Lomustine

233.7

233.70

235-859-2

7BRF0Z81KG

759635|79037

DTXSID2023222

C617

Solid|Yellow powder

L - Antineoplastic and immunomodulating agents

29299090

61.8

2.8

Solid

1.3840 (rough estimate)

89 °C (approx)

63.6°C (rough estimate)

1.5790 (estimate)

7.55e-01 g/L

−20°C

1.01X10-5 mm Hg at 25 deg C (est)

Oral-Rat  LD50: 70 mg/kg; Oral-Mouse  LD50:38 mg/kg

Flammable; decomposes toxic chloride and nitrogen oxide gas in the fire

Henry's Law constant = 1.9X10-10 atm-cu m/mole at 25 °C (est)

Hydroxyl radical reaction rate constant = 2.2X10-11 cu cm/molecule-sec at 25 °C (est)

II

6.1(a)

3249

3

45-25

53-45

YS4900000

T

The warehouse is low-temperature, ventilated and dry; stored separately from food materials

P201-P301 + P310-P308 + P313

H301-H350

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.|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.|/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 LOMUSTINE (14 total), please visit the HSDB record page.

Materials to avoid: Strong oxidizing agents, strong bases.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl lomustine, 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. 1-(2-Chloroethyl)-3-cyclohexyl-1-nitrosourea (13010-47-4) is listed as reasonably anticipated to be a human carcinogen. First listed in the Fourth Annual Report on Carcinogens (1985) as reasonably anticipated to be a human carcinogen.[Available from, as of July 31, 2009: http://ntp.niehs.nih.gov/ntp/roc/eleventh/profiles/s035ccnu.pdf]

|Danger|H301 (100%): Toxic if swallowed [Danger Acute toxicity, oral]|P201, P202, P264, P270, P281, P301+P310, P308+P313, P321, P330, P405, and P501|Aggregated GHS information provided by 41 companies from 4 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.|H301: Toxic if swallowed [Danger Acute toxicity, oral]|P201, P202, P260, P264, P270, P281, P301+P310, P307+P311, P308+P313, P309+P311, P314, P321, P330, P405, and P501

Respiratory protection: 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).|Hand protection: The selected protective gloves have to satisfy the specifications of EU Directive 89/686/EEC and the standard EN 374 derived from it. Handle with gloves.|Eye protection: Face shield and safety glasses.|Skin and body protection: Choose body protection according to the amount and concentration of the dangerous substance at the work place.|For more Personal Protective Equipment (PPE) (Complete) data for LOMUSTINE (10 total), please visit the HSDB record page.

Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide.|Special protective equipment for fire-fighters: Wear self contained breathing apparatus for fire fighting if necessary.

Personal precautions: Use personal protective equipment. Avoid dust formation. Avoid breathing dust. Ensure adequate ventilation. Evacuate personnel to safe areas.|Environmental precautions: Prevent further leakage or spillage if safe to do so. Do not let product enter drains.|Methods for cleaning up: 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/|For more Cleanup Methods (Complete) data for LOMUSTINE (6 total), please visit the HSDB record page.

In case of skin contact: Wash off with soap and plenty of water. Consult a physician.|In case of eye contact: Rinse thoroughly with plenty of water for at least 15 minutes and consult a physician.|Hygiene measures: Avoid contact with skin, eyes and clothing. Wash hands before breaks and immediately after handling the product.|/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/|For more Preventive Measures (Complete) data for LOMUSTINE (32 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.

most toxic

Oral, rat: LD50 = 70 mg/kg. Pulmonary toxicity has been reported at cumulative doses usually greater than 1,100 mg/m2. There is one report of pulmonary toxicity at a cumulative dose of only 600 mg. The onset of toxicity has varied from 6 months after initiation of therapy, to as late as 15 years after.

Mild and transient elevations in serum aminotransferase or alkaline phosphatase levels are found in a high proportion of patients treated antineoplastic regimens that include lomustine. The abnormalities are generally transient, do not cause symptoms and do not require dose modification. Clinically apparent liver injury from lomustine has been described, but is uncommon. The pattern of serum enzyme elevations were described as cholestatic and onset was after 3 to 4 months of therapy, but otherwise its clinical characteristics have not been clearly characterized. Lomustine is often given in combination with other antineoplastic agents, many of which are also hepatotoxic, so the effect of lomustine in causing liver injury is often difficult to assess. Lomustine has not been associated specifically with sinusoidal obstruction syndrome, but it is not generally given in high doses or used for myeloablation in preparation for bone marrow transplantation, the situations in which this syndrome generally occurs.

