Approved Drug Label (PDF)
Boxed Warning
(Additions and/or revisions are underlined)
WARNING: MYELOSUPPRESSION
and PULMONARY TOXICITY
Myelosuppression
BiCNU causes suppression
of marrow function
(including thrombocytopenia and leukopenia), which may contribute to bleeding and overwhelming
infections. Monitor blood counts weekly for at least 6 weeks after each
dose. Adjust dosage based on nadir blood counts from the prior dose. Do not administer a repeat course of BiCNU until
blood counts recover.
Pulmonary Toxicity
BiCNU causes
dose-related pulmonary toxicity…
4
Contraindications
(Additions and/or revisions are underlined)
BiCNU is contraindicated
in patients with previous hypersensitivity
to BiCNU or its components.
5
Warnings and Precautions
5.1 Myelosuppression
(Additions and/or revisions are underlined)
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…
5.2 Pulmonary Toxicity
(Additions and/or revisions are underlined)
…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…
5.3 Administration Reactions
(New subsection title added)
5.4 Carcinogenicity
(Additions and/or revisions are underlined; new
subsection title added)
…Carmustine was carcinogenic
when administered to laboratory animals. Nitrosourea therapy, such as BiCNU,
has carcinogenic potential in humans. Patients treated with BiCNU should be
monitored long-term for development of second malignancies.
5.5 Ocular Toxicity
(Additions and/or revisions are underlined; new
subsection title added)
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 intra- arterial
route have not been established.
5.6 Embryo-Fetal Toxicity
(Additions and/or revisions are underlined)
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 well- controlled studies in pregnant women. Advise pregnant women of the
potential risk to the fetus. 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.
6
Adverse Reactions
(Additions and/or revisions are underlined)
The following serious
adverse reactions are described elsewhere in the labeling:
Myelosuppression
Pulmonary
toxicity
Administration
Reactions
Carcinogenicity
Ocular
Toxicity
The following adverse
reactions associated with the use of BiCNU were identified in clinical studies
or postmarketing reports. Because some of
these reactions were reported voluntarily from a population of uncertain size, it
is not always possible to reliably estimate their frequency or establish a causal
relationship to drug exposure.
Cardiac Disorders
Tachycardia and chest
pain.
Eye Disorders
Conjunctival edema, conjunctival hemorrhage, blurred vision and loss of
depth perception
Gastrointestinal Toxicity
Nausea, vomiting,
anorexia, and diarrhea
Hepatotoxicity
Increased transaminase,
increased alkaline phosphatase, increased bilirubin levels
Infections and Infestations
Opportunistic infection
(including with fatal outcome).
Neoplasms Benign, Malignant and Unspecified (including
cysts and polyps)
Acute leukemia,
bone marrow dysplasias.
Nephrotoxicity
Progressive azotemia,
decrease in kidney size, renal failure
Nervous System Disorders
Headaches, encephalopathy,
and seizures
Pulmonary Toxicity
Pneumonitis, interstitial
lung disease
Reproductive System and Breast Disorders
Gynecomastia
Skin and Subcutaneous Tissue Disorders
Burning sensation, hyperpigmentation, swelling, pain, erythema,
skin necrosis, alopecia, allergic reaction
Vascular Disorders
Veno-occlusive disease.
7
Drug Interactions
7.1 Effects of Other Drugs on BiCNU
(Additions and/or revisions are underlined; new
subsection title added)
Cimetidine: Greater myelosuppression (e.g., leukopenia and neutropenia) has been
reported when oral cimetidine has been coadministered with carmustine. Consider
alternative drugs to cimetidine.
Phenobarbital: Phenobarbital induces the metabolism
of carmustine and may
compromise antitumor activity of BiCNU. Consider
alternative drugs to phenobarbital.
7.2 Effects of BiCNU on Other Drugs
(Newly added subsection)
Phenytoin: BiCNU when coadministered with phenytoin may reduce
phenytoin serum concentrations.
Consider alternative drugs to phenytoin.
8
Use in Specific Populations
8.1 Pregnancy
(Pregnancy and Lactation Labeling Rule (PLLR) Conversion;
additions and/or revisions are
underlined)
Risk Summary
BiCNU (carmustine for
injection) can cause fetal harm when administered to a pregnant woman based on
the mechanism of action and findings in animals. 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 woman.
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 15-20%, respectively.
Data
Animal Data
Intraperitoneal (IP)
administration of carmustine to pregnant rats 14 days prior to mating and during
the period of organogenesis at cumulative doses greater than or equal to 26 mg/kg
(158 mg/m squared), approximately 0.1 times the maximum cumulative human dose of
1400 mg/m squared, 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 greater
than or equal to 4 mg/kg (24 mg/m squared), approximately 0.02 times the maximum
cumulative human dose based on a mg/m squared 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 greater than or equal to 8 mg/kg (48 mg/m
squared), approximately 0.03 times the maximum cumulative human dose on a mg/m
squared basis. Intravenous (IV) administration
of carmustine to rats at a cumulative dose of 50 mg/kg (300 mg/m squared), approximately
0.2 times the maximum cumulative human dose on a mg/m squared 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
greater than or equal to 13 mg/kg (156 mg/m squared), approximately 0.1 times
the maximum cumulative human dose on a mg/m squared basis.
8.2 Lactation
(Pregnancy and Lactation Labeling Rule (PLLR) Conversion;
additions and/or revisions are
underlined)
Risk Summary
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 taking BiCNU.
8.3 Females and Males of Reproductive Potential
(Pregnancy and Lactation Labeling Rule (PLLR) Conversion;
additions and/or revisions are
underlined)
Contraception
Advise female patients
to avoid pregnancy during treatment with BiCNU because of the risk of fetal harm.
Advise female patients
of reproductive potential to use highly effective contraception during and for
up to six months after completion of treatment.
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.
Infertility
Based on nonclinical
findings, male fertility may be compromised by treatment with BiCNU.
8.5 Geriatric Use
(Additions and/or revisions are underlined)
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…
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION
(Newly added subsection)
Myelosuppression
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.
Pulmonary Toxicity
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.
Seizures
Inform the patient that
they may suffer from fits and advise them to get medical attention immediately
in such cases.
Pregnancy
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 treatment.
Lactation
Advise the female patient
to discontinue nursing while taking BiCNU.
Other
(Physician Labeling Rule (PLR) conversion; please refer to label)
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