Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/3278
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BICNU (Kit)
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The recommended dose of BiCNU as a single agent in previously untreated
patients is 150 to 200 mg/mintravenously every
6 weeks. This may be given as a single dose or divided into daily injections
such as 75 to 100 mg/mon 2 successive days. When
BiCNU is used in combination with other myelosuppressive drugs or in patients
in whom bone marrow reserve is depleted, the doses should be adjusted accordingly. Doses subsequent to the initial dose should be adjusted according to the hematologic response of the patient to the preceding dose. The following
schedule is suggested as a guide to dosage adjustment: A repeat course of BiCNU should not be given until circulating
blood elements have returned to acceptable levels (platelets above 100,000/mm,
leukocytes above 4,000/mm), and this is usually
in 6 weeks. Adequate number of neutrophils should be present on a peripheral
blood smear. Blood counts should be monitored weekly and repeat courses should
not be given before 6 weeks because the hematologic toxicity is delayed and
cumulative.<br/>Administration Precautions: As with other potentially toxic compounds, caution should be exercised
in handling BiCNU and preparing the solution of BiCNU. Accidental contact
of reconstituted BiCNU with the skin has caused transient hyperpigmentation
of the affected areas. The use of gloves is recommended. If BiCNU lyophilized
material or solution contacts the skin or mucosa, immediately wash the skin
or mucosa thoroughly with soap and water. The reconstituted solution should be used intravenously only and
should be administered by IV drip. Injection of BiCNU over shorter periods
of time than 1 to 2 hours may produce intense pain and burning at the site
of injection.<br/>Preparation of Intravenous Solutions: First, dissolve BiCNU with 3 mL of the supplied sterile diluent
(Dehydrated Alcohol Injection, USP). Second, aseptically add 27 mL Sterile
Water for Injection, USP. Each mL of resulting solution contains 3.3 mg of
BiCNU in 10% ethanol. Such solutions should be protected from light. Reconstitution as recommended results in a clear, colorless to
yellowish solution which may be further diluted with 5% Dextrose Injection,
USP. Parenteral drug products should be inspected visually for particulate
matter and discoloration prior to administration, whenever solution and container
permit.<br/>Important Note: The lyophilized dosage formulation contains no preservatives and
is not intended for use as a multiple dose vial.<br/>Stability: The unopened vial of the dry drug must be stored in a refrigerator
(2��-8��C, 36��-46��F). The diluent ampules may be stored at controlled room temperature
(59��-86��F, 15��-30��C) or in a refrigerator (2��-8��C, 36��-46��F). The recommended
storage of unopened BiCNU vials provides a stable product for up to 3 years.
After reconstitution as recommended, BiCNU is stable for 24 hours under refrigeration
(2��-8��C, 36��-46��F). Reconstituted vials should be examined for crystal formation
prior to use. If crystals are observed, they may be redissolved by warming
the vial to room temperature with agitation. Vials reconstituted as directed and further diluted to a concentration
of 0.2 mg/mL in 5% Dextrose Injection, USP, should be stored at room temperature,
protected from light and utilized within 8 hours. Glass containers were used for the stability data provided in this
section. Only use glass containers for BiCNU administration.<br/>Important Note: BiCNU has a low melting point (30.5��-32.0��C or 86.9��-89.6��F). Exposure
of the drug to this temperature or above will cause the drug to liquefy and
appear as an oil film on the vials. This is a sign of decomposition and vials
should be discarded. If there is a question of adequate refrigeration upon
receipt of this product, immediately inspect the vial in each individual carton.
Hold the vial to a bright light for inspection. The BiCNU will appear as a
very small amount of dry flakes or dry congealed mass. If this is evident,
the BiCNU is suitable for use and should be refrigerated immediately. Procedures for proper handling and disposal of anticancer drugs
should be considered. Several guidelines on this subject have been published.There
is no general agreement that all of the procedures recommended in the guidelines
are necessary or appropriate. To minimize the risk of dermal exposure, always wear impervious
gloves when handling vials containing BiCNU. This includes all handling activities
in clinical settings, pharmacies, storerooms, and home healthcare settings,
including during unpacking and inspection, transport within a facility, and
dose preparation and administration.
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| dailymed-instance:descripti... |
BiCNU (carmustine for injection)
is one of the nitrosoureas used in the treatment of certain neoplastic diseases.
It is 1,3-bis (2-chloroethyl)-1-nitrosourea. It is sterile lyophilized pale yellow
flakes or congealed mass with a molecular weight of 214.06. It is highly soluble
in alcohol and lipids, and poorly soluble in water. BiCNU is administered
by intravenous infusion after reconstitution as recommended. The structural formula is: BiCNU is available in 100 mg single dose vials of lyophilized material. Sterile diluent for constitution of BiCNU is co-packaged with the active drug product for use
in constitution of the lyophile. The diluent is supplied in an ampule containing 3 mL of Dehydrated Alcohol Injection, USP.
