Carmustine

214.05

214.05

205-838-2

U68WG3173Y

758392|409962

2811

DTXSID8022743

C349

Light yellow powder|Light yellow powder that melts to an oily liquid

L01AD01|L - Antineoplastic and immunomodulating agents

2924199090

61.8

1.5

Oily liquid to amorphous solid

1.5±0.1 g/cm3

31 °C

404ºC

1.549

H2O: <0.1 g/100 mL at 18 ºC

−20°C

2.9X10-4 mm Hg at 25 deg C (est)

Oral-rat LD50: 20 mg/kg; Oral-Mouse LD50: 19 mg/kg

Combustion produces toxic nitrogen oxides, chloride fumes; poisoning: nausea, vomiting, decreased white blood cells and platelets, bone marrow damage

Henry's Law constant = 4.8X10-11 atm-cu m/mol at 25 °C (est)

Polifeprosan 20 with carmustine implant ... off-white to pale yellow wafer /Gliadel wafer/|Hydroxyl radical reaction rate constant = 3.6X10-12 cu cm/molecule-sec at 25 °C (est)

Insoluble in water.

Amides and Imides

1,3-BIS(2-CHLOROETHYL)-1-NITROSOUREA decomposes rapidly in acid and in solutions above pH 7; most stable in petroleum ether or aqueous solution at pH 4. (NTP, 1992)

Ⅱ

6.1(a)

3249

3

45-46-60-61-28

53-22-36/37/39-45

YS2625000

T+

Treasury is ventilated, low temperature and dry; stored separately from food materials

May cause fatal harm to human respiratory system: pulmonary fibrosis, dyspnea and Verticillium wilt

P201-P264-P301 + P310-P308 + P313

H300-H350-H360

Dissolve or mix the material with a combustible solvent and burn in a chemical incinerator equipped with an afterburner and scrubber. Observe all federal, state, and local environmental regulations. Contact a licensed professional waste disposal service to dispose of this material.|SRP: Criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ All contaminated disposables should be contained in sealable bags for transfer to larger waste containers. /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ All bottles must be discarded as contaminated waste after decontamination of the biohazard cabinet. All protective apparel (gown, gloves, goggles, and respirator) should be discarded as contaminated waste. /Antineoplastic agents/|For more Disposal Methods (Complete) data for Carmustine (14 total), please visit the HSDB record page.

Materials to avoid: Acids.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl carmustine, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

National Toxicology Program. Eleventh Report on Carcinogens (2005). The Report on Carcinogens is an informational scientific and public health document that identifies and discusses substances (including agents, mixtures, or exposure circumstances) that may pose a carcinogenic hazard to human health. Bis(chloroethyl)nitrosourea (154-93-8) is listed as reasonably anticipated to be a human carcinogen.[Available from, as of September 29, 2009: http://ntp.niehs.nih.gov/ntp/roc/eleventh/profiles/s037bcnu.pdf]

Flash point data for this chemical are not available. It is probably combustible. (NTP, 1992)

|Danger|H300: Fatal if swallowed [Danger Acute toxicity, oral]|P201, P202, P260, P264, P270, P281, P301+P310, P307+P311, P308+P313, P314, P321, P330, P405, and P501

Excerpt from ERG Guide 154 [Substances - Toxic and/or Corrosive (Non-Combustible)]: As an immediate precautionary measure, isolate spill or leak area in all directions for at least 50 meters (150 feet) for liquids and at least 25 meters (75 feet) for solids. SPILL: Increase, in the downwind direction, as necessary, the isolation distance shown above. FIRE: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. (ERG, 2016)

SMALL SPILLS AND LEAKAGE: Should a spill occur while you are handling this chemical, FIRST REMOVE ALL SOURCES OF IGNITION, then you should dampen the solid spill material with 60-70% ethanol and transfer the dampened material to a suitable container. Use absorbent paper dampened with 60-70% ethanol to pick up any remaining material. Seal the absorbent paper, and any of your clothes, which may be contaminated, in a vapor-tight plastic bag for eventual disposal. Solvent wash all contaminated surfaces with 60-70% ethanol followed by washing with a soap and water solution. Do not reenter the contaminated area until the Safety Officer (or other responsible person) has verified that the area has been properly cleaned. STORAGE PRECAUTIONS: You should store this material in a refrigerator. (NTP, 1992)

RECOMMENDED RESPIRATOR: Where the neat test chemical is weighed and diluted, wear a NIOSH-approved half face respirator equipped with a combination filter cartridge, i.e. organic vapor/acid gas/HEPA (specific for organic vapors, HCl, acid gas, SO2 and a high efficiency particulate filter). (NTP, 1992)|Handle with gloves. Face shield and safety glasses.|Wear self contained breathing apparatus for fire fighting if necessary.|Where risk assessment shows air-purifying respirators are appropriate use a full-face particle respirator type N99 (US) or type P2 (EN 143) respirator cartridges as a backup to engineering controls. If the respirator is the sole means of protection, use a full-face supplied air respirator. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU).|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Protective apparel: Disposable closed-front gown or coveralls, disposable utility gloves over disposable latex gloves, NIOSH-approved air-purifying half-mask respirator equipped with a high efficiency filter, and eye protection should be worn. /Antineoplastic agents/|For more Personal Protective Equipment (PPE) (Complete) data for Carmustine (9 total), please visit the HSDB record page.

Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide.

Use personal protective equipment. Avoid dust formation. Avoid breathing dust. Ensure adequate ventilation. Evacuate personnel to safe areas. Prevent further leakage or spillage if safe to do so. Do not let product enter drains. Pick up and arrange disposal without creating dust. Keep in suitable, closed containers for disposal.|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Spill kits containing all materials needed to clean up spills of hazardous drugs should be assembled or purchased. These kits should be readily available in all areas where hazardous drugs are routinely handled. If hazardous drugs are being prepared or administered in a nonroutine area (home setting or unusual patient-care area), a spill kit should be obtained by the drug handler. The kit should include two pairs of disposable gloves (one outer pair of utility gloves and one inner latex pair); low-permeability, disposable protective garments (coveralls or gown and shoe covers); safety glasses or splash goggles; respirator; absorbent, plastic-backed sheets or spill pads; disposable toweling; at least 2 sealable thick plastic hazardous waste disposal bags (prelabeled with an appropriate warning label); a disposable scoop for collecting glass fragments; and a puncture-resistant container for glass fragments. All individuals who routinely handle hazardous drugs must be trained in proper spill management and cleanup procedures. Spills and breakages must be cleaned up immediately according to the following procedures. If the spill is not located in a confined space, the spill area should be identified and other people should be prevented from approaching and spreading the contamination. Wearing protective apparel from the spill kit, workers should remove any broken glass fragments and place them in the puncture-resistant container. Liquids should be absorbed with a spill pad; powder should be removed with damp disposable gauze pads or soft toweling. The hazardous material should be completely removed and the area rinsed with water and then cleaned with detergent. The spill cleanup should proceed progressively from areas of lesser to greater contamination. The detergent should be thoroughly rinsed and removed. All contaminated materials should be placed in the disposal bags provided and sealed and transported to a designated containment receptacle. Spills occurring in the biohazard cabinet should be cleaned up immediately; a spill kit should be used if the volume exceeds 150 ml or the contents of one drug vial or ampule. If there is broken glass, utility gloves should be worn to remove it and place it in the puncture-resistant container located in the biohazard cabinet. The biological safety cabinet, including the drain spillage trough, should be thoroughly cleaned. If the spill is not easily and thoroughly contained, the biological safety cabinet should be decontaminated after cleanup. If the spill contaminates the high efficiency particulate air filter, use of the biological safety cabinet should be suspended until the cabinet has been decontaminated and the high efficiency particulate air filter replaced. /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ If hazardous drugs are routinely prepared or administered in carpeted areas, special equipment is necessary to remove the spill. Absorbent powder should be substituted for pads or sheets and left in place on the spill for the time recommended by the manufacturer. The powder should then be picked up with a small vacuum unit reserved for hazardous drug cleanup. The carpet should then be cleaned according to usual procedures. The vacuum bag should be removed and discarded or cleaned, and the exterior of the vacuum cleaner should be washed with detergent and rinsed before being covered and stored. The contaminated powder should be discarded into a sealable plastic bag and segregated with other contaminated waste materials. Alternatively, inexpensive wet or dry vacuum units may be purchased for this express use and used with appropriate cleaners. All such units are contaminated, once used, and must be cleaned, stored, and ultimately discarded /properly/ ... The circumstances and handling of spills should be documented. Health-care personnel exposed during spill management should also complete an incident report or exposure form. /Antineoplastic agents/|PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured & the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed & labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/

Avoid contact with skin, eyes and clothing. Wash hands before breaks and immediately after handling the product. Choose body protection according to the amount and concentration of the dangerous substance at the work place.|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Accidental contamination of the health-care environment, resulting in exposure of personnel, patients, visitors, and family members to hazardous substances, is prevented by maintaining the physical integrity and security of packages of hazardous drugs. 1. Access to all areas where hazardous drugs are stored is limited to specified authorized staff. 2. A method should be present for identifying to personnel those drugs that require special precautions (eg, cytotoxics). One way to accomplish this is to apply appropriate warning labels to all hazardous drug containers, shelves, and bins where the drug products are stored. ... 3. A method of identifying, for patients and family members, those drugs that require special precautions in the home should be in place. This may be accomplished in the health-care setting, by providing specific labeling for discharge medications, along with written instructions. 4. Methods for identifying shipping cartons of hazardous drugs should be required from manufacturers and distributors of these drugs. 5. Written procedures for handling damaged packages of hazardous drugs should be maintained. Personnel involved in shipping and receiving hazardous drugs should be trained in these procedures, including the proper use of protective garments and equipment. Damaged shipping cartons of hazardous drugs should be received and opened in an isolated area (eg, in a laboratory fume hood, if available, not in a vertical laminar airflow biological safety cabinet used for preparing sterile products). /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Facilities (eg, shelves, carts, counters, and trays) for storing hazardous drugs are designed to prevent breakage and to limit contamination in the event of leakage. Bins, shelves with barriers at the front, or other design features that reduce the chance of drug containers falling to the floor should be used. Hazardous drugs requiring refrigeration should be stored separately from nonhazardous drugs in individual bins designed to prevent breakage and to contain leakage. /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Until the reproductive risks (or lack thereof) associated with handling hazardous drugs within a safety program have been substantiated, staff who are pregnant or breast-feeding should be allowed to avoid contact with these drugs. Policies should be in effect that provide these individuals with alternative tasks or responsibilities if they so desire. /Antineoplastic agents/|For more Preventive Measures (Complete) data for Carmustine (30 total), please visit the HSDB record page.

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Methods for transporting hazardous drugs to the health-care setting should be consistent with environmental protection and national or local regulations for transporting hazardous substances. When hazardous drugs are being transported to the home-care setting, appropriate containers (eg, lined cardboard boxes) and procedures should be used to prevent breakage and contain leakage. ... The drugs must be securely capped or sealed and properly packaged and protected during transport to reduce further the chance of breakage and spillage in a public area such as a corridor or elevator. /Antineoplastic agents/|PRECAUTIONS FOR "CARCINOGENS": Procurement ... of unduly large amt ... should be avoided. To avoid spilling, carcinogens should be transported in securely sealed glass bottles or ampoules, which should themselves be placed inside strong screw-cap or snap-top container that will not open when dropped & will resist attack from the carcinogen. Both bottle & the outside container should be appropriately labelled. ... National post offices, railway companies, road haulage companies & airlines have regulations governing transport of hazardous materials. These authorities should be consulted before ... material is shipped. /Chemical Carcinogens/|PRECAUTIONS FOR "CARCINOGENS": When no regulations exist, the following procedure must be adopted. The carcinogen should be enclosed in a securely sealed, watertight container (primary container), which should be enclosed in a second, unbreakable, leakproof container that will withstand chem attack from the carcinogen (secondary container). The space between primary & secondary container should be filled with absorbent material, which would withstand chem attack from the carcinogen & is sufficient to absorb the entire contents of the primary container in the event of breakage or leakage. Each secondary container should then be enclosed in a strong outer box. The space between the secondary container & the outer box should be filled with an appropriate quantity of shock-absorbent material. Sender should use fastest & most secure form of transport & notify recipient of its departure. If parcel is not received when expected, carrier should be informed so that immediate effort can be made to find it. Traffic schedules should be consulted to avoid ... arrival on weekend or holiday ... /Chemical Carcinogens/

May cause respiratory tract irritation. ... May cause skin irritation. ... May cause eye irritation.

highly toxic

The oral LD50s in rat and mouse are 20 mg/kg and 45 mg/kg, respectively. Side effects include leukopenia, thrombocytopenia, nausea. Toxic effects include pulmonary fibrosis (20-0%) and bone marrow toxicity.

Mild and transient elevations in serum aminotransferase levels are found in up to 25% of patients treated with carmustine. Because carmustine is typically given in combination with other agents, its role in causing these serum enzyme elevations is not always clear. The abnormalities are generally transient, do not cause symptoms and do not require dose modification. Clinically apparent liver injury from carmustine has been limited to a small number of cases of cholestatic hepatitis and more frequent instances of sinusoidal obstruction syndrome, reported mostly with its use in high doses or as a conditioning agent in preparation for hematopoietic cell transplantation. The onset of sinusoidal obstruction syndrome is usually within two to three weeks of the myeloablation and is characterized by a sudden onset of abdominal pain, weight gain, ascites, marked increase in serum aminotransferase levels (and LDH), and subsequent jaundice and hepatic dysfunction. The severity of sinusoidal obstruction syndrome varies from a transient, self-limited injury to acute liver failure. The diagnosis of sinusoidal obstruction syndrome is usually based on clinical features of tenderness and enlargement of the liver, weight gain, ascites and jaundice occurring within 3 weeks of chemotherapy. Liver biopsy is diagnostic but often contraindicated, because of severe thrombocytopenia after hematopoietic cell transplantation.

In patients receiving carmustine and phenytoin, serum concentrations of phenytoin may be decreased. In patients receiving carmustine therapy, serum concentrations of phenytoin should be monitored carefully and dosage adjustments made as necessary.|Qualitative and quantitative changes in tear films leading to damage of the corneal and conjunctival epithelium have been reported in patients receiving high doses of carmustine and mitomycin.|Cimetidine may potentiate the myelosuppressive effects (e.g., neutropenia, agranulocytosis) of myelosuppressive drugs (e.g., alkylating agents, antimetabolites) or therapies (e.g., radiation). Concomitant cimetidine therapy has been reported to potentiate the neutropenic and thrombocytopenic effect of carmustine alone or combined with radiation therapy.

LD50 Rat oral 20 mg/kg|LD50 Rat ip 17,420 ug/kg|LD50 Rat sc 83,200 ug/kg|LD50 Rat iv 13,800 ug/kg|For more Non-Human Toxicity Values (Complete) data for Carmustine (9 total), please visit the HSDB record page.

80%

Carmustine's production and use as a medication to treat cancer of the lymph system, cancerous brain tumors, and a certain type of bone marrow cancer(1) may result in its release to the environment through various waste streams(SRC).

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 150(SRC), determined from a structure estimation method(2), indicates that carmustine is expected to have high mobility in soil(SRC). However, by analogy to N-nitroso-N-ethylurea which exhibited a hydrolysis half-life of 47 minutes at pH 9(3), adsorption may be precluded by hydrolysis(SRC). Volatilization of carmustine from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 4.8X10-11 atm-cu m/mole(SRC), using a fragment constant estimation method(4). Carmustine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 2.9X10-4 mm Hg(SRC), determined from a fragment constant method(5). Biodegradation data were not available(SRC, 2009).|AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 150(SRC), determined from a structure estimation method(2), indicates that carmustine is expected to adsorb to suspended solids and sediment(SRC). However, by analogy to N-nitroso-N-ethylurea which exhibited a hydrolysis half-life of 47 minutes at pH 9(3), adsorption may be precluded by hydrolysis(SRC). Volatilization from water surfaces is not expected(4) based upon an estimated Henry's Law constant of 4.8X10-11 atm-cu m/mole(SRC), developed using a fragment constant estimation method(5). According to a classification scheme(6), an estimated BCF of 5(SRC), from its log Kow of 1.53(7) and a regression-derived equation(8), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Carmustine is an alkylating agent that may hydrolyze under environmental conditions(4). Biodegradation data were not available(SRC, 2009).|ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), carmustine, which has an estimated vapor pressure of 2.9X10-4 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase carmustine is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 4.4 days(SRC), calculated from its rate constant of 3.6X10-12 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(3). Particulate-phase carmustine may be removed from the air by wet or dry deposition(SRC). Carmustine contains chromophores that absorb at wavelengths >290 nm(4) and therefore may be susceptible to direct photolysis by sunlight(SRC).

The rate constant for the vapor-phase reaction of carmustine with photochemically-produced hydroxyl radicals has been estimated as 3.6X10-12 cu cm/molecule-sec at 25 °C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 4.4 days at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). Carmustine is an alkylating agent that may hydrolyze under environmental conditions(2). The analogous compound N-nitroso-N-ethylurea exhibited a half-life of 47 minutes at pH 9(3). Carmustine contains chromophores that absorb at wavelengths >290 nm(2) and therefore may be susceptible to direct photolysis by sunlight(SRC).