The combined action of the antitumor antibiotic bleomycin and chloroethylnitrosourea was studied in human lymphocytes in vitro. All the experiments were carried out with 20 ug/mL bleomycin for a given treatment time. By adding 0.7 and 3.5 ug/mL chloroethylnitrosourea at late G1-S phase we have demonstrated a considerable increase in both percent of aberrant cells and production of dicentrics and rings (5-fold, p < 0.001). At late S-G2 the combined treatment led to a significant enhancement of breaks per cell (p < 0.0001) and cells with more than 12 aberrations. A possible explanation could be the known repair inhibitory potential of chloroethylnitrosourea, but its pure clastogenic action still has to be considered. The results presented here point out the need for seeking chemotherapeutic regimens with reduced concentrations of the drugs in combination.|Three patients developed the sudden onset of total blindness several months after treatment with oral CCNU and low dose whole brain radiation. The anterior visual system was included in the radiation field in all patients. Radiotherapy was given for a frontal lobe glioblastoma multiforme, for central nervous system prophylaxis in a patient with oat cell carcinoma of the lung, and for a parietal lobe glioblastoma multiforme. None of the neoplasms involved the anterior visual system. The radiation dose ranged from 3000 to 4650 rad and the oral CCNU dosage from 300 mg to 1050 mg. Patients 1 and 2 also received other chemotherapeutic agents. Patient 3 who was treated only with oral CCNU and cranial irradiation died. At autopsy the brain showed a widely infiltrating residual high grade glioma as well as patchy coagulative necrosis with swollen axons and dystrophic calcifications. The optic chiasm showed severe demyelination, axonal loss, and hyalinized vessels. Synergism between oral CCNU and radiation may account for the blindness produced.

LD50 Rat oral 70 mg/kg|LD50 Rat ip 50,350 ug/kg|LD50 Mouse female oral 38 mg/kg bw|LD50 Mouse male oral 51 mg/kg|For more Non-Human Toxicity Values (Complete) data for LOMUSTINE (7 total), please visit the HSDB record page.

50%

Lomustine's production and use as an antineoplastic(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 200(SRC), determined from a structure estimation method(2), indicates that lomustine is expected to have moderate 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 lomustine from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 1.8X10-10 atm-cu m/mole(SRC), using a fragment constant estimation method(4). Lomustine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 2.6X10-5 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 200(SRC), determined from a structure estimation method(2), indicates that lomustine 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 1.8X10-10 atm-cu m/mole(SRC), developed using a fragment constant estimation method(5). According to a classification scheme(6), an estimated BCF of 34(SRC), from its log Kow of 2.83(7) and a regression-derived equation(8), suggests the potential for bioconcentration in aquatic organisms is moderate(SRC). Lomustine 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), lomustine, which has an estimated vapor pressure of 2.6X10-5 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 lomustine 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 18 hours(SRC), calculated from its rate constant of 2.2X10-11 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(3). Particulate-phase lomustine may be removed from the air by wet or dry deposition(SRC). Lomustine does not contain chromophores that absorb at wavelengths >290 nm(4) and therefore is not expected to be susceptible to direct photolysis by sunlight(SRC).

The rate constant for the vapor-phase reaction of lomustine with photochemically-produced hydroxyl radicals has been estimated as 2.2X10-11 cu cm/molecule-sec at 25 °C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 18 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). Lomustine 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). Lomustine does not contain chromophores that absorb at wavelengths >290 nm(2) and therefore is not expected to be susceptible to direct photolysis by sunlight(SRC).

An estimated BCF of 34 was calculated in fish for lomustine(SRC), using a log Kow of 2.83(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is moderate(SRC).

