>10%) 8 |
| veno-occlusive disease 7 (high-dose therapy <1%) 11 | |
Adapted from standard reference5 unless specified otherwise.
IMPLANTABLE CARMUSTINE-IMPREGNATED WAFER:
| ORGAN SITE | SIDE EFFECT |
| Clinically important side effects are in bold, italics 18 | |
| ORGAN SITE | SIDE EFFECT |
| Clinically important side effects are in bold, italics 18 | |
| allergy/immunology | allergic reaction (1%) |
| cardiovascular (arrhythmia) | tachycardia (2%) |
| cardiovascular (general) | hypertension (3%) |
| hypotension (3%) | |
| constitutional symptoms | accidental injury (1-5%) 1 |
| aggravation reaction, defined as progression of tumour or disease or general deterioration (82%) 1 | |
| asthenia (1%) | |
| insomnia (1-10%) 8 | |
| dermatology/skin | alopecia does not occur 18 |
| wound healing complications, at site of implantation, 19 including cerebrospinal fluid leaks, subdural fluid collection and wound healing (12%) | |
| endocrine | Cushing's syndrome (3%) 1 |
| Diabetes mellitus (5%) 1 | |
| gastrointestinal | emetogenic potential: rare |
| constipation (1%) | |
| dysphagia (1%) | |
| vomiting (2%) | |
| hemorrhage | hemorrhage, gastrointestinal (1%) |
| infection | intracranial infection, meningitis, or abscess 6 (1-10%) 8 |
| oral moniliasis (3%) | |
| lymphatics | edema, cerebral (1-10%) 8 |
| edema, peripheral (3%) | |
| metabolic/laboratory | hyponatremia (3%) |
| hypokalemia (1%) | |
| hyperglycemia (2%) | |
| neurology | brain swelling: amnesia (1-10% 8 ); aphasia (1-10%) 8 ; ataxia (1-10%) 8 ; confusion (1- 10%) 8 ; convulsion (1-10%) 8 ; dizziness (1-10%) 8 ; hemiplegia (1-10%) 8 ; hydrocephalus (1-10%) 8 ; monoplegia (2%) 8 ; seizures (> 10%) 8 ; somnolence (1- 10%) 8 ; stupor (1-10%) 8 ; abnormal thinking (3%) |
| ocular/visual | diplopia (1-10%) 8 |
| pain | chest pain (1%) |
| headache (1-10%) 8 | |
| pain (4%) | |
| renal/genitourinary | urinary incontinence (2%) |
| vascular | phlebitis (10%) 1 |
| pulmonary embolism (4-8%, at initial surgery) 1 | |
Adapted from standard reference6 unless specified otherwise. Injection reaction: Burning and hyperemia at the injection site, or along the course of the vein, are common during carmustine injection.5 Vasospasm is also common, but thrombosis and thrombophlebitis are rare.1 Rapid IV infusion may result in flushing of the skin and conjunctiva, likely due to the alcohol diluent. These effects can occur within 2 hours and may continue for 4 hours after administration of carmustine. Infusions should run over 1-2 hours; for high-dose carmustine, the maximum rate is 3 mg/m2/minute to avoid excessive flushing, agitation, and hypotension.8 Myelosuppression: Delayed myelosuppression occurs frequently with carmustine injection, and may be severe.5 This is cumulative and usually occurs 4-6 weeks after administration of the drug.1 Thrombocytopenia is generally greater than leukopenia; however, both may be dose-limiting toxicities. Anemia also occurs but is generally less severe. Due to the delayed and cumulative myelosuppressive effects, carmustine is usually given at intervals of at least 6 weeks. However, repeat courses of carmustine should not be administered until leukocyte and platelet counts have returned to acceptable levels. For more information, see Dosage Guidelines. Pulmonary toxicity: Pulmonary fibrosis and pulmonary infiltrates can occur with carmustine injection. Pulmonary toxicities20 are more common with prolonged therapy and with cumulative doses >1,400 mg/m2; however, pulmonary toxicity has occurred with lower doses.1 Early-onset pulmonary toxicity appears within 3 years of therapy (9 days to 43 months)5; however, late-onset pulmonary fibrosis has been reported up to 17 years after treatment. Risk factors include smoking, pre-existing respiratory condition(s), sequential or concomitant thoracic irradiation, and the use of other drugs that cause lung damage. Pulmonary function tests should be preformed at baseline and throughout treatment. Patients should be advised to immediately report any signs of respiratory complications, and this should result in discontinuation