An estimated BCF of 5 was calculated in fish for carmustine(SRC), using a log Kow of 1.53(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).

Using a structure estimation method based on molecular connectivity indices(1), the Koc of 150 can be estimated to be carmustine(SRC). According to a classification scheme(2), this estimated Koc value suggests that carmustine is expected to have high mobility in soil. However, by analogy to N-nitroso-N-ethylurea which exhibited a hydrolysis half-life of 47 minutes at pH 9(3), adsorption may be precluded by hydrolysis(SRC).

The Henry's Law constant for carmustine is estimated as 4.8X10-11 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that carmustine is expected to be essentially nonvolatile from water surfaces(2). Carmustine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 2.9X10-4 mm Hg(SRC), determined from a fragment constant method(3).

While data specific to carmustine were not located(SRC, 2009), the literature suggests that some pharmaceutically active compounds originating from human and veterinary therapy are not eliminated completely in municipal sewage treatment plants and are therefore discharged into receiving waters(1). Wastewater treatment processes often were not designed to remove them from the effluent(2). Selected organic waste compounds may be degrading to new and more persistent compounds that may be released instead of or in addition to the parent compound(2).

Following IV infusion of carmustine, the steady-state volume of distribution averaged 3.25 L/kg. .... Carmustine metabolites are distributed into milk, but in concentrations less than those in maternal plasma.

NIOSH (NOES Survey 1981-1983) has statistically estimated that 14,122 workers (10,338 of these were female) were potentially exposed to carmustine in the US(1). Occupational exposure to carmustine may occur through dermal contact with this compound at workplaces where carmustine is produced or used(SRC). The general population may only be exposed to carmustine via use as a drug, an antineoplastic(SRC).

For the treatment of brain tumors, multiple myeloma, Hodgkin's disease and Non-Hodgkin's lymphomas.|FDA Label|Carmustine is effective in the following malignant neoplasms as a single agent or in combination with other antineoplastic agents and/or other therapeutic measures (radiotherapy, surgery):, , , Brain tumours (glioblastoma, brain-stem gliomas, medulloblastoma, astrocytoma and ependymoma), brain metastases, Secondary therapy in non-Hodgkin's lymphoma and Hodgkin's disease, as conditioning treatment prior to autologous haematopoietic progenitor cell transplantation (HPCT) in malignant haematological diseases (Hodgkin's disease / Non-hodgkin's lymphoma)., ,|Drug: Carmustine|Drug: Carmustineimplant

Carmustine (BCNU) is a parenterally administered alkylating agent used alone and in combination with other antineoplastic agents in the treatment of several forms of cancer including leukemias, lymphomas, and breast, testicular, ovarian, gastric and pancreatic cancer. Carmustine therapy is associated with minor transient serum enzyme elevations and has been linked to cases of acute liver injury including cholestatic hepatitis and acute veno-occlusive disease.

Antineoplastic Agents, Alkylating Agents

BiCNU is indicated as palliative therapy as a single agent or in established combination therapy with other approved chemotherapeutic agents in the following: Brain tumors-glioblastoma, brainstem glioma, medulloblastoma, astrocytoma, ependymoma, and metastatic brain tumors. Multiple myeloma-in combination with prednisone. 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. 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.|bis(Chloroethyl) nitrosourea has been used since 1971 as an antineoplastic agent in the treatment of Hodgkin's lymphoma, multiple myeloma, and primary or metastatic brain tumors.|Reported to have antiviral, antibacterial, and antifungal activity, but no evidence was found that it is currently used for these purposes. Former use.|MEDICATION (VET): A chemotherapeutic protocol using carmustine in combination with vincristine and prednisone was tested in dogs with multicentric malignant lymphosarcoma. Of seven dogs treated, six (85.7%) achieved complete remission. A partial response occurred in one dog. Median survival time was 224 days (mean 386 days), and median duration of remission was 183 days (mean 323 days). Marked neutropenia was observed following carmustine administration. There were no significant alterations in platelets and red blood cell counts during treatment, and no abnormalities attributable to the chemotherapy were found in serum biochemical profiles. Results of this study showed that carmustine is an effective alternative option in the treatment of canine lymphosarcoma.