Using a structure estimation method based on molecular connectivity indices(1), the Koc of lomustine can be estimated to be 200(SRC). According to a classification scheme(2), this estimated Koc value suggests that lomustine is expected to have moderate 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 lomustine is estimated as 1.8X10-10 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that lomustine is expected to be essentially nonvolatile from water surfaces or moist soils(2). Lomustine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 2.6X10-5 mm Hg(SRC), determined from a fragment constant method(3).

While data specific to lomustine 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).

Lomustine metabolites are present in milk, but in concentrations than those in maternal plasma.

NIOSH (NOES Survey 1981-1983) has statistically estimated that 2457 workers (1069 of these were female) were potentially exposed to lomustine in the US(1). Occupational exposure to lomustine may occur through inhalation dermal contact with this compound at workplaces where lomustine is produced or used(SRC). Exposure to lomustine among the general population may be limited to those administered the drug, an antineoplastic(SRC).

For the treatment of primary and metastatic brain tumors as a component of combination chemotherapy in addition to appropriate surgical and/or radiotherapeutic procedures. Also used in combination with other agents as secondary therapy for the treatment of refractory or relapsed Hodgkin's disease.|Drug: Lomustine|Drug: Pcv

Lomustine is an orally administered alkylating agent used alone and in combination with other antineoplastic agents in the treatment of several malignancies including Hodgkin disease, lymphoma, and brain cancer. Lomustine therapy is associated with minor transient serum enzyme elevations and has been linked to rare cases of clinically apparent acute liver injury.

Antineoplastic Agents, Alkylating Agents

Antineoplastic Agents, Alkylating|CeeNU has been shown to be useful as a single agent in addition to other treatment modalities, or in established combination therapy with other approved chemotherapeutic agents in the following: Brain tumors-both primary and metastatic, in patients who have already received appropriate surgical and/or radiotherapeutic procedures. Hodgkin's Disease-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. /Included in US product label/|Antineoplastic agent. The compound has had limited use since the early 1970s in the treatment of Hodgkin's disease and various solid tumors. These include primary and metastatic brain tumors, colorectal tumors, and certain pulmonary malignancies. It is usually used in conjunction with other antineoplastic drugs.|Although lomustine is labeled for use in combination with other agents as secondary therapy for the treatment of refractory or relapsed Hodgkin's disease, combination regimens containing other agents currently are preferred for this cancer. /Included in US product label/|For more Therapeutic Uses (Complete) data for LOMUSTINE (8 total), please visit the HSDB record page.

/BOXED WARNING/ WARNINGS: CeeNU (lomustine) 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 CeeNU. 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 CeeNU should not be given more frequently than every 6 weeks. The bone marrow toxicity of CeeNU is cumulative and therefore dosage adjustment must be considered on the basis of nadir blood counts from prior dose|Because some lomustine metabolites are present in milk, women receiving the drug probably should not nurse their infants.|Delayed onset of pulmonary fibrosis occurring up to 17 years after treatment has been reported in patients receiving related nitrosoureas combined with cranial radiation therapy for intracranial tumors during childhood and adolescence (age 1-16 years). Late onset of reduction in pulmonary function was observed in all long-term survivors. Nitrosourea-induced pulmonary fibrosis may be slowly progressive and can cause death.|Nausea and vomiting occur in 45-100% of patients within 45 min to 6 hr after ingestion of an oral dose of lomustine. Although these symptoms are not severe and usually abate within 24 hr, they may persist up to 36 hr and are often followed by 2-3 days of anorexia. Stomatitis has occurred infrequently.|For more Drug Warnings (Complete) data for LOMUSTINE (25 total), please visit the HSDB record page.

Lomustine is an alkylating agent of the nitrosourea type. Lomustine and its metabolites interferes with the function of DNA and RNA. It is cell cycle–phase nonspecific. Cancers form when some cells within the body multiply uncontrollably and abnormally. These cells then spread and destroy nearby tissues. Lomustine acts by slowing this process down. It kills cancer cells by damaging the DNA (the genetic material inside the cells) and stops them from dividing.

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.)

