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BiCNU injection

SCHEDULING STATUS:

BiCNU	S4
Diluent	S1

PROPRIETARY NAME
(and dosage form):

BiCNU injection
(Lyophilized powder in vial for reconstitution)
Dehydrated Alcohol, injection USP

COMPOSITION
BiCNU is a lyophilized powder for injection containing 100 mg carmustine per vial. When reconstituted with 3 mL dehydrated alcohol and 27 mL sterile water for injection, each mL of the resulting solution will contain 3,3 mg of carmustine in 10% ethanol.
Diluent contains 3 mL dehydrated alcohol.

PHARMACOLOGICAL CLASSIFICATION

BiCNU injection	A 26 Cytostatic agents
Diluent	A 34 Other

PHARMACOLOGICAL ACTION
BiCNU (1,3 - bis(2 chloroethyl)-1-nitrosourea) is one of the nitrosoureas. The structural formula is:
{illustrated here}
BiCNU alkylates DNA and RNA and has been shown to inhibit several enzymes by carbamoylation of amino acids in proteins. BiCNU is not cross resistant with other alkylating agents.
Intravenously administered BiCNU is rapidly degraded, with no intact drug detectable after 15 minutes. However in studies with C¹⁴ labelled drug, prolonged levels of the isotope were observed in the plasma and tissue, probably representing radioactive fragments of the parent compound.
It is thought that the antineoplastic and toxic activities of BiCNU may be due to metabolites. Approximately 60 to 70 percent of a total dose is excreted in the urine in 96 hours and about 10 percent as respiratory CO2. The fate of the remainder is undetermined. Because of high lipid solubility and the relative lack of ionization at a physiological pH, BiCNU crosses the blood brain barrier quite effectively. Levels of radioactivity in the CSF are greater than those measured concurrently in plasma.

INDICATIONS
BiCNU is indicated as palliative therapy as a single agent or in established combination therapy with other approved chemotherapeutic agents in the following:

1.	Brain tumours - glioblastoma, brainstem glioma, medulloblastoma, astrocytoma, ependymoma and metastatic brain tumours.
2.	Multiple myeloma - in combination with prednisone.
3.	Hodgkin's Disease - as secondary therapy in combination with other approved drugs in patients who relapse while being treated with primary therapy, or who fail to respond to primary therapy.
4.	Non-Hodgkin's lymphomas - as secondary therapy in combination with other approved drugs for patients who relapse while being treated with primary therapy or who fail to respond to primary therapy.

CONTRA-INDICATIONS
BiCNU is contraindicated in individuals who have demonstrated a previous hypersensitivity to it.

WARNINGS
SAFE USE IN PREGNANCY AND DURING LACTATION HAS NOT BEEN ESTABLISHED.
BiCNU is embryotoxic and teratogenic in rats and embryotoxic in rabbits at dose levels equivalent to the human dose. BiCNU also affects fertility in male rats at doses somewhat higher than the human dose.
BiCNU is carcinogenic in rats and mice, producing a marked increase in tumour incidence in doses approximating those employed clinically.
Nitrosourea therapy does have carcinogenic potential. The occurrence of acute leukaemia and bone marrow dysplasias has been reported in patients following nitrosourea therapy.
BiCNU-induced pulmonary toxicity has been reported to occur with a frequency ranging up to 30%. Early onset pulmonary toxicity usually occurs within 3 years of therapy and is characterised by pulmonary infiltrates and/or fibrosis, and cases of fatal pulmonary toxicity have occurred. Age of onset has been reported from 1 year and 10 months to 72 years of age. Risk factors include smoking, the presence of a respiratory condition, pre-exisiting radiographic abnormalities, sequential or concomitant thoracic irradiation, and association with other agents that cause lung damage. The incidence appears to be dose related with total cumulative doses of 1200-1500 mg/m² being associated with increased likelihood of lung fibrosis. 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_co) are particularly at risk.
Cases of late pulmonary fibrosis, occurring up to 17 years after treatment, have also been reported. In a recent long-term follow-up of 17 patients who survived childhood brain tumours, eight (47%) died of lung fibrosis. Of these eight deaths, two occurred with 3 years of treatment, and six occurred 8 - 13 years after treatment. Of the patients who died, the median age at treatment was 2,5 years (ranging from 1-12); the median age of the long term survivors was 10 years (5 - 16 years at treatment). All five patients treated below the age of 5 years have died of pulmonary fibrosis. In this series, dose of BiCNU did not influence fatal outcome nor did co-administration of vincristine or spinal irradiation. Of the remaining survivors available for follow-up, evidence of lung fibrosis was detected in all patients.
The risks and benefits of BiCNU therapy must be carefully considered, especially in young patients, due to the extremely high risk of pulmonary toxicity.
Bone marrow suppression, notably thrombocytopenia and leukopenia, which may contribute to bleeding and overwhelming infections in an already compromised patient, is a common and severe toxic effect of BiCNU. Complete blood counts should be monitored frequently for at least 6 weeks after a dose. Repeat doses 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 directions for use").
It is recommended that liver function, pulmonary function and renal function tests also be monitored.
BiCNU has been administered through an intra-arterial intra-carotid route: this procedure is investigational and has been associated with ocular toxicity. BiCNU should be administered only by individuals experienced in antineoplastic therapy.

DOSAGE AND DIRECTIONS FOR USE
The recommended dose of BiCNU as a single agent in previously untreated patients is 200 mg/m² intravenously every 6 weeks. This may be given as a single dose or divided into daily injections such as 100 mg/m² on 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.
A repeat course of BiCNU should not be given until circulating blood elements have returned to acceptable levels (platelets above 100,000/mm³; leukocytes above 4,000/mm³); this usually occurs within 6 weeks. Blood counts should be monitored frequently and repeat courses should not be given before 6 weeks because of delayed toxicity.
Doses subsequent to the initial dose should be adjusted according to the haematologic response of the patient to the preceding dose. The following schedule is suggested as a guide to dosage adjustment:
Nadir After Prior Dose               

Leukocytes	Platelets	Percentage of Prior dose to be given
>4,000	>100,000	100 percent
3,000 - 3,999	75,000 - 99,999	100 percent
2,000 - 2,999	25,000 - 74,999	70 percent
<2,000	< 25,000	50 percent

Preparation of Intravenous Solutions
Use only glass containers for preparation and administration. To facilitate reconstitution, allow BiCNU and the supplied sterile diluent (dehydrated alcohol) to come to controlled room temperature (15 to 30°C) before mixing. Dissolve BiCNU completely with 3 mL of the supplied sterile diluent and then aseptically add 27 mL of Sterile Water for Injection to the alcohol solution. Each mL of the resulting solution will contain 3,3 mg of BiCNU in 10 percent alcohol having a pH of 5,6 - 6,0. SOLUTION IN THE ALCOHOL MUST BE COMPLETE BEFORE STERILE WATER FOR INJECTION IS ADDED. Accidental contact of reconstituted BiCNU with the skin has caused transient hyperpigmentation of the affected areas. If BiCNU lyophilized material or solution contacts the skin or mucosa, immediately wash the skin or mucosa thoroughly. Reconstitution as recommended results in a clear, colourless to light yellow solution which may be further diluted with either 0,9% Sodium Chloride for Injection or 5% Dextrose for Injection.

THE RECONSTITUTED SOLUTION SHOULD BE USED INTRAVENOUSLY ONLY AND SHOULD BE ADMINISTERED BY IV DRIP OVER A 1 TO 2-HOUR PERIOD. INJECTION OF BiCNU OVER SHORTER PERIODS OF TIME MAY PRODUCE INTENSE PAIN AND BURNING AT THE SITE OF INJECTION. RAPID IV INFUSION OF BiCNU MAY PRODUCE INTENSIVE FLUSHING OF THE SKIN AND SUFFUSION OF THE CONJUNCTIVA WITHIN 2 HOURS, LASTING ABOUT 4 HOURS.

