Included as part of the PRECAUTIONS section.
Bone marrow toxicity is a dose-limiting, common and
severe toxic effect of BiCNU occurring 4-6 weeks after drug administration
(thrombocytopenia occurs at about 4 weeks post-administration persisting for 1
to 2 weeks; leukopenia occurs at 5 to 6 weeks after a dose of BiCNU persisting
for 1 to 2 weeks; thrombocytopenia is generally more severe than leukopenia;
anemia is less frequent and less severe compared to thrombocytopenia and/or
leukopenia) Complete blood count should therefore be monitored weekly for at
least six weeks after a dose. Repeat doses of BiCNU should not be given more frequently
than every six weeks. The bone marrow toxicity of BiCNU is cumulative and
therefore the dosage adjustment must be considered on the basis of nadir blood
counts from prior dose [see ADVERSE REACTIONS]. Greater
myelotoxicity (e.g., leukopenia and neutropenia) has been reported when carmustine
was combined with cimetidine [see DRUG INTERACTIONS].
Cases of fatal pulmonary toxicity with BiCNU have been
reported. Pulmonary toxicity characterized by pulmonary infiltrates and/or
fibrosis has been reported to occur from 9 days to 43 months after treatment with
BiCNU and related nitrosoureas. Pulmonary toxicity from BiCNU is dose-related.
Patients receiving greater than 1400 mg/m² cumulative dose are at significantly
higher risk than those receiving less. However, there have been reports of
pulmonary fibrosis in patients receiving lower total doses. Interstitial
fibrosis (with lower doses) occurred rarely. Additionally, delayed onset
pulmonary fibrosis occurring up to 17 years after treatment has been reported
in patients who received BiCNU (in cumulative doses ranging from 770 to 1800
mg/m² combined with cranial radiotherapy for intracranial tumors) in childhood
and early adolescence. Other risk factors include past history of lung disease
and duration of treatment. Baseline pulmonary function studies should be
conducted along with frequent pulmonary function tests during treatment.
Patients with a baseline below 70% of the predicted forced vital capacity (FVC)
or carbon monoxide diffusing capacity (DLCO) are particularly at risk.
Injection site reactions may occur during the
administration of BiCNU. Rapid intravenous infusion of BiCNU may produce
intensive flushing of the skin and suffusion of the conjunctiva within 2 hours,
lasting about 4 hours. It is also associated with burning at the site of
injection although true thrombosis is rare. Given the possibility of
extravasation, close monitoring of the infusion site for possible infiltration
during drug administration is recommended. A specific treatment for
extravasation reactions is unknown at this time.
Long-term use of nitrosoureas, such as BiCNU, has been
reported to be associated with the development of secondary malignancies.
Carmustine was carcinogenic when administered to laboratory animals [see Nonclinical
Toxicity]. Nitrosourea therapy, such as BiCNU, has carcinogenic potential
in humans. Patients treated with BiCNU should be monitored long-term for
development of second malignancies.
BiCNU has been administered through an intraarterial
intracarotid route; this procedure is investigational and has been associated
with ocular toxicity. Safety and effectiveness of the intraarterial route have
not been established.
Carmustine was embryotoxic in rats and rabbits and
teratogenic in rats when given in doses lower than the maximum cumulative human
dose based on body surface area. There are no adequate and wellcontrolled studies
in pregnant women. Advise pregnant women of the potential risk to the fetus [see
Use In Specific Populations]. Advise females of reproductive potential
to use highly effective contraception during and after treatment with BiCNU for
at least 6 months after therapy. Advise males of reproductive potential to use
effective contraception during and after treatment with BiCNU for at least 3
months after therapy [see Use In Specific Populations].
Patient Counseling Information
[see WARNINGS AND PRECAUTIONS].
A serious and frequent toxicity of BiCNU is delayed
myelosuppression and usually occurs 4 to 6 weeks after drug administration.
Hence, patients should be advised to get blood counts monitored weekly for at
least 6 weeks. The bone marrow toxicity of BiCNU is cumulative.
[see WARNINGS AND PRECAUTIONS].
Advise patients to contact a health care professional
immediately for any of the following: shortness of breath, particularly during
exercise, dry, hacking cough, fast, shallow breathing, gradual unintended weight
loss, tiredness, aching joints and muscles, clubbing (widening and rounding) of
the tips of the fingers or toes.
[see ADVERSE REACTIONS]
Inform the patient that they may suffer from fits and advise
them to get medical attention immediately in such cases.
[see WARNINGS AND PRECAUTIONS and Use In Specific
Advise pregnant women and females of reproductive
potential that BiCNU exposure during pregnancy can result in fetal harm. Advise
female patients to contact their healthcare provider with a known or suspected
pregnancy. Advise women of reproductive potential to avoid becoming pregnant.
Advise females of reproductive potential to use effective contraception during
[see Use In Specific Populations]
Advise the female patient to discontinue nursing while
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carmustine is carcinogenic in rats and mice, producing a
marked increase in tumor incidence in doses approximating those employed
clinically. Nitrosourea therapy does have carcinogenic potential in humans [see
Carmustine was mutagenic and clastogenic in multiple in
vitro and in vivo genetic toxicology studies.