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Although it is generally agreed that carmustine alkylates DNA and
RNA, it is not cross-resistant with other alkylators. As with other nitrosoureas,
it may also inhibit several key enzymatic processes by carbamoylation of amino
acids in proteins. Intravenously administered carmustine is rapidly degraded, with
no intact drug detectable after 15 minutes. However, in studies withC-labeled
drug, prolonged levels of the isotope were detected in the plasma and tissue,
probably representing radioactive fragments of the parent compound. It is thought that the antineoplastic and toxic activities of carmustine
may be due to metabolites. Approximately 60% to 70% of a total dose is excreted
in the urine in 96 hours and about 10% as respiratory CO.
The fate of the remainder is undetermined. Because of the high lipid solubility and the relative lack of ionization
at physiological pH, carmustine crosses the blood-brain barrier quite effectively.
Levels of radioactivity in the CSF are���50% of those measured concurrently
in plasma.
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BiCNU should not be given to individuals who have demonstrated
a previous hypersensitivity to it.
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BiCNU (carmustine for injection). Each
package includes a vial containing 100 mg carmustine and an ampule containing
3 mL sterile diluent. NDC 0015-3012-60<br/>STORAGE: Store in a refrigerator (2��-8��C, 36��-46��F). Store diluent at controlled room temperature (59��-86��F, 15��-30��C)
or in a refrigerator (2��-8��C, 36��-46��F).
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WARNINGS: BiCNU (carmustine for injection) should be administered under the
supervision of a qualified physician experienced in the use of cancer chemotherapeutic
agents. Bone marrow suppression, notably thrombocytopenia and leukopenia,
which may contribute to bleeding and overwhelming infections in an already
compromised patient, is the most common and severe of the toxic effects of
BiCNU . Since the major toxicity is delayed bone marrow suppression, blood
counts should be monitored weekly for at least 6 weeks after a dose . At the recommended dosage, courses
of BiCNU should not be given more frequently than every 6 weeks. The bone marrow toxicity of BiCNU is cumulative and therefore dosage
adjustment must be considered on the basis of nadir blood counts from prior
dose (see���Dosage Adjustment Table���under DOSAGE AND
ADMINISTRATION). Pulmonary toxicity from BiCNU appears to be dose related. Patients
receiving greater than 1400 mg/mcumulative
dose are at significantly higher risk than those receiving less. Delayed pulmonary toxicity can occur years after treatment, and
can result in death, particularly in patients treated in childhood (see ADVERSE REACTIONS and PRECAUTIONS:
Pediatric Use).
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General: In all instances where the use of BiCNU is considered for chemotherapy,
the physician must evaluate the need and usefulness of the drug against the
risks of toxic effects or adverse reactions. Most such adverse reactions are
reversible if detected early. When such effects or reactions do occur, the
drug should be reduced in dosage or discontinued and appropriate corrective
measures should be taken according to the clinical judgment of the physician.
Reinstitution of BiCNU therapy should be carried out with caution, and with
adequate consideration of the further need for the drug and alertness as to
possible recurrence of toxicity.<br/>Laboratory Tests: Due to delayed bone marrow suppression, blood counts should be
monitored weekly for at least 6 weeks after a dose. 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 (DL) are particularly at risk. Since BiCNU may cause liver dysfunction, it is recommended that
liver function tests be monitored. Renal function tests should also be monitored periodically.<br/>Drug Interactions: Greater myelotoxicity (e.g., leukopenia and neutropenia) have been reported when carmustine was combined with cimetidine .<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: BiCNU 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 ADVERSE
REACTIONS). BiCNU also affects fertility in male rats at doses
somewhat higher than the human dose.<br/>Pregnancy:<br/>Pregnancy Category D: See WARNINGS.<br/>Nursing Mothers: It is not known whether this drug is excreted in human milk. Because
of the potential for serious adverse events in nursing infants, nursing should
be discontinued while taking BiCNU.<br/>Pediatric Use: 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 five patients initially
treated at less than five years of age, died of pulmonary fibrosis. Therefore,
the risks and benefits of BiCNU therapy must be carefully considered, due
to the extremely high risk ofpulmonary toxicity. (See ADVERSE
REACTIONS: Pulmonary Toxicity.)<br/>Geriatric Use: No data from clinical studies of BiCNU are available for patients
65 years of age and over to determine whether they respond differently than
younger patients. Other reported clinical experience has not identified differences
in responses between 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 therapy. 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.