Well and rapidly absorbed from the gastrointestinal tract.|Following oral administration of radioactive CeeNU at doses ranging from 30 mg/m2 to 100 mg/m2, about half of the radioactivity given was excreted in the urine in the form of degradation products within 24 hours.|Lomustine is excreted primarily in the urine as metabolites. Following oral administration of (14)C-labeled lomustine, about 50% of the radioactivity is excreted within 12 hr and about 75% within 4 days.|Lomustine is reported to be widely distributed. Lomustine and/or its metabolites cross the blood-brain barrier and are rapidly transported into cells due to their high lipid solubility. Although intact lomustine is not detectable in the CSF, active metabolites of the drug appear in substantial concentrations within 30 minutes after oral administration of lomustine. CSF concentrations of metabolites have been reported to be 15-50% or greater than concurrent plasma concentrations. Lomustine metabolites are present in milk, but in concentrations than those in maternal plasma.|Lomustine is rapidly absorbed from the GI tract; the drug is also absorbed following topical application. Peak plasma concentrations of metabolites occur within 1-6 hours following administration of an oral dose of lomustine.|Following its ip or iv injection or oral administration, (14)C-labelled CCNU was rapidly distributed to many tissues in mice, rats, rabbits and dogs.. About 80% of label was excreted in the urine of mice 24 hours after a single parenteral or oral dose of 50 mg/kg bw.

Hepatic. Rapid and complete, with active metabolites.|CCNU undergoes spontaneous decomposition under physiological conditions to release both alkylating and carbamoylating entities. It disappears from plasma within 5 minutes following its oral administration, but the antitumor effect of its metabolites may persist for up to 15 minutes. ... In addition to chemical decomposition, CCNU may be converted by microsomal metabolism to 6 isomeric hydroxylated derivatives, some of which may differ in their biological properties from CCNU.|Virtually all of a dose of lomustine is metabolized within 1 hour after oral administration. The half-life of lomustine metabolites is biphasic; although the initial plasma half-life is 6 hours, the second phase plasma half-life is 1-2 days, and 15-20% of the metabolites remain in the body 5 days after administration of lomustine. Prolongation of plasma concentrations is thought to reflect a combination of protein binding and enterohepatic circulation of metabolites.

Approximately 94 minutes, however the metabolites have a serum half-life of 16 to 48 hours.|The half-life of lomustine metabolites is biphasic; although the initial plasma half-life is 6 hours, the second phase plasma half-life is 1-2 days, and 15-20% of the metabolites remain in the body 5 days after administration of lomustine.

Lomustine is a highly lipophilic nitrosourea compound which undergoes hydrolysis in vivo to form reactive metabolites. These metabolites cause alkylation and cross-linking of DNA (at the O6 position of guanine-containing bases) and RNA, thus inducing cytotoxicity. Other biologic effects include inhibition of DNA synthesis and some cell cycle phase specificity. Nitrosureas generally lack cross-resistance with other alkylating agents. As lomustine is a nitrosurea, it may also inhibit several key processes such as carbamoylation and modification of cellular proteins.|Although lomustine is believed to act by alkylation, the mechanism of action has not been completely elucidated, and other effects 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.

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/ The occurrence of acute leukemia and bone marrow dysplasias have been reported in patients following long-term nitrosourea therapy.|/SIGNS AND SYMPTOMS/ Pulmonary toxicity, sometimes fatal, has occurred rarely in patients receiving lomustine. Pulmonary toxicity characterized by pulmonary infiltrates and/or fibrosis has occurred at 6 months or longer following initiation of lomustine therapy in patients typically receiving cumulative doses exceeding 1100 mg/sq m; however, pulmonary fibrosis has occurred with lower total doses.|/SIGNS AND SYMPTOMS/ Delayed onset of pulmonary fibrosis occurring up to 17 years after treatment has been reported in patients receiving related nitrosoureas combined with cranial radiation therapy for intracranial tumors during childhood and adolescence (age 1-16 years). Late onset of reduction in pulmonary function was observed in all long-term survivors. Nitrosourea-induced pulmonary fibrosis may be slowly progressive and can cause death.|For more Human Toxicity Excerpts (Complete) data for LOMUSTINE (11 total), please visit the HSDB record page.

Belustine

Belustine|Cecenu|Ceenu|Table: Lemustine Preparations [Table#6039]

Made in Italy|An alkylating agent of value against both hematologic malignancies and solid tumors.

Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients