Fotemustine

315.69

315.69

UPB2NN83AR|QY93P3GN94

Solid

L - Antineoplastic and immunomodulating agents

97.3

0.68 (est)

light yellow

1.4±0.1 g/cm3

85 °C

188 °C(lit.)

104 °F

1.524

H2O: ≥1mg/mL

2-8°C

9.1X10-7 mm Hg at 25 deg C (est)

Henry's Law constant = 4.1X10-15 atm-cu m/mol at 25 °C (est)

Hydroxyl radical reaction rate constant = 4.9X10-11 cu cm/molecule-sec at 25 °C (est)

III

6.1(b)

UN 3336 3/PG 2

3

40

36/37

Xn

P281

H351

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/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ The contaminated filters must be removed, bagged in thick plastic and prepared for disposal in a hazardous waste dump site or incinerator licensed by the Environmental Protection Agency (EPA). /Antineoplastic agents/|For more Disposal Methods (Complete) data for Fotemustine (8 total), please visit the HSDB record page.

|Warning|H351 (97.44%): Suspected of causing cancer [Warning Carcinogenicity]|P201, P202, P281, P308+P313, P405, and P501|Aggregated GHS information provided by 39 companies from 2 notifications to the ECHA C&L Inventory.

It is recommended to wear a protective mask and gloves during the preparation of the solution. ...|/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/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Class 100 clean-air work stations, both horizontal and vertical airflow (with no containment characteristics), are inappropriate engineering controls for handling hazardous drugs because they provide no personnel protection and permit environmental contamination. Although there are no engineering controls designed specifically for the safe handling of hazardous chemicals as sterile products, Class II contained vertical-flow biological safety cabinets (biohazard cabinets) have been adopted for this use. Biohazard cabinetry is, however, designed for the handling of infectious agents, not hazardous chemicals. ... Based on design, ease of use, and cost considerations, Class II contained-vertical-flow biohazard cabinetry is currently recommended for use in preparing sterile doses of hazardous drugs. Class II cabinetry design and performance specifications are defined in NSF Standard 49. Biological safety cabinets selected for use with hazardous drugs should meet NSF Standard 49 specifications to ensure the maximum protection from these engineering controls. /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Workers should wear powder free, disposable surgical latex gloves of good quality when preparing hazardous drugs. Selection criteria for gloves should include thickness (especially at the fingertips where stress is the greatest), fit, length, and tactile sensation. ... The practice of double gloving is supported by research that indicates that many glove materials vary in drug permeability even within lots; therefore, double gloving is recommended. ... In general, surgical latex gloves fit better, have appropriate elasticity for double gloving and maintaining the integrity of the glove-gown interface, and have sufficient tactile sensation (even during double gloving) for stringent aseptic procedures. ... Powdered gloves should be avoided. /Antineoplastic agents/|For more Personal Protective Equipment (PPE) (Complete) data for Fotemustine (6 total), please visit the HSDB record page.

/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/

Avoid any contact with skin, mucosa and any absorption of the reconstituted solution. ... In case of splashing profusely rinse with water. Contaminated equipment should be disposed of safely.|/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 Fotemustine (20 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/

Pulmonary toxicity (acute respiratory distress syndrome) has been observed after the sequential combination dacarbazine and fotemustine, likely due to O6 alkyltransferase inhibition provoked by a high dose of dacarbazine. This mode of combination should be avoided.

As no studies have been conducted, it is not recommended to use fotemustine in children in the present state of knowledge.

Antineoplastic[The Merck Index, Fourteenth Edition (2006)|The indication "disseminated malignant melanoma", including cerebral metastases, is currently the preferential indication for fotemustine, administered alone or in combination with other anticancer agents.|/EXPERIMENTAL THERAPY:/ ... Patients with progressive glioblastoma multiforme after radiotherapy plus concomitant and/or adjuvant temozolomide received three-weekly doses (100-75 mg/ sq m) of fotemustine followed, after a 5-week rest, by fotemustine (100 mg/sq m) every 3 weeks for < or =1 year. Forty-three patients (29 M, 14 F; median age 51 years, range 34-68; median KPS 90) were enrolled. Progression-free survival at 6 months (PFS-6) was 20.9% (95% CI: 9-33%); three patients (7.1%) had partial response (PR); 15 (34.9%), disease stabilization (SD). The median survival was 6 months (95% CI: 5-7). O6-Methylguanine-DNA methyltransferase (MGMT) promoter status was methylated in 8 (18.6%) and unmethylated in 26 (60.5%) and not assessable in 9 (20.9%) patients, respectively. Disease control was 75% versus 34.6% in methylated and unmethylated MGMT patients (P = 0.044); no significant difference was found between groups for PFS-6 and survival. Grade 3 and 4 thrombocytopenia and neutropenia were observed in 20.9 and 16.3% of patients, during the induction phase, and in 0 and 9.5% patients during the maintenance phase, respectively. The findings of the present trial, that evaluate fotemustine in a homogeneous population, may represent a new benchmark for nitrosourea activity. Moreover, this is the first study to evaluate correlation between MGMT promoter status and outcome of fotemustine for relapsing glioblastoma multiforme previously treated with radiotherapy and temozolomide.|/EXPERIMENTAL THERAPY:/ ... This study investigated the impact of hepatic arterial chemotherapy in patients with ocular and cutaneous melanoma. In a retrospectively analyzed observational study, 36 consecutive patients with hepatic metastases from ocular or cutaneous melanoma were assigned for surgical hepatic port-catheter implantation. Fotemustine was delivered weekly for a 4-week period, followed by a 5-week rest and a maintenance period every 3 weeks until progression. Overall survival, response and toxicity were analysed and compared. After port-catheter implantation 30/36 patients were finally treated (18 with ocular and 12 with cutaneous melanoma). A median of 8 infusions per patient were delivered (range 3-24). 30% thrombocytopenia grade >or=3, 7% neutropenia grade >or= 3 but no nausea or vomiting grade >or= 3 were encountered. Nine out of 30 patients achieved partial remission, 10/30 stable disease; 11/30 patients were progressive. Median survival for all treated patients was 14 months. Partial remission and stable disease were associated with a survival advantage compared to progressive disease (19 vs. 5 months). No significant difference in survival was observed for ocular versus cutaneous melanoma. Serum LDH was a significant predictor of both response and survival. Hepatic arterial fotemustine chemotherapy was well tolerated. Meaningful response and survival rates were achieved in ocular as well as cutaneous melanoma. Careful patient selection in consideration of extra-hepatic involvement is crucial for the effectiveness of this treatment. Independent from the primary melanoma, it is debatable if patients with highly elevated serum-LDH may benefit from this approach.|For more Therapeutic Uses (Complete) data for Fotemustine (6 total), please visit the HSDB record page.

Because of the known mutagenic and carcinogenic potential of nitrosoureas, administration to pregnant women is contraindicated. Contraindicated in lactation.|As no studies have been conducted, it is not recommended to use fotemustine in children in the present state of knowledge.|It is recommended not to administer the product to patients who have already received chemotherapy in the previous 4 weeks (or 6 weeks in the case of previous treatment with a nitrosourea).|Treatment can only be considered when the platelet count and/or granulocyte count is acceptable, with minimum values of 100,000/cu mm and 2000/cu mm respectively.|For more Drug Warnings (Complete) data for Fotemustine (10 total), please visit the HSDB record page.

Substances that inhibit or prevent the proliferation of NEOPLASMS. (See all compounds classified as Antineoplastic Agents.)

The pharmacokinetics and metabolism of intravenously infused (14)C-fotemustine (about 100 mg/sq m) were examined in 2 cancer patients. Plasma levels of radioactivity increased to a maximum of 4.1 and 5.5 ug equivalents per g when the infusion stopped then declined triexponentially with mean half-lives of about 1/2, 10 and 80 hr for the initial, mid and terminal phases, respectively. Plasma levels of intact drug were lower, with maximum levels of 1.1 and 2.8 micrograms/ml, and declined monophasically with a half-life of about 24 min. Plasma clearance was high (1426 and 764 mL/min) with the volume of distribution based on areas of 47.7 and 26.4 L. Most of the radioactivity was eliminated in urine (50.1 and 61.3%) over 7 days with smaller amounts in the feces (6.8 and 0.3%) and only minimal quantities (under 0.1%) as expired carbon dioxide. ...|After administration in /humans/ of the drug labelled with (14)C on the chloroethyl group, the radioactivity is slowly eliminated with a terminal half-life of 83 hours. About 50 to 60% of the radioactivity administered is detected in the urine, 30 to 40% of which is detected during the first 24 hours, but the unchanged molecule is not detected in the urine. 5% of the radioactivity is eliminated in the feces and less than 0.2% in the form of expired CO2.|In /humans/, during administration by intravenous infusion, the plasma levels of fotemustine are close to the steady-state value after 45 minutes. After the end of the infusion, plasma levels go down rapidly and three hours later the molecule can no longer be detected in the blood.|In animals, the tissue distribution is rapid and very extensive. Fotemustine crosses the blood-brain barrier (2 to 5 minutes after bolus administration in the rat, it is detected in the brain at sufficiently high levels to be active).

The pharmacokinetics and metabolism of intravenously infused (14)C-fotemustine (about 100 mg/sq m) were examined in 2 cancer patients. ... Metabolites of fotemustine were identified as chloroethanol and N-nitroso-1-imidazolone-ethyl-diethylphosphonate in plasma and as 1-hydantoin-ethyl-diethyl-phosphonate and acetic acid in urine.

After administration in /humans/ of the drug labelled with (14)C on the chloroethyl group, the radioactivity is slowly eliminated with a terminal half-life of 83 hours.|The pharmacokinetics and metabolism of intravenously infused (14)C-fotemustine (about 100 mg/sq m) were examined in 2 cancer patients. Plasma levels of radioactivity increased to a maximum of 4.1 and 5.5 ug equivalents per g when the infusion stopped then declined triexponentially with mean half-lives of about 1/2, 10 and 80 hr for the initial, mid and terminal phases, respectively. ...

... The mode of cell death in 11 melanoma cell lines upon exposure to temozolomide and fotemustine /is determined/. ... For both temozolomide and fotemustine apoptosis is the dominant mode of cell death. The contribution of necrosis to total cell death varied between 10 and 40%. The O(6)-methylguanine-DNA methyltransferase (MGMT) activity in the cell lines was between 0 and 1100 fmol mg(-1) protein, and there was a correlation between MGMT activity and the level of resistance to temozolomide and fotemustine. MGMT inactivation by O(6)-benzylguanine sensitized all melanoma cell lines expressing MGMT to temozolomideand fotemustine-induced apoptosis, and MGMT transfection attenuated the apoptotic response. This supports that O(6)-alkylguanines are critical lesions involved in the initiation of programmed melanoma cell death. One of the cell lines (MZ7), derived from a patient subjected to DTIC therapy, exhibited a high level of resistance to temozolomide without expressing MGMT. This was related to an impaired expression of MSH2 and MSH6. The cells were not cross-resistant to fotemustine. Although these data indicate that methylating drug resistance of melanoma cells can be acquired by down-regulation of mismatch repair, a correlation between MSH2 and MSH6 expression in the different lines and temozolomide sensitivity was not found. Apoptosis in melanoma cells induced by temozolomide and fotemustine was accompanied by double-strand break formation (as determined by H2AX phosphorylation) and caspase-3 and -7 activation as well as PARP cleavage. For temozolomide, double-strand breaks correlated significantly with the apoptotic response, whereas for fotemustine a correlation was not found. Melanoma lines expressing p53 wild-type were more resistant to temozolomide and fotemustine than p53 mutant melanoma lines, which is in marked contrast to previous data reported for glioma cells treated with temozolomide. Overall, the findings are in line with the model that in melanoma cells temozolomide-induced O(6)-methylguanine triggers the apoptotic (and necrotic) pathway through double-strand breaks, whereas for chloroethylating agents apoptosis is triggered in a more complex manner.

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/

/CASE REPORTS/ Hematological toxicity characterized by delayed and reversible neutropenia and/or thrombocytopenia is an adverse effect observed in 40% of patients receiving fotemustine. ... The case of a 66-year-old man with metastatic malignant melanoma treated with fotemustine as monotherapy /is reported/. A severe persistent and prolonged thrombocytopenia occurred, so that chemotherapy was discontinued. Bone marrow involvement was excluded. The physician should be aware of this prolonged thrombocytopenia secondary to fotemustine, so that it may be recognized early and not attributed erroneously to tumor evolution. This observation could be substantial for the design of combination regimens with fotemustine and other myelotoxic drugs in pretreated melanoma patients.|/CASE REPORTS/ ... The case of a female patient in partial response following 10 courses of fotemustine and featuring a rapidly progressing mental impairment /is reported/. The clinical and radiological patterns were consistent with a fotemustine-related toxic encephalopathy, as described previously in a recent report. The physician should be aware of this neurological complication of fotemustine, so that it may be recognized early and not attributed erroneously to tumour evolution.|/CASE REPORTS/ The cases of 2 women who developed myelodysplasia 2 and 9 months after treatment /with/ dacarbazine and fotemustine for visceral metastases of a malignant melanoma /is reported/. The frequency of these rare complications is probably underestimated because of the rapid unfavorable outcome of metastatic malignant melanoma. /The investigators/ were unable to determine whether dacarbazine, fotemustine or their combination was incriminated in this complication. Risk could be reduced by carefully determining the cumulative doses of these antimitotics.|/GENOTOXICITY/ The aim of this study was to investigate the in vitro genotoxic effects of the anticancer drugs fotemustine and vinorelbine on human lymphocytes and to determine individual and sex-related responses to these drugs. Fotemustine is a DNA-alkylating drug while vinorelbine is a semi-synthetic Vinca alkaloid. The study was carried out with twenty independent healthy donors for each drug. ... Tthe ability of these drugs to induce chromosome aberrations and sister chromatid exchanges as well as effect on the mitotic index in cultured human lymphocytes /was tested/. Fotemustine was shown to induce chromosome aberrations and sister chromatid exchanges at all concentrations tested (2, 4 and 8 ug/ml) in a dose-dependent manner. Additionally it also decreased the mitotic index in a similar dose-dependent manner. ... Two-way analyses of variance were used to compare the individual and gender-related susceptibilities to fotemustine and vinorelbine with respect to the chromosome aberration, sister chromatid exchange and mitotic index values. The results indicated that individuals in fotemustine treatment groups showed different genotoxic responses with respect to chromosome aberration and sister chromatid exchange induction and additional findings indicated a gender-specific response in this group. ...|/GENOTOXICITY/Fotemustine is ...clastogenic /in/ in vitro human lymphocyte assay.

diethyl-1-(3-(2-chloroethyl)-3-nitrosoureido)ethylphosphonate

208 mg powder for injection, Muphoran (Servier Lab (Aust) Pty Ltd, Server Lab (NZ) Ltd.

Experimental