BiCNU®
Bristol
Carmustine
Antineoplastic Agent
Action And Clinical Pharmacology: Carmustine alkylates DNA and RNA and has been shown to inhibit several enzymes by carbamoylation of amino acids in proteins.
In a series of in vivo and in vitro experiments with formate 4, adenine-8-4 and DL-leucine-4,5-, Wheeler and Bowdon obtained results indicating that carmustine interferes with the de novo synthesis of purine nucleotides and with the conversion of purine nucleotides to components of DNA but to a much lesser extent of RNA. Inhibition of DNA synthesis occurred in the absence of inhibition of the synthesis of protein. In a more recent study, D.P. Groth et al confirmed that carmustine altered de novo purine biosynthesis. It is suggested that carmustine inhibits a reaction(s) involved with the insertion of the C-8 position of the purine ring. These biochemical effects are similar to those described by Wheeler and Alexander for the accepted biological alkylating agents like nitrogen mustards and suggest the inclusion of carmustine in this class of agents.
On the other hand, by chemical evaluation the alkylating properties of carmustine have been shown to be quite weak compared to the above mentioned alkylating agents and it is still an open question whether this activity is sufficient to account for the observed biological effects of carmustine.
Carmustine is not cross resistant with other alkylators.
Protein Binding: The average extent of binding of carmustine with human plasma proteins is about 80% at 0°C. (The experiments were carried out at 0°C because of carmustine’s extreme instability in plasma.)
Plasma Level: Plasma samples taken as early as 5 minutes after oral or parenteral drug administration did not contain intact carmustine. Plasma levels of the radioactivity were prolonged with a half-life of about 34 hours for the orally and 67 hours for the i.v. administered 4 carmustine.
CSF: After i.v. administration of 4 carmustine, radioactive 4 was found in the CSF of man equilibrating with plasma radioactivity in about 1 hour, showing 97 and 30% of plasma level in 2 men, respectively.
Urinary Excretion: Extremely small amounts of intact carmustine were detected in urine samples collected at one half hour following drug administration (i.v. or oral). After the second half hour urine samples did not contain unaltered carmustine.
Urinary excretion of the radioactivity was strikingly similar in all patients regardless of the route of administration (i.v. or oral) and quite comparable to monkeys. By 96 hours, an average of 65% of the isotope had been recovered in the urine.
Pulmonary Excretion: Over 24 hours, the radioactivity excretion of 4 carmustine as 4 O2 was approximately 10% of the dose after oral administration and 6% when given i.v. Although carmustine is well absorbed after oral, intraperitoneal and s.c. administration, it is mainly used by the i.v. route. The active moiety of carmustine is still unknown but the high degradation rate of carmustine in plasma suggests that the biological activity as well as the delayed toxicity of carmustine are related at least partly to its degradation products. The in vitro decomposition of carmustine has been studied quite extensively. However, to date, nothing is known on its biodegradation, except for the fact that part of it is excreted as CO2 as determined with 4 labeled carmustine.
Indications And Clinical Uses: As adjuvant therapy to surgery and radiotherapy or in combination therapy with other chemotherapeutic agents in the following: Primary Brain Tumors: Carmustine is a small molecule which is virtually un-ionized in aqueous solution at pH 7 and is therefore highly lipid soluble. These characteristics allow it to cross the blood brain barrier and make it attractive in the treatment of brain tumors. An overall 47% response rate with carmustine compares favorably with any other method of treating brain tumors, such as glioblastoma, brainstemglioma, medulloblastoma, astrocytoma, ependymoma, and metastatic brain tumors.
Malignant Lymphomas: Hodgkin’s disease, non-Hodgkin’s lymphomas either alone or in combination with other chemotherapeutic agents. Carmustine has a striking antineoplastic effect against Hodgkin’s disease even when the tumor has become resistant to standard chemotherapeutic agents including radiotherapy.
Virtually all of these studies in which carmustine was used to treat patients with Hodgkin’s disease resulted in a 40 to 50% response rate.
Multiple Myeloma: Carmustine is effective in the treatment of myeloma producing improvement in 30% of the patients. In combination with prednisone, it is particularly active in that it shows 70% response. Carmustine has been used as part of a five-drug regimen (melphalan, cyclophosphamide, prednisone and vincristine) in 29 patients with a 90% response rate.
Malignant Melanoma (disseminated): In combination with vincristine sulfate, carmustine has been shown to give response rates up to 45% in malignant melanoma.
Gastrointestinal Carcinoma: A 12.5% response rate was obtained with carmustine in the therapy of gastrointestinal cancer. Such a result suggests the use of carmustine only after other more appropriate agents have failed in advanced disease.
Contra-Indications: Carmustine should not be given to individuals who have demonstrated a previous hypersensitivity to it. Also, it is contraindicated in patients with decreased circulating platelets, leukocytes or erythrocytes either from previous chemotherapy or other causes, and severe hepatic and/or renal impairment.
Manufacturers’ Warnings In Clinical States: Caution: Carmustine is a potent drug and should be used only by physicians experienced with cancer chemotherapeutic drugs (see Precautions). Blood counts as well as renal and hepatic function tests should be taken regularly. Discontinue the drug if abnormal depression of bone marrow or abnormal renal or hepatic function is seen.
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 carmustine.
Pulmonary toxicity from carmustine appears to be dose related. Patients receiving greater than 1 400 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 Effects).
Nitrosourea therapy does have carcinogenic potential. The occurrence of acute leukemia and bone marrow dysplasias have been reported in patients following nitrosourea therapy.
Pregnancy: Safe use in pregnancy has not been established. Carmustine is embryotoxic and teratogenic in rats and embryotoxic in rabbits at dose levels equivalent to the human dose. Carmustine also affects fertility in male rats at doses somewhat higher than the human dose. Carmustine is carcinogenic in rats and mice, producing a marked increase in tumor incidence in doses approximating those employed clinically.
Precautions: Carmustine should be administered preferably by individuals experienced with antineoplastic therapy. Since delayed bone marrow toxicity is the major toxicity, complete blood counts should be monitored frequently for at least 6 weeks after a dose. Repeat doses of carmustine should not be given more frequently than every 6 weeks. The bone marrow toxicity of carmustine is cumulative, and therefore dosage adjustment must be considered on the basis of nadir blood counts from prior dose.
It is recommended that liver and renal function tests also be monitored.
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.
Since pulmonary toxicity has been reported with increasing frequency, patients on carmustine therapy should be instructed to report immediately any signs of respiratory complications. In such cases, therapy should be discontinued and evaluation of respiratory gas exchange and spirometry should be performed. If necessary, patients should then be treated with corticosteroids.
Pregnancy: Safe use in pregnancy has not been established. Therefore the benefit to risk of toxicity must be carefully weighed.
Lactation: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from carmustine, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Children: Safety and effectiveness in children have not been established.
Adverse Reactions: Hematopoietic: thrombocytopenia (platelets below 100 000/mm and leukopenia (leukocytes below 4 000/mm.
The most frequent and most serious toxicity of carmustine is delayed myelosuppression. It usually occurs 4 to 6 weeks after drug administration and is dose-related. Myelosuppression is the major dose limiting factor with carmustine as is with so many drugs of this type. Thrombocytopenia is generally more severe than leukopenia; however, both may be dose-limiting toxicities. Anemia may also occur but it is generally less severe.
Carmustine 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.
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 carmustine and related nitrosoureas and appears to be dose related. Most of these patients were receiving prolonged therapy with total doses of carmustine greater than 1 400 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 carmustine have been reported.
In a long-term study of 17 patients who survived childhood brain tumors, very delayed onset pulmonary toxicity occurring up to 17 years after treatment with carmustine has been reported. These children ranged between 2 and 16 years of age when treated with carmustine at doses of 800 mg/mor more. All received cranial irradiation and most received spinal radiotherapy. Chest radiographs and CT scans have demonstrated upper-zone fibrotic changes primarily. All children exhibited reduced pulmonary function and the toxicity was shown to be progressive, resulting in death in approximately 50% of cases. Severity was related to age at treatment. Five children treated at age less than 5 years died of pulmonary fibrosis.
Hepatic: Carmustine produces reversible hepatic toxicity which is manifested by increased transaminase, alkaline phosphatase and bilirubin levels when high doses are employed. It has been rarely noted at therapeutic doses. Hepatotoxicity is delayed up to 60 days after dosing.
Skin: Burning and hyperemia at the site of injection are common, but true thrombophlebitis is rare. Accidental contact of reconstituted carmustine with the skin has caused hyperpigmentation of the affected areas. Within 2 hours after rapid i.v. administration of carmustine, intense flushing of the skin and suffusion of the conjunctiva could last for about 4 hours. Skin rash has also been reported.
Renal: Renal abnormalities consisting of decreases in kidney size, progressive azotemia and renal failure have been reported in patients who receive large cumulative doses after prolonged therapy with carmustine and related nitrosoureas. Kidney damage has also been reported occasionally in patients receiving lower total doses.
Neurological: There have been rare instances of encephalopathy reported.
Gastrointestinal: Nausea and vomiting frequently appear within 2 hours and usually last 4 to 6 hours and are dose-related. Prior administration of antiemetics and sedatives is effective in diminishing and sometimes preventing nausea or vomiting.
Endocrine: Gynecomastia has been observed in a few rare cases.
Other: Muscular pain has been infrequently reported. Neuroretinitis has been reported.
Symptoms And Treatment Of Overdose: Symptoms and Treatment: In the case of overdosage, the patient should be treated symptomatically.
Dosage And Administration: The recommended dose of carmustine as a single agent in previously untreated patients is 200 mg/mi.v. every 6 weeks. This may be given as a single dose or divided into daily injections such as 100 mg/mon 2 successive days. When carmustine 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 carmustine 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. 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 hematologic response of the patient to the preceding dose.
Reconstitution: Preparation of I.V. Solutions: To facilitate reconstitution, allow the supplied sterile diluent to come to controlled room temperature (15 to 30°C) before mixing.
Dissolve carmustine completely with 3 mL of the supplied sterile diluent and then aseptically add 27 mL of Sterile Water for Injection, USP, to the alcohol solution. Each mL of the resulting solution will contain 3.3 mg of carmustine in 10% ethanol having a pH of 5.6 to 6.0. (Solution in the ethanol must be complete before sterile water for injection is added.) Accidental contact of reconstituted carmustine with the skin has caused transient hyperpigmentation of the affected areas. If carmustine lyophilized material or solution contacts the skin, immediately wash thoroughly with soap and water. If carmustine lyophilized material or solution contacts mucosa, flush thoroughly with water.
Reconstitution as recommended results in a clear colorless solution which may be further diluted with Sodium Chloride for Injection, USP, or 5% Dextrose for Injection, USP. The reconstituted solution should be used i.v. only and should be administered by i.v. drip over a 1 to 2 hour period. Injection of carmustine over shorter periods of time may produce intense pain and burning at the site of injection.
Stability of Reconstituted Solutions: The lyophilized dosage formulation contains no preservatives and is not intended as a multiple dose vial.
After reconstitution as recommended carmustine is stable for 8 hours at or below 25°C, 3 hours at 30°C or 24 hours under refrigeration (4°C).
The reconstituted solution further diluted with 500 mL of 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP, in glass containers, is stable for 24 hours under refrigeration (4°C). Further diluted carmustine should be used immediately if not refrigerated.
Note: 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 and agitation.
Handling and Disposal: Preparation of carmustine should be done in a vertical laminar flow hood (Biological Safety Cabinet – Class II). Personnel preparing carmustine should wear PVC gloves, safety glasses, disposable gowns and masks. All needles, syringes, vials and other materials which have come in contact with carmustine should be segregated and incinerated at 1 000°C or more. Sealed containers may explode. Intact vials should be returned to the manufacturer for destruction. Proper precautions should be taken in packaging these materials for transport. Personnel regularly involved in the preparation and handling of carmustine should have biannual blood examinations.
Availability And Storage: Each 30 mL amber glass vial contains: carmustine 100 mg with a 3 mL vial of absolute ethanol as sterile diluent. Nonmedicinal ingredients: none. Boxes of 10.
The unopened vial may have a physical appearance ranging from lacy flakes to a congealed mass, with no evident degradation of the active ingredient, carmustine. Do not use if product has liquified.
Unopened vials of the dry powder must be stored in a refrigerator (2 to 8°C). This recommended storage of unopened vials prevents significant decomposition for 24 months. Normal room temperature storage (22°C) of the unopened vials will result in a slow decomposition of the drug (approximately 3%) in 36 days.
Note: Carmustine has a low melting point (approximately 30 to 32°C). Vials of the drug exposed to this temperature or above will cause the drug to liquify and appear as an oil film in the bottom of the vials. This is a sign of decomposition and vials should be discarded. For inspection, hold the vial to a bright light.
BiCNU® Bristol Carmustine Antineoplastic Agent
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