/BOXED WARNING/ 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. Pulmonary toxicity from BiCNU appears to be dose related. Patients receiving greater than 1400 mg/sq m cumulative 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.|Human systemic effects by parenteral, intravenous, and possibly other routes: nausea or vomiting, reduced white blood cell and blood platelet counts, bone marrow damage, and potentially fatal respiratory system effects, including lung fibrosis, dyspnea, and cyanosis.|In a study of 17 children (aged 1-16 years) receiving carmustine in cumulative doses ranging from 770-1800 mg/sq m combined with cranial radiation therapy for intracranial tumors, 8 children (47%) died of delayed pulmonary fibrosis, including all of those who received initial treatment at less than 5 years of age (5 children). Onset of pulmonary fibrosis has been observed up to 17 years following carmustine therapy. Clinical findings include pulmonary hypoplasia with upper zone contraction on chest radiographs, and an unusual pattern of upper zone fibrosis on thoracic CT scans; no abnormal findings were observed on gallium scans.105 Late onset of reduction in pulmonary function was observed in all long-term survivors in the study. Carmustine-induced pulmonary fibrosis may be slowly progressive and cause death.|Pulmonary toxicity, including acute or delayed onset of pulmonary fibrosis causing death, has occurred in patients receiving systemic carmustine therapy. Pulmonary toxicity characterized by pulmonary infiltrates and/or fibrosis occurring 9 days to 43 months following treatment has been reported in patients receiving carmustine or related nitrosoureas. Most reported cases of pulmonary toxicity have occurred in patients receiving prolonged carmustine therapy with total doses exceeding 1400 mg/sq m; however, pulmonary fibrosis has occurred with lower total doses. Other risk factors include prior history of pulmonary disease and duration of carmustine therapy. Pulmonary toxicity occasionally has been rapidly progressive and/or fatal.|For more Drug Warnings (Complete) data for Carmustine (41 total), please visit the HSDB record page.

Carmustine is one of the nitrosoureas indicated as palliative therapy as a single agent or in established combination therapy with other approved chemotherapeutic agents in treatment of brain tumors, multiple myeloma, Hodgkin's disease, and non-Hodgkin's lymphomas. 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.

A class of drugs that differs from other alkylating agents used clinically in that they are monofunctional and thus unable to cross-link cellular macromolecules. Among their common properties are a requirement for metabolic activation to intermediates with antitumor efficacy and the presence in their chemical structures of N-methyl groups, that after metabolism, can covalently modify cellular DNA. The precise mechanisms by which each of these drugs acts to kill tumor cells are not completely understood. (From AMA, Drug Evaluations Annual, 1994, p2026) (See all compounds classified as Antineoplastic Agents, Alkylating.)

5 to 28% bioavailability|Approximately 60% to 70% of a total dose is excreted in the urine in 96 hours and about 10% as respiratory CO2.|Following IV infusion of carmustine, the steady-state volume of distribution averaged 3.25 L/kg. Because of their high lipid solubility, carmustine and/or its metabolites readily cross the blood-brain barrier. Substantial CSF concentrations occur almost immediately after IV administration of carmustine, and CSF concentrations of radioactivity have been variously reported to range from 15-70% of concurrent plasma concentrations. Carmustine metabolites are distributed into milk, but in concentrations less than those in maternal plasma.|The absorption of the copolymer contained in carmustine wafers has not been evaluated in humans. Plasma concentrations of carmustine following intracranial implantation of the wafers have not been determined in humans, but in rabbits undergoing surgical implantation of wafers containing 3.85% carmustine, no detectable levels of carmustine were observed in plasma.|When the carmustine wafer is exposed to the aqueous environment of the resection cavity, hydrolysis of the anhydride bonds in the copolymer occurs, resulting in the release of carmustine and two monomers, carboxyphenoxypropane, and sebacic acid. The carmustine contained in the wafer diffuses into the surrounding brain tissue. The metabolism and excretion of the copolymer contained in carmustine wafers has not been evaluated in humans. Animal studies have shown that more than 70% of the copolymer degrades within 3 weeks following implantation of carmustine wafers into brain tissue; following hydrolysis of the copolymer, carboxyphenoxypropane is eliminated renally, while sebacic acid (an endogenous fatty acid) is metabolized in the liver and expired as carbon dioxide. In humans, wafer remnants have been observed on brain imaging scans or located during subsequent surgical procedures up to 8 months following intracranial implantation. Wafer remnants retrieved from 2 patients approximately 2-3 months after implantation were analyzed and found to consist mostly of water and monomeric components with minimal detectable amounts of carmustine.|The disappearance of 1,3-bis(2-chlorethyl)-1-nitrosourea (BCNU) from plasma, liver, kidney, lung, brain, spleen, tumor tissue and epididymal adipose tissue of Walker 256/B carcinoma-bearing rats and healthy animals was measured by differential pulse polarography after i.v. bolus of the drug. Only BCNU, not its decomposition products, was detected by the polarographic assay. Levels of BCNU in liver of tumor-bearing animals were significantly lower (about 10 times) than those on healthy rats. A bi-exponential fit was used to calculate the kinetics of BCNU in plasma, kidney, lung and brain, but no difference could be found between healthy and Walker tumor-bearing rats. BCNU disappeared faster from adipose tissue of tumor-bearing animals than from normals.|Some 40 minutes after injection, BCNU is no longer an effective antitumour agent, and a few minutes after administration no unchanged BCNU can be detected in plasma. Following its ip or sc injection or oral administration, BCNU was rapidly distributed to most tissues, including brain and cerebrospinal fluid. Excretion was primarily in the urine; it was most rapid in mice (80% of the dose excreted in 24 hours) and less rapid in monkeys and dogs.