IMPORTANT NOTE
THE LYOPHILIZED DOSAGE FORMULATION CONTAINS NO PRESERVATIVES AND IS NOT INTENDED AS A MULTIPLE DOSE VIAL.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS
Haematopoietic:
Delayed myelosuppression is a frequent and serious adverse event associated with BiCNU. It usually occurs 4 to 6 weeks after drug administration and is dose-related. Platelet nadirs occur at 4 to 5 weeks; leukocyte nadirs occur at 5 to 6 weeks post therapy. Thrombocytopenia is generally more severe than leukopenia, however, both may be dose limiting toxicities. Anaemia also occurs, but is generally less severe. BiCNU may produce cumulative myelosuppression, (See WARNINGS).
The occurrence of acute leukaemia and bone marrow dysplasias have been reported in patients following long-term nitrosourea therapy.
Gastrointestinal:
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 anti-emetics is effective in diminishing and sometimes preventing this adverse event. Diarrhoea and oesophagitis may occur.
Hepatic:
High doses of BiCNU have been associated with a reversible type of hepatic toxicity manifested by increased transaminase, alkaline phosphatase and bilirubin levels.
Pulmonary toxicity: (See WARNINGS)
Renal: Renal abnormalities consisting of decrease in kidney size, progressive azotaemia and renal failure have been reported in patients who receive large cumulative doses after prolonged therapy with BiCNU and related nitrosoureas. Kidney damage has also been reported occasionally in patients receiving lower total doses.
Cardiovascular: Hypotension, tachycardia.
Other: Burning at the site of injection is common but true thrombosis is rare. Accidental contact of reconstituted BiCNU with the skin has caused burning and hyperpigmentation of the affected areas. Rapid IV infusion of BiCNU may produce intensive flushing of the skin and suffusion of the conjunctiva within 2 hours, lasting about 4 hours. Neuroretinitis, chest pain, headache, allergic reactions.
Optic neuritis may occur.
Also see "Warnings".
Carmustine is potentially carcinogenic, mutagenic and teratogenic.
Use in Pregnancy: Safe use in pregnancy has not been established. BiCNU is embryotoxic and teratogenic in rats and embryotoxic in rabbits at dose levels equivalent to the human dose. BiCNU also affects fertility in male rats at doses somewhat higher than the human dose. BiCNU is carcinogenic in rats and mice, producing a marked increase in tumour incidence in doses approximating those employed clinically. The benefit to the mother versus the risk of toxicity to the mother and foetus must be carefully weighed.
Nursing Mothers: It is not known whether BiCNU is excreted in human milk. Because of the potential for serious adverse events in nursing infants, nursing should be discontinued while taking BiCNU.
Paediatric Use: BiCNU should be used with extreme caution in children due to the high risk of pulmonary toxicity (see WARNINGS).

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
Excessive doses of BiCNU are likely to lead to severe myelosuppression and nausea and vomiting.
Treatment should be restricted to supportive and symptomatic measures.

IDENTIFICATION
BiCNU: Thin, lacy, brittle, pale yellow discontinuous flakes when refrigerated. Highly soluble in alcohol, and poorly soluble in water. It is also highly soluble in lipids.
Diluent: Transparent, colourless liquid.

PRESENTATION
Each combination pack has a vial containing 100 mg carmustine and a vial containing 3 mL sterile diluent.
IMPORTANT NOTE: The Lyophilized dosage formulation contain no preservatives and is a single-dose vial.

STORAGE INSTRUCTIONS
Refrigerate (2 –8°C).
KEEP OUT OF REACH OF CHILDREN.
The unopened vial may have a physical appearance ranging from lacy flakes to a congealed mass, with no evident degradation of the BiCNU active ingredient. Do not use if product has liquefied.
Unopened vials of the dry powder should be shipped and stored under refrigeration (2°C –8°C). Alternatively, BiCNU may be shipped on dry ice and subsequently stored under refrigeration (2°C –8°C). The recommended storage of unopened vials prevents significant decomposition until expiration date indicated on package. After reconstitution as recommended, BiCNU is stable for 8 hours at room temperature (25°C) or 24 hours under refrigeration (4°C). Reconstituted vials stored under refrigeration 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.
Further dilution of the reconstituted solution with 500 mL of Sodium Chloride for Injection of 5% Dextrose for Injection results in a solution which should be utilized within 8 hours and be protected from light. These solutions are also stable for 24 hours under refrigeration (4°C) and an additional 6 hours at room temperature (25°C) protected from light. Glass containers were used for the stability data provided in this section. Only use glass containers for BiCNU administration.
IMPORTANT NOTE:
BiCNU has a low melting point (approximately 30,5°C - 32,0°C). Exposure of the medicine to this temperature or above will cause the drug to liquefy and appear as an oil film in the bottom of the vials. THIS IS A SIGN OF DECOMPOSITION AND VIALS SHOULD BE DISCARDED.
If there is any question of adequate refrigeration of this product, immediately inspect the larger vial in each individual carton. Hold the vial to a bright light for inspection. The carmustine will appear as a very small amount of dry flakes or dry congealed mass. If this is evident, BiCNU is suitable for use and should be refrigerated immediately.

REGISTRATION NUMBER
T/26/2: BiCNU powder in vial
T/34/3: Diluent - Dehydrated alcohol, injection USP

NAME AND BUSINESS ADDRESS OF APPLICANT
Bristol-Myers Squibb (Pty.) Ltd.*
47 Van Buuren Road
BEDFORDVIEW
2008.

DATE OF PUBLICATION OF THIS PACKAGE INSERT
JUNE 1997

* Authorised user of the TM BiCNU

New addition to this site: June 2005
Source: Pharmaceutical Industry
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