シクロホスファミド

log Kow = 0.63

0.8

0.63

0.63

LIQUEFIES ON LOSS OF ITS WATER OF CRYSTALLIZATION

Crystalline solid

10 to 50 mg/mL at 73 °F (NTP, 1992)

Soluble. 1-5 g/100 mL at 23 °C

1 in 25 parts water

1 in 1 parts alcohol

Slightly soluble in benzene, carbon tetrachloride; very slightly soluble in ether and acetone

Soluble in chloroform, dioxane and glycols and insoluble in carbon tetrachloride and carbon disulfide.

Breast Feeding; Lactation; Milk, Human; Antineoplastic Agents; Alkylating Agents

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

Cytotoxic medicines

Danger

H301 (63.2%): Toxic if swallowed [Danger Acute toxicity, oral]

P203, P260, P264, P264+P265, P270, P280, P301+P316, P301+P317, P305+P354+P338, P317, P318, P319, P321, P330, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 68 reports by companies from 8 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Danger

H301: Toxic if swallowed [Danger Acute toxicity, oral]

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

Combustible. Gives off irritating or toxic fumes (or gases) in a fire.

SYMPTOMS: Symptoms of exposure to this compound may include nausea, vomiting, leukopenia, thrombocytopenia, alopecia and anorexia. Other symptoms may include pigmentation of the skin, oral mucosal ulcerations and sterile hemorrhagic cystitis. It can cause non-specific dermatitis, pigmentation of the nails, regrowth of hair, anemia, hematuria, fibrosis of the ovaries, gonadal suppression resulting in amenorrhea or azoospermia, hemorrhagic colitis and jaundice. It can also cause damage to the hair follicles, dizziness of short duration, transverse ridging of the nails and hepatic toxicity. Secondary neoplasia and nephrotoxicity have been reported. Other symptoms may include irritation of the skin, gastrointestinal disturbances and hepatic dysfunction. High doses over a prolonged period can cause interstitial pulmonary fibrosis. Other symptoms of exposure may include granulocytopenia, myocardial damage, interstitial pneumonia and hypoplasia of all elements of bone marrow. It has been known to cause blurred vision, pulmonary fibrosis, cardiomyopathy and sterility. Fetal abnormalities can occur if ingested while pregnant. Eye contact can cause transient blurring of vision, dry eye syndrome, viral and other keratitis and severe keratoconjunctivitis associated with graft-versus-host disease leading to scarring of the corneas. It may also cause lymphocytopenia.

A skin, eye, and respiratory tract irritant; May cause effects on the blood, bladder, CNS, lungs, and heart; Carcinogenic to humans and may cause reproductive toxicity and heritable genetic damage; [ICSC] A severe skin irritant; Common side effects at therapeutic doses include alopecia, sterility, gastrointestinal disturbances, thrombocytopenia, anemia, leukopenia, and life-threatening hemorrhagic cystitis; Rare side effects include hepatitis, interstitial pneumonitis, and pulmonary fibrosis; Teratogenic; [HSDB] May cause serious eye injury; Can be absorbed through skin; [MSDSonline]

The major hazards encountered in the use and handling of cyclophosphamide stem from its toxicologic properties. Exposure to this odorless, white, crystalline powder may occur from its manufacture, formulation, or distribution for use as an antineoplastic drug. Effects from exposure may include fever, chills, shortness of breath, dizziness, fatigue, headache, nausea, hemorrhagic colitis, hepatitis, leukopenia, and pneumonitis or interstitial pulmonary fibrosis. Cyclophosphamide has been indicated as a human carcinogen (Group 1) by the International Agency for Research on Cancer (IARC). Exposure should be controlled by mechanical ventilation with high-efficiency particulate arrestors (HEPA) or charcoal filters to minimize the amount of the substance in exhausted air. In activities or situations where over-exposure may occur, wear protective clothing and a carefully fitted respirator. Potentially exposed skin should be thoroughly washed with soap and water. Contaminated clothing should be removed and discarded or left at the work site for cleaning before reuse. Smoking, eating, and drinking should be prohibited in cyclophosphamide work areas. Cyclophosphamide should be stored and transported in securely sealed glass bottles or ampoules, which are in turn placed inside strong screw-cap or snap-top containers. Also, the material should be stored cool (below 30 °C), dry, and shielded from light. This substance is a good candidate for disposal by rotary kiln, or fluidized bed forms of incineration.

Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392).

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. Cyclophosphamide (50-18-0) is listed as known to be a human carcinogen.[Available from, as of July 31, 2009: http://ntp.niehs.nih.gov/ntp/roc/eleventh/profiles/s052cycl.pdf]

Anderson D et al; Mutat Res 330 (1-2): 115-81 (1995). Cyclophosphamide: Review of its Mutagenicity for an Assessment of Potential Germ Cell Risks.

U058; As stipulated in 40 CFR 261.33, when cyclophosphamide, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to Federal and/or State hazardous waste regulations. Also defined as a hazardous waste is any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5).

CYCLOPHOSPHAMIDE is sensitive to exposure to light (darkens). Also sensitive to oxidation. Aqueous solutions may be kept for a few hours at room temperature, but hydrolysis occurs at temperatures above 86 °F. Solutions in DMSO, 95% ethanol or acetone are stable for 24 hours under normal lab conditions. Incompatible with benzyl alcohol. Undergoes both acid and base hydrolysis at extreme pHs (NTP, 1992)

Fires involving this material can be controlled with a dry chemical, carbon dioxide or Halon extinguisher. (NTP, 1992)

Use water spray, powder, foam, carbon dioxide.

Fresh air, rest.

Remove contaminated clothes. Rinse skin with plenty of water or shower.

Rinse with plenty of water for several minutes (remove contact lenses if easily possible).

Rinse mouth. Refer for medical attention .

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.

Cyclophosphamide should be preserved in tight containers, at a temperature between 2 & 32 °C.

Protect from light.

PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practicable to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion proof refrigerator or freezer (depending on chemicophysical properties ...) that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen & date it was acquired ... Facilities for dispensing ... should be contiguous to storage area. /Chemical Carcinogens/

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 available 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/

/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/

SMALL SPILLS AND LEAKAGE: If you spill this chemical, you should dampen the solid spill material with water, then transfer the dampened material to a suitable container. Use absorbent paper dampened with water to pick up any remaining material. Seal your contaminated clothing and the absorbent paper in a vapor-tight plastic bag for eventual disposal. Wash all contaminated surfaces 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.

Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number U058, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste.

A potential candidate for rotary kiln incineration at a temperature range of 820 to 1,600 °C and residence times of seconds for liquids and gases, and hours for solids. A potential candidate for fluidized bed incineration at a temperature range of 450 to 980 °C and residence times of seconds for liquids and gases, and longer for solids.

/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 CYCLOPHOSPHAMIDE (9 total), please visit the HSDB record page.

Personal protection: particulate filter respirator adapted to the airborne concentration of the substance. Sweep spilled substance into covered sealable containers. If appropriate, moisten first to prevent dusting. Carefully collect remainder. Then store and dispose of according to local regulations.

PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food & beverage containers or utensils, & the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, & rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/

PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should remove their outdoor clothes & wear protective suits (preferably disposable, one piece & close fitting at ankles & wrists), gloves, hair covering & overshoes. ... clothing should be changed daily but ... discarded immediately if obvious contamination occurs ... /also,/ workers should shower immediately. In chemical laboratory, gloves & gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, & disposable plastic aprons might provide addnl protection. If gowns are of distinctive color, this is a reminder that they should not be worn outside of lab. /Chemical Carcinogens/

PRECAUTIONS FOR "CARCINOGENS": ... Operations connected with synth & purification ... should be carried out under well ventilated hood. Analytical procedures ... should be carried out with care & vapors evolved during ... procedures should be removed. ... Expert advice should be obtained before existing fume cupboards are used ... & when new fume cupboards are installed. It is desirable that there be means for decreasing the rate of air extraction, so that carcinogenic powders can be handled without ... powder being blown around the hood. Glove boxes should be kept under negative air pressure. Air changes should be adequate, so that concn of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/

PRECAUTIONS FOR "CARCINOGENS": Vertical laminar flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, & contaminated air plenums that are under positive pressure are leak tight. Horizontal laminar flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) & label fixed to it, giving date of test & avg air flow measured. This test should be repeated periodically & after any structural changes. /Chemical Carcinogens/

For more Preventive Measures (Complete) data for CYCLOPHOSPHAMIDE (29 total), please visit the HSDB record page.

In a cross-sectional study, the urine of 20 hospital workers occupationally exposed to cyclophosphamide and 21 unexposed controls was monitored for excretion of cyclophosphamide. During the week in which samples were collected, most of the workers handled cyclophosphamide fewer than 5 times and the amount handled each time ranged from 100-1000 mg (mean +/- 350 mg). All workers claimed to have taken regular safety precautions, ie, at least wearing gloves during handling. The drug was identified in 5 cases (range: 0.7-2.5 ug excreted/24 hr urine). A clear relationship between cyclophosphamide handling and urinary detection was shown. 4 of 5 persons with detectable urinary cyclophosphamide had handled cyclophosphamide 10 times or more during the week.

Cyclophosphamide (along with ifosfamide) was detected in the urine of 8 pharmacy technicians and nurses (along with ifosfamide) at amounts ranging from <0.001-0.5 ug(1). 21 nurses and pharmacy personnel in a Munich, Germany hospital were monitored for compound exposure; on days when 3,900 mg/l cyclophosphamide was mixed, 12 of 31 urine samples tested positive with concentrations ranging from 3.5 to 38 ug/24 hr urine(2).

PRIOR TREATMENT WITH ALLOPURINOL SIGNIFICANTLY PROLONGS /THE HALF-LIFE OF CYCLOPHOSPHAMIDE/.

CYCLOPHOSPHAMIDE MAY ENHANCE NEUROMUSCULAR BLOCKADE PRODUCED BY SUCCINYLCHOLINE BY INHIBITING ITS METABOLISM.

THE ENZYME INHIBITOR SKF 525-A, WHICH INCREASES THE TERATOGENICITY OF CYCLOPHOSPHAMIDE, CAUSED AN INCREASE IN THE CONCN OF CYCLOPHOSPHAMIDE IN THE MOUSE EMBRYO & ALSO CAUSED A DECREASE IN METABOLITE FORMATION AFTER ADMIN OF CYCLOPHOSPHAMIDE TO PREGNANT MICE.

Cultured human osteosarcoma cell lines (OST strain and HT 1080) and specimens obtained during surgery on humans (osteosarcoma, malignant fibrous histiocytoma, rhabdomyosarcoma, epithelioid sarcoma, mesenchymal chondrosarcoma, synovial sarcoma, leiomyosarcoma, and malignant giant cell tumor) were used to study the synergistic effect of caffeine on anticancer drugs, including cyclophosphamide as its active form 4-hydroxyperoxycyclophosphamide. Cell concentrations were 10,000 per dish for the osteosarcoma strain, 50,000 per dish for the HT 1080 strain, and 100,000 to 500,000 for the fresh cells. After a 1 hour exposure of the cells to the anticancer agent, caffeine was added to the top layer for the subsequent 10 day to 3 week combined exposure. Treatment with 3.0 ug/ml (1/10 of the usual peak plasma concentration) cyclophosphamide alone showed colony inhibition of 14.2% in the OST strain and 8.5% in the HT 1080 strain. Addition of 0.2 mM caffeine showed synergism, 27.8% and 56.2% inhibition, respectively. When 2 mM caffeine was used with cyclophosphamide, colony inhibition was 57.1% in the OST strain. At a cyclophosphamide concentration of 0.3 ug/ml and either 0.2 or 2 mM caffeine, synergism still was observed. Using fresh human tumor specimens with cyclophosphamide alone (3.0 ug/ml) 4 of 18 specimens showed positive sensitivity. With 2 mM caffeine exposure in combination, 8 of 18 specimens (44.4%) showed a significant synergistic effect; of these, 7 showed positive sensitivity. An additive effect was observed in one specimen and a subadditive effect in 3 specimens. Continuous exposure to 0.2 mM caffeine in combination resulted in significant synergism in specimens. For comparison, caffeine alone at 0.2 mM produced colony inhibition of 9.2% (OST strain) and 12.5% (HT 10890 strain) in the cultured cells; at 2.0 mM, 15.0% (OST strain) and 100.0% (HT 1080 strain). In fresh sarcoma specimens, caffeine alone at 2 mM produced inhibition of 0.0% to 48.2% (mean, 19.1%) and there was no case with positive sensitivity.

For more Interactions (Complete) data for CYCLOPHOSPHAMIDE (29 total), please visit the HSDB record page.

Mild and transient elevations in serum aminotransferase levels are found in up to 43% of patients with cancer who are treated with cyclophosphamide. The abnormalities are generally asymptomatic and transient and do not require dose modification. Enzyme elevations are more common with higher doses and with intravenous therapy. In some instances, marked elevations arise warranting dose modification or discontinuation of cyclophosphamide (Case 3).

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 52(SRC), determined from a log Kow of 0.63(2) and a regression-derived equation(3), indicates that cyclophosphamide is expected to have high mobility in soil(SRC). Volatilization of cyclophosphamide from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 1.4X10-11 atm-cu m/mole(SRC), using a fragment constant estimation method(4). Cyclophosphamide is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 4.4X10-5 mm Hg(SRC), determined from a fragment constant method(5). Cyclophosphamide has been shown to be non-biodegradable using laboratory-scale sewage treatment studies(6), suggesting that biodegradation in soil may be slow(SRC).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 52(SRC), determined from a log Kow of 0.63(2) and a regression-derived equation(3), indicates that cyclophosphamide is not expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 1.4X10-11 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). The neutral hydrolysis calculated half-life for cyclophosphamide at 25 °C is 41 days(5). According to a classification scheme(6), an estimated BCF of 3(SRC), from its log Kow(2) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Cyclophosphamide has been shown to be non-biodegradable using laboratory-scale sewage treatment studies(8).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), cyclophosphamide, which has an estimated vapor pressure of 4.4X10-5 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 cyclophosphamide 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 5.5 hrs(SRC), calculated from its rate constant of 7.0X10-11 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(3). Particulate-phase cyclophosphamide may be removed from the air by wet and dry deposition(SRC). Cyclophosphamide is susceptible to light(4) and therefore the potential for direct photolysis exists(SRC).

Occupational hepatotoxin - Secondary hepatotoxins: the potential for toxic effect in the occupational setting is based on cases of poisoning by human ingestion or animal experimentation.

The main areas of concern regarding the adverse side effects of cyclophosphamide are associated with bladder and gonadal toxicity. Common adverse side effects reported in several studies and clinical trials involving the use of cyclophosphamide include hemorrhagic cystitis, amenorrhea, myelosuppression, alopecia, and spells of nausea and vomiting. Chronic or recurrent hemorrhagic cystitis is a side effect of particular clinical significance and may arise from the use of cyclophosphamide without adequate hydration or concurrent administration of mesna. The limiting factor in cyclophosphamide dosage in the treatment of neoplasms and immune-inflammatory conditions is urinary tract toxicity. The severity of hemorrhagic cystitis may vary from light pinkish to exsanguinating hemorrhage. Other urinary tract symptoms include increased urinary frequency and urgency due to urinary clot retention, nocturia, and dysuria.As previously outlined, acrolein is the principal-agent involved in the precipitation of hemorrhagic cystitis. The metabolite causes heightened vascular fragility and dilatation, irritation of the bladder mucosa, the release of pro-inflammatory mediators like tumor necrosis factor-alpha, IL-1 beta, and endogenous nitric oxide leading to hemorrhage. Prolonged exposure to acrolein may increase the severity of hemorrhagic cystitis. Due to the dose and time-dependent nature of the severity of this symptom, th recommendation is that the patient intake adequate fluids to force diuresis and reduce exposure of urothelium to acrolein. Continuous bladder irrigation and mesna use are also helpful in the management of drug-induced hemorrhagic cystitis.

The substance can be absorbed into the body by ingestion and by inhalation of its aerosol.

After oral administration, peak concentrations occur at one hour.

Clinicians need to consider possible side effects, interactions, and associated toxicities should before administering cyclophosphamide. As an immunosuppressive agent, cyclophosphamide toxicity correlates with the development of leukopenia, thrombocytopenia, and anemia. These conditions may lead to the occurrence of recurrent infections and may interfere with wound healing. Other symptoms of cyclophosphamide toxicity include GI disturbances, alopecia, hemorrhagic cystitis, renal tubular necrosis, infertility, pulmonary fibrosis, and cardiotoxicity. The manifestation of cyclophosphamide toxicity becomes aggravated by concurrent use of phenobarbital, other myelosuppressives, radiation, and succinylcholine.

Alkylating agents work by three different mechanisms: 1) attachment of alkyl groups to DNA bases, resulting in the DNA being fragmented by repair enzymes in their attempts to replace the alkylated bases, preventing DNA synthesis and RNA transcription from the affected DNA, 2) DNA damage via the formation of cross-links (bonds between atoms in the DNA) which prevents DNA from being separated for synthesis or transcription, and 3) the induction of mispairing of the nucleotides leading to mutations.

Diarrhoea. Dizziness. Nausea. Vomiting. Abdominal pain.

Adverse reactions reported most often include neutropenia, febrile neutropenia, fever, alopecia, nausea, vomiting, and diarrhea.

The following link will take the user to the National Toxicology Program (NTP) Test Agent Search Results page, which tabulates all of the "Standard Toxicology & Carcinogenesis Studies", "Developmental Studies", and "Genetic Toxicity Studies" performed with this chemical. Clicking on the "Testing Status" link will take the user to the status (i.e., in review, in progress, in preparation, on test, completed, etc.) and results of all the studies that the NTP has done on this chemical. [http://ntp-apps.niehs.nih.gov/ntp_tox/index.cfm?fuseaction=ntpsearch.searchresults&searchterm=50-18-0]

The following link will take the user to the National Toxicology Program (NTP) Test Agent Search Results page, which tabulates all of the "Standard Toxicology & Carcinogenesis Studies", "Developmental Studies", and "Genetic Toxicity Studies" performed with this chemical. Clicking on the "Testing Status" link will take the user to the status (i.e., in review, in progress, in preparation, on test, completed, etc.) and results of all the studies that the NTP has done on this chemical. /Cyclophosphamide monohydrate/ [http://ntp-apps.niehs.nih.gov/ntp_tox/index.cfm?fuseaction=ntpsearch.searchresults&searchterm=6055-19-2]

PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning ... /cytogenetic and/or other/ tests that might become useful or mandatory. /Chemical Carcinogens/

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ There is no method available for routine monitoring of personnel for evidence of hazardous drug exposure. Tests for the presence of mutagens or chromosomal damage are not drug specific and are of value only in controlled studies. Chemical analysis of urine for the presence of hazardous drugs at the sensitivity level needed to detect occupational exposure is limited to a few drugs and is not yet commercially available. /Antineoplastic agents/

Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392).

U058; As stipulated in 40 CFR 261.33, when cyclophosphamide, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to Federal and/or State hazardous waste regulations. Also defined as a hazardous waste is any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5).

Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 10 lb or 4.54 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b).

L - Antineoplastic and immunomodulating agents

QL - Antineoplastic and immunomodulating agents

L01AA01

Cyclophosphamide is an antineoplastic in the class of alkylating agents and is used to treat various forms of cancer. Alkylating agents are so named because of their ability to add alkyl groups to many electronegative groups under conditions present in cells. They stop tumor growth by cross-linking guanine bases in DNA double-helix strands - directly attacking DNA. This makes the strands unable to uncoil and separate. As this is necessary in DNA replication, the cells can no longer divide. In addition, these drugs add methyl or other alkyl groups onto molecules where they do not belong which in turn inhibits their correct utilization by base pairing and causes a miscoding of DNA. Alkylating agents are cell cycle-nonspecific. Alkylating agents work by three different mechanisms all of which achieve the same end result - disruption of DNA function and cell death.

Alkylating agents work by three different mechanisms: 1) attachment of alkyl groups to DNA bases, resulting in the DNA being fragmented by repair enzymes in their attempts to replace the alkylated bases, preventing DNA synthesis and RNA transcription from the affected DNA, 2) DNA damage via the formation of cross-links (bonds between atoms in the DNA) which prevents DNA from being separated for synthesis or transcription, and 3) the induction of mispairing of the nucleotides leading to mutations.

The chemotherapeutic alkylating agents have in common the property of becoming strong electrophiles through the formation of carbonium ion intermediates or of transition complexes with the target molecules. These reactions result in the formation of covalent linkages by alkylation of various nucleophilic moieties such as phosphate, amino, sulfhydryl, hydroxyl, carboxyl, & imidazole groups. The chemotherapeutic & cytotoxic effects are directly related to the alkylation of DNA. The 7 nitrogen atom of guanine is particularly susceptible to the formation of a covalent bond with bifunctional alkylating agents & may well represent the key target that determines their biological effects. It must be appreciated, however, that other atoms in the purine & pyrimidine bases of DNA- particularly, the 1 & 3 nitrogens of adenine, the 3 nitrogen of cytosine, & the 6 oxygen of guanine- also may be alkylated, as will be the phosphate atoms of the DNA chains & amino & sulfhydryl groups of proteins. /Alkylating agents/

Cyclophosphamide can be used to cause immunologically mediated regression of the immunogenic, cyclophosphamide-resistant L5178Y lymphoma in syngeneic and semisyngeneic mice (B6D2F1 (C57BL/6 x DBA/2) females). In order to cause tumor regression it was necessary to give cyclophosphamide (125-200 mg/kg of body wt, iv shortly before or shortly after tumor implantation. Regardless of whether cyclophosphamide was given before or after tumor implantation, tumor regression was associated with the presence in the spleen of an incr number of Lyt-2+ T-cells capable of passively transferring immunity to tumor bearing recipients. This augmented level of immunity was sustained throughout the period of tumor regression. In contrast, a lower level of concomitant immunity generated by control tumor bearers decayed after day 12 of tumor growth. Because the therapeutic effect of cyclophosphamide could be inhibited by passive transfer of L3T4+ T-cells from normal donor mice it is apparent that the therapeutic effect of cyclophosphamide is based on its ability to preferentially destroy L3T4+ suppressor T-cells. These putative precursor suppressor T-cells were regenerated 4 days after being destroyed by cyclophosphamide.

These studies enable the pattern of emesis and nausea for 3 days following high-dose cyclophosphamide to be described and give some insight into the mechanisms of emesis which may be operating. Nausea and vomiting induced by cyclophosphamide-based chemotherapy has long latency of onset (8-13 hr) and continues for at least 3 days. These findings are of particular importance as many of these patients receive chemotherapy as outpatients and emphasize the need for appropriate anti-emetic prophylaxis for patients at home. Ondansetron was extremely effective over this time in the control of emesis and nausea. These results suggest that high-dose cyclophosphamide-induced emesis over days 1-3 is largely mediated via 5-hydroxytryptamine (5-HT) and 5-HT3 receptors.

The most likely mechanism by which cyclophosphamide augments immune responses relates to preferential elimination of suppressor and relative sparing of effector and helper cells. Thus, precursors and mature murine suppressor cells are very sensitive to cyclophosphamide whereas the mature effector cells are relatively insensitive ... . Cyclophosphamide induced immunological regression of murine leukemia is reversed by the infusion of normal spleen cells as a source of precursors of suppressor cells ... . Memory and helper T cells are relatively resistant to the cytotoxic effect of cyclophosphamide ... . NK activity against YAC lymphoma targets by non T and non B cells is depressed by cyclophosphamide ... .

3-12 hours

Maximal concns in plasma are achieved 1 hr after oral admin, & the half-life in plasma is about 7 hr.

Metabolism and activation occurs at the liver. 75% of the drug is activated by cytochrome P450 isoforms, CYP2A6, 2B6, 3A4, 3A5, 2C9, 2C18, and 2C19. The CYP2B6 isoform is the enzyme with the highest 4-hydroxylase activity. Cyclophosphamide undergoes activation to eventually form active metabolites, phosphoramide mustard and acrolein. Cyclophosphamide appears to induce its own metabolism which results in an overall increase in clearance, increased formation of 4-hydroxyl metabolites, and shortened t1/2 values following repeated administration.

... /Cyclophosphamide/ is activated by the hepatic cytochrome P450 system. Cyclophosphamide is first converted to 4-hydroxycyclophosphamide, which is in a steady state with the acyclic tautomer aldophosphamide. In vitro studies with human liver microsones & cloned P450 isoenzymes have shown that cyclophosphamide is activated by the CYP2B group of P450 isoenzymes... . 4-hydroxycyclophosphamide may be oxidized further by aldehyde oxidase either in liver or in tumor tissue & perhaps by other enzymes, yielding the metabolites carboxyphosphamide & 4-ketocyclophsphamide, neither of which possesses significant biological activity. It appears that hepatic damage is minimized by theses secondary reactions, whereas significantl amoutns of the active metabolies, such as 4-hydroxycyclophosphamide & its tautomer, aldophosphamed, are transported to the target sites by the circulatory system. In tumor cells, the aldophosphamide cleaves spontaneously, generating stoichiometric amounts of phosphoramide mustard & acrolein. The former is believed to be responsible for antitumor effects. The latter cmpd may be responsible for the hemorrhagic cystitis seen during therapy with cyclophosphamide. Cystitis can be reduced in intensity or prevented by the pareneteral admin of mesna, a sulfhydryl cmpd that reacts readily with acrolein in the acid environment of the urinary tract. ... Urinary & fecal recovery of unchanged cyclophosphamide is minimal after iv admin. Maximal concns in plasma are achieved 1 hr after oral admin, & the half-life in plasma is about 7 hr.

SHEEP WERE ORALLY DOSED WITH CYCLOPHOSPHAMIDE. IN COLLECTED URINE, 2 METABOLITES WERE OBSERVED AND CHARACTERIZED AS O-(2-CARBOXYETHYL)-N,N-BIS (2-CHLOROETHYL)PHOSPHORODIAMIDATE & 2-(BIS (2-CHLOROETHYL)AMINO)TETRAHYDRO-2H-1,3,2-OXAZOPHOSPHORINE 2,4-DIOXIDE (4-KETOCYCLOPHOSPHAMIDE).

A REACTIVE METABOLITE, N,N-BIS-(2-CHLOROETHYL)PHOSPHORODIAMIDIC ACID, WHICH POSSESSES POTENT ALKYLATING & CYTOTOXIC PROPERTIES, HAS RECENTLY BEEN ISOLATED FROM THE OXYGENATION PRODUCTS OF CYCLOPHOSPHAMIDE AND MOUSE LIVER MICROCHROMOSOMES.

Cyclophosphamide is well absorbed orally, and peak plasma levels appear about one hour after oral use. It is also administered intravenously. This drug is metabolized in the liver to the cytotoxic metabolite, 4-hydroxycyclophosphamide, which is in equilibrium with the acyclic tautomer, aldophosphamide. Although the major fraction of these metabolites is oxidized further to inactive products, some aldophosphamide is converted to phophoramidemustard, which alkylates DNA, and to acrolein.

For more Metabolism/Metabolites (Complete) data for CYCLOPHOSPHAMIDE (8 total), please visit the HSDB record page.

6UXW23996M

CYCLOPHOSPHAMIDE ANHYDROUS

Mechanisms of Action [MoA] - Alkylating Activity

Established Pharmacologic Class [EPC] - Alkylating Drug

Cyclophosphamide anhydrous is an Alkylating Drug. The mechanism of action of cyclophosphamide anhydrous is as an Alkylating Activity.

Agents that suppress immune function by one of several mechanisms of action. Classical cytotoxic immunosuppressants act by inhibiting DNA synthesis. Others may act through activation of T-CELLS or by inhibiting the activation of HELPER CELLS. While immunosuppression has been brought about in the past primarily to prevent rejection of transplanted organs, new applications involving mediation of the effects of INTERLEUKINS and other CYTOKINES are emerging.

Chemical agents that increase the rate of genetic mutation by interfering with the function of nucleic acids. A clastogen is a specific mutagen that causes breaks in chromosomes.

Drugs that are used to treat RHEUMATOID ARTHRITIS.

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)

Agents that destroy bone marrow activity. They are used to prepare patients for BONE MARROW TRANSPLANTATION or STEM CELL TRANSPLANTATION.

After oral administration, peak concentrations occur at one hour.

Cyclophosphamide is eliminated primarily in the form of metabolites. 10-20% is excreted unchanged in the urine and 4% is excreted in the bile following IV administration.

30-50 L

Total body clearance = 63 ± 7.6 L/kg.

Cyclophosphamide is well absorbed orally.

PLACENTAL TRANSFER OF (14)CARBON-CYCLOPHOSPHAMIDE HAS BEEN DEMONSTRATED IN MICE; AND A POSITIVE CORRELATION BETWEEN THE ALKYLATION OF EMBRYONIC DNA AND PRODUCTION OF CONGENITAL ABNORMALITIES IN MICE HAS BEEN REPORTED. A SIMILAR CORRELATION HAS BEEN FOUND FOR NUCLEAR-DNA-DEPENDENT RNA POLYMERASES IN RAT EMBRYOS. IN MOST SPECIES, CYCLOSPHSPHAMIDE IS RAPIDLY ABSORBED, METABOLIZED AND EXCRETED. IN RATS, THE SPECIFIC ACTIVITY IN TISSUES IS HIGHEST WITHIN 20-30 MIN FOLLOWING IP INJECTION; UP TO 75% OF THE RADIOACTIVITY IS EXCRETED WITHIN 5-8 HR. /MONOHYDRATE/

Used as defleecing agent for sheep and as an antineoplastic and immunosuppressant drug; [Merck Index] An alkylating agent; [HSDB]

Therap Cat: Antineoplastic

Immunosupressive

Antineoplastic for treatment of leukemia, etc; tested for use in chemical shearing of sheep and as an insect chemosterilant.

MEDICATION

MEDICATION (VET)

Cyclophosphamide can be prepared by treating N,N-bis(B-chloroethyl)-phosphamide dichloride with propanolamine in the presence of trimethylamine and dioxane.

Prepn: H. Arnold et al., Naturwiss 45, 64 (1957); eidem, Nature 181, 931 (1958); H. Arnold, F. Bourseaux, Angew Chem. 70, 539 (1958).

CYCLOPHOSPHAMIDE IS SUPPLIED AS 25 & 50 MG TABLETS & AS A POWDER (100 TO 2000 MG) IN STERILE VIALS.

Grade: USP, measured as containing 95.0 - 105.0% active ingredient calculated as the monohydrate, 5.7 - 6.8% max. water content, 0.002% max. heavy metals, and producing an aqueous solution (1 in 100) at pH 3.9 - 7.1.

Available as 25 and 50 mg tablets ... and in vials for injection in amounts of 100, 200 or 500 mg measured as containing 90.0 - 110.0% of the stated amount of anhydrous cyclophosphamide.