Male rats treated with carmustine at cumulative doses
≥ 36 mg/kg (216 mg/ m²), approximately 0.15 times the maximum cumulative
human dose on a mg/ m² basis, showed decreases in reproductive potential when
mated with untreated female rats (e.g., decreased implantations, increased
resorption rate, and a decrease in viable fetuses).
Use In Specific Populations
BiCNU (carmustine for injection) can cause fetal harm
when administered to a pregnant woman based on the mechanism of action [see CLINICAL
PHARMACOLOGY] and findings in animals [see Data]. Limited available
data with BiCNU use in pregnant women are insufficient to inform a
drug-associated risk of major birth defects and miscarriage. Carmustine was
embryotoxic in rats and rabbits and teratogenic in rats (thoracoabdominal
closure, neural tube, and eye defects and malformations of the skeletal system
of the fetus) when given in doses lower than the maximum cumulative human dose
based on body surface area. Consider the benefits and risks of BiCNU for the
mother and possible risks to the fetus when prescribing BiCNU to a pregnant
Adverse outcomes in pregnancy occur regardless of the
health of the mother or the use of medications. The estimated background risk
of major birth defects and miscarriage for the indicated population is unknown.
In the U.S. general population, the estimated background risk of major birth
defects and miscarriage in clinically recognized pregnancies is 2-4% and
Intraperitoneal (IP) administration of carmustine to
pregnant rats 14 days prior to mating and during the period of organogenesis at
cumulative doses ≥ 26 mg/kg (158 mg/ m²), approximately 0.1 times the maximum
cumulative human dose of 1400 mg/m², resulted in pre-implantation loss,
increased resorptions (including completely resorbed litters), and reduced the
number of live births in the presence of maternal toxicity.
Carmustine administered IP to pregnant rats during the
period of organogenesis at cumulative doses ≥ 4 mg/kg (24 mg/m²),
approximately 0.02 times the maximum cumulative human dose based on a mg/m² basis,
resulted in reduced fetal weight and various malformations, which included
thoracoabdominal closure defects, neural tube defects, and eye defects,
including microphthalmia/anophthalmia, and skeletal anomalies in the skull,
sternebra, vertebrae and ribs, and reduced skeletal ossification) in the presence
of maternal toxicity. Embryo-fetal death was observed at cumulative doses
≥ 8 mg/kg (48 mg/m²), approximately 0.03 times the maximum cumulative
human dose on a mg/ m² basis. Intravenous (IV) administration of carmustine to
rats at a cumulative dose of 50 mg/kg (300 mg/ m²), approximately 0.2 times the
maximum cumulative human dose on a mg/m² basis, during the last quarter of
pregnancy resulted in the death of offspring within 4 months. Carmustine
administered IV to rabbits during the period of organogenesis resulted in
spontaneous abortions in mothers and growth defects in the fetus, mainly at
cumulative doses ≥ 13 mg/kg (156 mg/ m²), approximately 0.1 times the
maximum cumulative human dose on a mg/ m² basis.
There is no information regarding the presence of
carmustine in human milk, the effects on the breastfed infant, or the effects
on milk production. Because many drugs are excreted in human milk and because
of the potential for serious adverse events (e.g., carcinogenicity and
myelosuppression) in nursing infants, nursing should be discontinued while
Females And Males Of Reproductive Potential
Advise female patients to avoid pregnancy during
treatment with BiCNU because of the risk of fetal harm [see Use In Specific
Advise female patients of reproductive potential to use
highly effective contraception during and for up to six months after completion
Advise males with female sexual partners of reproductive
potential to use effective contraception during BiCNU treatment and for at
least three months after the final dose of BiCNU [see Nonclinical Toxicology].
Based on nonclinical findings, male fertility may be
compromised by treatment with BiCNU [see Nonclinical Toxicology].
Safety and effectiveness in children have not been
established. Delayed onset pulmonary fibrosis occurring up to 17 years after
treatment has been reported in a long-term study of patients who received BiCNU
in childhood and early adolescence (1-16 years). Eight out of the 17 patients
(47%) who survived childhood brain tumors, including all the 5 patients
initially treated at less than 5 years of age, died of pulmonary fibrosis. [see
Clinical studies of BiCNU did not include sufficient
numbers of subjects aged 65 and over to determine whether they respond
differently from younger subjects. Other reported clinical experience has not identified
differences in responses between the elderly and younger patients. In general,
dose selection for an elderly patient should be cautious, usually starting at
the low end of the dose range, reflecting the greater frequency of decreased
hepatic, renal, or cardiac function, and of concomitant disease or other drug
BiCNU and its metabolites are known to be substantially
excreted by the kidney, and the risk of toxic reactions to this drug may be
greater in patients with impaired renal function. Because elderly patients are
more likely to have decreased renal function, care should be taken in dose
selection, and renal function should be monitored.