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No proven antidotes have been established for BiCNU overdosage.
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CARMUSTINE
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BICNU (Kit)
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Pulmonary Toxicity: 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. Most of these patients were receiving
prolonged therapy with total doses of BiCNU greater than 1400 mg/m.
However, there have been reports of pulmonary fibrosis in patients receiving
lower total doses. Other risk factors include past history of lung disease
and duration of treatment. Cases of fatal pulmonary toxicity with BiCNU have
been reported. Additionally, delayed onset pulmonary fibrosis occurring up to
17 years after treatment has been reported in a long-term study with 17 patients
who received BiCNU in childhood and early adolescence (1���16 years) in cumulative
doses ranging from 770 to 1800 mg/mcombined with
cranial radiotherapy for intracranial tumors. Chest x-rays demonstrated pulmonary
hypoplasia with upper zone contraction. Gallium scans were normal in all cases.
Thoracic CT scans have demonstrated an unusual pattern of upper zone fibrosis.
There was some late reduction of pulmonary function in all long-term survivors.
This form of lung fibrosis may be slowly progressive and has resulted in death
in some cases. In this long-term study, 8 of 17 died of delayed pulmonary
lung fibrosis, including all those initially treated (5 of 17) at less than
5 years of age.<br/>Hematologic Toxicity: A frequent and serious toxicity of BiCNU is delayed myelosuppression.
It usually occurs 4 to 6 weeks after drug administration and is dose related.
Thrombocytopenia occurs at about 4 weeks postadministration and persists for
1 to 2 weeks. Leukopenia occurs at 5 to 6 weeks after a dose of BiCNU and
persists for 1 to 2 weeks. Thrombocytopenia is generally more severe than
leukopenia. However, both may be dose-limiting toxicities. BiCNU may produce cumulative myelosuppression, manifested by more
depressed indices or longer duration of suppression after repeated doses. The occurrence of acute leukemia and bone marrow dysplasias have
been reported in patients following long-term nitrosourea therapy. Anemia also occurs, but is less frequent and less severe than thrombocytopenia
or leukopenia. Greater myelotoxicity (e.g., leukopenia and neutropenia) has been reported when carmustine was combined with cimetidine .<br/>Gastrointestinal Toxicity: Nausea and vomiting after IV administration of BiCNU are noted
frequently. This toxicity appears within 2 hours of dosing, usually lasting
4 to 6 hours, and is dose related. Prior administration of antiemetics is
effective in diminishing and sometimes preventing this side effect.<br/>Hepatotoxicity: A reversible type of hepatic toxicity, manifested by increased
transaminase, alkaline phosphatase and bilirubin levels, has been reported
in a small percentage of patients receiving BiCNU.<br/>Nephrotoxicity: Renal abnormalities consisting of progressive azotemia, decrease
in kidney size and renal failure have been reported in patients who received
large cumulative doses after prolonged therapy with BiCNU and related nitrosoureas.
Kidney damage has also been reported occasionally in patients receiving lower
total doses.<br/>Other Toxicities: Accidental contact of reconstituted BiCNU with skin has caused
burning and hyperpigmentation of the affected areas. Rapid IV infusion of BiCNU (carmustine for injection) 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. Neuroretinitis, chest pain, headache, allergic reaction, hypotension
and tachycardia have been reported as part of ongoing surveillance.
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| dailymed-instance:warning |
BiCNU (carmustine for injection) should be administered under the
supervision of a qualified physician experienced in the use of cancer chemotherapeutic
agents. Bone marrow suppression, notably thrombocytopenia and leukopenia,
which may contribute to bleeding and overwhelming infections in an already
compromised patient, is the most common and severe of the toxic effects of
BiCNU . Since the major toxicity is delayed bone marrow suppression, blood
counts should be monitored weekly for at least 6 weeks after a dose . At the recommended dosage, courses
of BiCNU should not be given more frequently than every 6 weeks. The bone marrow toxicity of BiCNU is cumulative and therefore dosage
adjustment must be considered on the basis of nadir blood counts from prior
dose (see���Dosage Adjustment Table���under DOSAGE AND
ADMINISTRATION). Pulmonary toxicity from BiCNU appears to be dose related. Patients
receiving greater than 1400 mg/mcumulative
dose are at significantly higher risk than those receiving less. Delayed pulmonary toxicity can occur years after treatment, and
can result in death, particularly in patients treated in childhood (see ADVERSE REACTIONS and PRECAUTIONS:
Pediatric Use).
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| dailymed-instance:indicatio... |
BiCNU is indicated as palliative therapy as a single agent or in
established combination therapy with other approved chemotherapeutic agents
in the following:
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BICNU
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