of therapy. Note that carmustine therapy during childhood may result in asymptomatic lung fibrosis that may become symptomatic in adulthood. Unlike the toxicity described above, a condition called BCNU pneumonitis,17 BCNU lung, or idiopathic pneumonia syndrome,21-23 may occur following a single dose or course of therapy. BCNU pneumonitis requires emergency treatment as it is potentially fatal.13 Patients typically present 30-100 days after autologous BMT with fever, cough, dyspnea and pulmonary infiltrates on x-ray.17 risk factors include the ones identified previously, as well as female sex.21,24 It has been suggested that doses <475 mg/m2 may reduce the risk,25 particularly in females.21 However, BCNU pneumonitis can occur with lower doses; e.g., 300 mg/m2. Treatment includes high-dose prednisone, as well as antibiotics if pneumonia is suspected. If this complication is suspected, please contact one of the physicians affiliated with the Leukemia / Bone Marrow Transplant Program of BC.13
Table refers to IV dosing. Interactions with the implantable carmustine-impregnated wafer have not been evaluated.6
| AGENT | EFFECT | MECHANISM | MANAGEMENT |
| cimetidine 26 | delayed, major, suspected; increased carmustine toxic effect | possible inhibition of carmustine metabolism | avoid concomitant use |
| digoxin tablets 26,27 | delayed, moderate, suspected; decreased effect of digoxin | changes to intestinal mucosa may decrease digoxin absorption | consider monitoring digoxin levels; adjust digoxin dose as needed |
| melphalan 20,28,29 | increased risk of pulmonary toxicity | melphalan may reduce the threshold for carmustine- induced pulmonary toxicity | caution; monitor for pulmonary toxicity |
| phenytoin 26 | delayed, moderate, suspected; decreased phenytoin levels | decreased absorption or increased metabolism of phenytoin | monitor serum phenytoin levels during and after carmustine therapy; adjust phenytoin dose as needed |
Carmustine in polifeprosan wafer6
: available in a single-dose treatment box containing eight individually pouched wafers. Each wafer contains 7.7 mg (3.85%) of carmustine. Each wafer is packaged in two aluminum foil laminate pouches. The inner pouch is sterile and maintains the sterility of the wafer. The second pouch is a peelable
overwrap. The aluminum foil pouches containing GLIADEL(r) should be delivered to the operating room and remain unopened until ready to implant the wafers. 5 The product must be stored at or below -20oC. Unopened foil pouches may be kept at ambient room temperature for a maximum of six hours.
Injection: For basic information on the current brand used at the BC Cancer Agency, see Chemotherapy Preparation and Stability Chart in Appendix.
For basic information on the current brand used at the BC Cancer Agency, see Chemotherapy Preparation and Stability Chart in Appendix.
Additional information for carmustine injection:
The powder in the unopened vial should have a physical appearance ranging from lacy flakes to a congealed mass.5 If the vial has been exposed to temperatures higher than 30.5-32.0 oC, the powder will liquefy and appear as an oily film in the bottom of the vial. This is a sign of decomposition and the vial should be discarded.
Allow supplied diluent (absolute alcohol) to come to room temperature before mixing.5
Use glass or polyolefin containers when preparing carmustine.15 The rate of loss of carmustine in D5W in PVC containers due to sorption is substantially greater than in glass or polyolefin containers.15 For infusion times longer than1-2 hours use a polyethylene-lined administration set to avoid sorption.15
Reconstituted vials stored under refrigeration should be examined for crystal formation prior to use. Crystals can be redissolved by warming the vial to room temperature and shaking the vial.
Compatibility of selected drugs15:
The following are compatible via Y-site injection: amifostine, aztreonam, cefepime, etoposide phosphate, filgrastim, fludarabine, gemcitabine, granisetron, melphalan, ondansetron, piperacillin, sargramostim, teniposide, thiotepa, vinorelbine.
Incompatibility of selected drugs15:
The following is incompatible via Y-site injection: allopurinol. The following is incompatible in the same infusion solution: sodium bicarbonate.
| BCCA administration guideline noted in bold , italics | |
| Subcutaneous | not used due to corrosive nature |
| Intramuscular | not used due to corrosive nature |
| Intratumoral | implantable carmustine-impregnated wafer |
| Direct intravenous | no information found |
| Intermittent infusion | over 1-2 h 15 |
| Continuous infusion | not used due to corrosive nature |
| Intraperitoneal | no information found |
| Intrapleural | not used due to corrosive nature |
| Intrathecal | not used due to corrosive nature |
| Intra-arterial | has been used 5 |
| Intravesical | no information found |
Refer to protocol by which patient is being treated. Numerous dosing schedules exist and depend on disease, response and concomitant therapy. Guidelines for dosing also include consideration of absolute neutrophil count (ANC). Dosage may be reduced, delayed or discontinued in patients with bone marrow depression due to cytotoxic/radiation therapy or with other toxicities.
Adults: Cycle Length: BCCA usual dose noted in bold, italics Intravenous: 4-6 weeks8: 20-65 mg/m2 (0.5-1 mg/kg) IV for one dose on day 1 (total dose per cycle 20-65 mg/m2 [0.5-1 mg/kg])
30100 mg/m2 IV for one dose on day 1 for 3-6 cycles (total dose per cycle 100 mg/m2)
6 weeks
:
6-8 weeks8: 150-200 mg/m2 IV once daily as a single dose on day 1, or divided into daily injections on 2 consecutive days starting on day 1 (total dose per cycle 150-200 mg/m2) 6-8 weeks8: 75-120 mg/m2 IV once daily for 2 consecutive days starting on day 1 (total dose per cycle 150-240 mg/m2) weeks8: 40-80 mg/m2 IV once daily for three consecutive days starting on day 1 (total dose per cycle 120-240 mg/m2)
Bone marrow transplant:
31,32
Bone marrow transplant33:
: 500 mg/m2 IV for one dose (on day
combination therapy
-2)
(total dose 500 mg/m2)
Note: these doses are fatal without bone marrow/stem cell transplant.
300 mg/m2 IV for one dose (on day
combination therapy:
-6)
(total dose 300 mg mg/m2)
Note: these doses are fatal without bone marrow/stem cell transplant.
Intratumoral6: n/a: implantation: up to 8 wafers placed in the resection cavity (total dose 61.6 mg); if the size and shape does not accommodate 8 wafers, the maximum number of wafers allowed should be placed In patients undergoing surgery and intracranial implantation of carmustine wafers for recurrent malignant glioma, chemotherapy is held for at least 4 weeks (6 weeks for nitrosureas) prior to and 2 weeks after surgery.
1,6
Topical1: n/a: 10 mg daily (as an alcoholic solution or ointment) usually applied once daily for 7-14 weeks (maximum 17 weeks). If inadequate response, a second course of topical therapy is administered after a rest interval of 6 weeks, using 20 mg daily for 4-8 weeks, as tolerated. Concurrent radiation: * carmustine injection13: consolidation irradiation may be required to residual masses post transplant after count recovery and overall improvement
implantable carmustine-impregnated wafer6: external beam radiation initiated no sooner than 3 weeks after implantation
Dosage in myelosuppression:
modify according to protocol by which patient is being treated; suggested dose modification30; not to be used for BMT dosing
| ANC x 10 9 /L | Platelets x 10 9 /L | Percent of prior dose to be given |
| >1.5 | >125 | 100% |
| 1-1.5 | 100-125 | 75% |
| <1 | <100 | omit |
Dosage in renal failure34: GFR <10 mL/min: discontinue
Dosage in hepatic failure4: dosage adjustment may be necessary based on liver function test results, no specific guidelines available
Dosage in dialysis34: no information found
| Cycle Length: | ||
| Intravenous 35 : | 4-6 week: | 200-250 mg/m 2 IV for one dose on day 1 (total dose per cycle 200-250 mg/m 2 ) |
Children:
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