Hepatic and rapid with active metabolites. Metabolites may persist in the plasma for several days.|The in vitro metabolism of the anticancer agent 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) has been studied in male Fischer 344 rat liver microsomal preparations. The previously identified product, 1,3-bis(2-chloroethyl)urea (BCU), has been shown to be the major metabolite. Stable isotope labeling and mass spectral analysis of isolated metabolites indicate that BCU is formed exclusively from the metabolic denitrosation of BCNU. The rate of BCNU chemical decomposition in rat liver microsomal preparations deficient in NADPH and the metabolic disappearance rate in preparations containing added NADPH were measured and compared with the measured rate of metabolic formation of BCU under the same conditions. The rate of NADPH-dependent BCNU metabolism and BCU formation are equal within experimental error. BCNU was found to inhibit the rat liver 9000 g supernatant metabolism of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU).

15-30 minutes

Carmustine causes cross-links in DNA and RNA, leading to the inhibition of DNA synthesis, RNA production and RNA translation (protein synthesis). Carmustine also binds to and modifies (carbamoylates) glutathione reductase. This leads to cell death.|Temozolomide (TMZ) and carmustine (BCNU), cancer-drugs usually used in the treatment of gliomas, are DNA-methylating agents producing O6-methylguanine. It has been shown that 06-methylguanine triggers DNA mismatch repair and in turn induce apoptosis and senescence, respectively, over a 4 and 6 days period. Temozolomide and carmustine have an earlier effect on nuclear organization and chromatin structure. In particular, temozolomideZ and carmustine induce clustering of pericentromeric heterochromatin regions and increase the amount of heterochromatic proteins MeCP2 and HP1alpha bound to chromatin. These drugs also decrease global levels of histone H3 acetylation and increase levels of histone H3 trimethylated on lysine 9 (H3-triMeK9). These events precede the senescence status. ... Temozolomide and carmustine efficacy in glioma treatment may implicate a first event characterized by changes in heterochromatin organization and its silencing which is then followed by apoptosis and senescence.|Although carmustine is believed to act by alkylation of DNA and RNA, the mechanism of action has not been completely elucidated and other effects such as carbamoylation and modification of cellular proteins may be involved. The overall result is thought to be the inhibition of both DNA and RNA synthesis.

SYMPTOMS: Symptoms of exposure to this compound may include bone-marrow suppression; delayed onset of leukopenia and thrombocytopenia; cytotoxic effects on the liver, kidneys and central nervous system; nausea; vomiting; flushing of the skin; esophagitis; diarrhea; dyspnea and hepatotoxicity. ACUTE/CHRONIC HAZARDS: When heated to decomposition this compound emits toxic fumes. (NTP, 1992)

EYES: First check the victim for contact lenses and remove if present. Flush victim's eyes with water or normal saline solution for 20 to 30 minutes while simultaneously calling a hospital or poison control center. Do not put any ointments, oils, or medication in the victim's eyes without specific instructions from a physician. IMMEDIATELY transport the victim after flushing eyes to a hospital even if no symptoms (such as redness or irritation) develop. SKIN: IMMEDIATELY flood affected skin with water while removing and isolating all contaminated clothing. Gently wash all affected skin areas thoroughly with soap and water. If symptoms such as redness or irritation develop, IMMEDIATELY call a physician and be prepared to transport the victim to a hospital for treatment. INHALATION: IMMEDIATELY leave the contaminated area; take deep breaths of fresh air. IMMEDIATELY call a physician and be prepared to transport the victim to a hospital even if no symptoms (such as wheezing, coughing, shortness of breath, or burning in the mouth, throat, or chest) develop. Provide proper respiratory protection to rescuers entering an unknown atmosphere. Whenever possible, Self-Contained Breathing Apparatus (SCBA) should be used; if not available, use a level of protection greater than or equal to that advised under Protective Clothing. INGESTION: If the victim is conscious and not convulsing, give 1 or 2 glasses of water to dilute the chemical and IMMEDIATELY call a hospital or poison control center. Generally, the induction of vomiting is NOT recommended outside of a physician's care due to the risk of aspirating the chemical into the victim's lungs. However, if the victim is conscious and not convulsing and if medical help is not readily available, consider the risk of inducing vomiting because of the high toxicity of the chemical ingested. Ipecac syrup or salt water may be used in such an emergency. IMMEDIATELY transport the victim to a hospital. If the victim is convulsing or unconscious, do not give anything by mouth, ensure that the victim's airway is open and lay the victim on his/her side with the head lower than the body. DO NOT INDUCE VOMITING. IMMEDIATELY transport the victim to a hospital. OTHER: Since this chemical is a known or suspected carcinogen you should contact a physician for advice regarding the possible long term health effects and potential recommendation for medical monitoring. Recommendations from the physician will depend upon the specific compound, its chemical, physical and toxicity properties, the exposure level, length of exposure, and the route of exposure. (NTP, 1992)

Maintain an open airway and assist ventilation if necessary. Treat coma, seizures, hypotension, and arrhythmias if they occur. Treat nausea and vomiting with metoclopramide and fluid loss caused by gastroenteritis with intravenous crystalloid fluids. Bone marrow depression should be treated with the assistance of an experienced hematologist or oncologist. Extravasation: Immediately stop the infusion and withdraw as much fluid as possible by negative pressure on the syringe. Then give the following specific treatment: Place a heating pad over the area and apply heat intermittently for 24 hours; elevate the limb. Local injection of hyaluronidase may be beneficial. Do not use ice packs. /For/ decontamination administer activated charcoal orally if conditions are appropriate. Gastric lavage is not necessary after small to moderate ingestions if activated charcoal can be given promptly. Because of the rapid intracellular incorporation of these agents, dialysis and other extracorporeal removal procedures are generally not effective. /Antineoplastic agents/|/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

/SIGNS AND SYMPTOMS/ Pulmonary toxicity, including acute or delayed onset of pulmonary fibrosis causing death, has occurred in patients receiving systemic carmustine therapy. Pulmonary toxicity characterized by pulmonary infiltrates and/or fibrosis occurring 9 days to 43 months following treatment has been reported in patients receiving carmustine or related nitrosoureas. Most reported cases of pulmonary toxicity have occurred in patients receiving prolonged carmustine therapy with total doses exceeding 1400 mg/sq m; however, pulmonary fibrosis has occurred with lower total doses. Other risk factors include prior history of pulmonary disease and duration of carmustine therapy. Pulmonary toxicity occasionally has been rapidly progressive and/or fatal.|/SIGNS AND SYMPTOMS/ In a randomized trial, encephalopathy, sometimes fatal, was reported in patients receiving intra-arterial carmustine.|/SIGNS AND SYMPTOMS/ ... bis(chloroethyl) nitrosourea is associated with acute nonlymphocytic leukemia following its use with other anticancer therapies in the treatment of previously existing cancer.|/SIGNS AND SYMPTOMS/ Human systemic effects by parenteral, intravenous, and possibly other routes: nausea or vomiting, reduced white blood cell and blood platelet counts, bone marrow damage, and potentially fatal respiratory system effects, including lung fibrosis, dyspnea, and cyanosis.|For more Human Toxicity Excerpts (Complete) data for Carmustine (26 total), please visit the HSDB record page.

1,3-Bis(2-Chloroethyl)-1-Nitrosourea

Carmubris|Carmustin|Nitrumon|Local: Implants: 7.7 mg (of carmustine per wafer) Gliadel Wafer (MGI Pharma).|Parenteral: For injection, for IV infusion: 100 mg BiCNU (Bristol-Myers Squibb).

An antineoplastic nitrosourea|... designed to deliver carmustine directly into the surgical cavity created when a brain tumor is resected /Gliadel wafer/

Human drugs -> Carmustine Obvius -> EMA Drug Category|Antineoplastic agents -> Human pharmacotherapeutic group|Human drugs -> Rare disease (orphan)|Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients