Altretamine

210.28

210.28

211-428-4

Q8BIH59O7H

758231|13875

DTXSID4022579

C544

Needles from absolute ethanol|Solid

L - Antineoplastic and immunomodulating agents

2933699090

48.4

2.7

solid

1.1±0.1 g/cm3

172-174 °C

301ºC

159.1±23.2 °C

1.610

H2O: Insoluble

Refrigerator

2.95X10-4 mm Hg at 25 deg C (est)

LD50 in rats, guinea pigs (mg/kg): 350, 255 orally (Jasper)

Henry's Law constant = 1.72X10-8 atm-cu m/mol at 25 °C (est)

pKa1 = 4.88 (imine) (est)

145.6 Ų [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]

Hydroxyl radical reaction rate constant = 8.25X10-12 cu cm/molec-sec at 25 °C (est)

Insoluble in water.

Amines, Phosphines, and Pyridines

HEXAMETHYLMELAMINE neutralizes acids in exothermic reactions to form salts plus water. May be incompatible with isocyanates, halogenated organics, peroxides, phenols (acidic), epoxides, anhydrides, and acid halides. Flammable gaseous hydrogen may be generated in combination with strong reducing agents, such as hydrides.

NONH for all modes of transport

3

22-36/37/38

26-36

OS1050000

Xn

Bulk: The bulk drug is stable at room temperature. Solution: Aqueous solutions at pH 4, 7, and 10 are stable for 24 hours at room temperature (UV).

P261-P305 + P351 + P338

H302-H315-H319-H335

SRP: At the time of review, 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 ALTRETAMINE (8 total), please visit the HSDB record page.

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

|Warning|H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]|P261, P264, P270, P271, P280, P301+P312, P302+P352, P304+P340, P305+P351+P338, P312, P321, P330, P332+P313, P337+P313, P362, P403+P233, 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.

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

RECOMMENDED RESPIRATOR: Where the neat test chemical is weighed and diluted, wear a NIOSH-approved half face respirator equipped with an organic vapor/acid gas cartridge (specific for organic vapors, HCl, acid gas and SO2) with a dust/mist filter. (NTP, 1992)|/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/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Workers who are not protected by the containment environment of a biohazard cabinet should use respiratory protection when handling hazardous drugs. Respiratory protection should be an adjunct to and not a substitute for engineering controls. Surgical masks of all types provide no respiratory protection against powdered or liquid aerosols of hazardous drugs. In situations where workers may be exposed to potential eye contact with hazardous drugs, an appropriate plastic face shield or splash goggles should be worn. /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ During compounding of hazardous drugs (eg, crushing, dissolving, and preparing an ointment), workers should wear low permeability gowns and double gloves. Compounding should take place in a protective area such as a disposable glove box. If compounding must be done in the open, an area away from drafts and traffic must be selected, and the worker should use appropriate respiratory protection. /Antineoplastic agents/

/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/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ The pharmacy should provide access to information on toxicity, treatment of acute exposure (if available), chemical inactivators, solubility and stability of hazardous drugs (including investigational agents) used in the workplace. /Antineoplastic agents/|For more Preventive Measures (Complete) data for ALTRETAMINE (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/

Altretamine therapy is associated with a low rate of serum enzyme elevations, but these are generally mild and self limited, not requiring dose adjustment. Rare instances of clinically apparent acute liver injury attributed to altretamine have been reported, but the clinical features have not been characterized. Altretamine has not been linked specifically to sinusoidal obstruction syndrome, but it is rarely used in high doses in neoplastic disease or in conditioning regimens for bone marrow transplantation, situations in which alkylating agents are commonly associated with this complication.

Blood dyscrasia causing medications (leukopenic and/or thrombocytopenic effects of altretamine may be increased with concurrent or recent therapy if these medications cause the same effects; dosage adjustment of altretamine, if necessary, should be based on blood counts)|Additive bone marrow depression may occur /with radiation therapy/; dosage reduction may be required when two or more bone marrow depressants, including radiation, are used concurrently or consecutively.|Concurrent use of altretamine with monoamine oxidase (MAO) inhibitors, including furazolidone, procarbazine, and selegiline use may result in severe orthostatic hypotension.|Because normal defense mechanisms may be suppressed by altretamine therapy, the patient's antibody response to /a killed/ vaccine may be decreased. The interval between discontinuation of medications that cause immunosuppression and restoration of the patient's ability to respond to the vaccine depends on the intensity and type of immunosuppression-causing medication used, the underlying disease, and other factors; estimates vary from 3 months to 1 year)|For more Interactions (Complete) data for ALTRETAMINE (6 total), please visit the HSDB record page.

LD50 Rat oral 350 mg/kg|LD50 Guinea pig oral 255 mg/kg

94%

While data specific to altretamine were not located(SRC, 2007), 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).

It is not known whether altretamine or its metabolites are distributed into breast milk.

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ ... exposure may be through inadvertent ingestion of the drug on foodstuffs (eg, workers' lunches), inhalation of drug dusts or droplets or direct skin contact. /Antineoplastic agents/

For use as a single agent in the palliative treatment of patients with persistent or recurrent ovarian cancer following first-line therapy with a cisplatin and/or alkylating agent-based combination.

Altretamine is an orally administered alkylating agent, formerly known as hexamethylmelamine, which is currently used as a secondary therapy for advanced ovarian carcinoma. Altretamine therapy has been associated with low rates of serum enzyme elevations during therapy and with rare instances of acute, clinically apparent injury.

Antineoplastic Agents, Alkylating Agents

Antineoplastic|Altretamine is indicated for use as a single agent in the palliative treatment of patients with persistent or recurrent epithelial ovarian cancer following first-line therapy with a cisplatin- and/or alkylating agent-based combination. /Included in US product label/|Altretamine, in combination therapy, is considered reasonable medical therapy at some point in the management of small cell lung carcinoma (Evidence rating: IA). /Not included in US product label/

Secondary malignancies are potential delayed effects of many antineoplastic agents, although it is not clear whether the effect is related to their mutagenic or immunosuppressive action. The effect of dose and duration of therapy is also unknown, although risk seems to increase with long-term use. Although information is limited, available data seem to indicate that the carcinogenic risk is greatest with the alkylating agents.|The bone marrow depressant effects of altretamine may result in an increased incidence of microbial infection, delayed healing, and gingival bleeding. Dental work, whenever possible, should be completed prior to initiation of therapy or deferred until blood counts have returned to normal. Patients should be instructed in proper oral hygiene during treatment, including caution in use of regular toothbrushes, dental floss, and toothpicks.|Adverse events ... indicating the need for medical attention /occurring/ at an incidence more frequent: Anemia (unusual tiredness); leukopenia (fever or chills; cough or hoarseness; lower back or side pain; painful or difficult urination); neurotoxicity, including central nervous system (CNS) effects (anxiety; clumsiness; confusion; dizziness; mental depression; weakness; seizures); neurotoxicity, including peripheral neuropathy (numbness in arms or legs); thrombocytopenia (unusual bleeding or bruising; black, tarry stools; blood in urine or stools; pinpoint red spots on skin). Incidence /occurring/ rarely Hepatotoxicity; skin rash or itching.|/Altretamine is/ contraindicated in patients with known sensitivity to altretamine.|For more Drug Warnings (Complete) data for ALTRETAMINE (11 total), please visit the HSDB record page.

Altretamine is a novel antineoplastic agent. The precise mechanism by which altretamine exerts its cytotoxic effect is unknown, although a number of theoretical possibilities have been studied. Structurally, altretamine resembles the alkylating agent triethylenemelamine, yet in vitro tests for alkylating activity of altretamine and its metabolitics have been negative. Altretamine has been demonstrated to be efficacious for certain ovarian tumors resistant to classical alkylating agents. Metabolism of altretamine is a requirement of cytotoxicity. Synthetic monohydroxymethylmelamines, and products of altretamine metabolism, in vitro and in vivo, can form covalent adducts with tissue macromolecules including DNA, but the relevance of these reactions to antitumor activity is unknown.

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.)

Human urinary metabolites were Ndemethylated homologues of altretamine with <1% unmetabolized altretamine excreted at 24 hours.|Rapidly and well-absorbed following oral administration; however, because of rapid hepatic metabolism, peak plasma concentrations are variable.|... The inter-hand intrapatient variability of the bioavailability of altretamine after oral administration represents an important drawback for effective clinical use of this drug. The variability appears to be mostly related to the first-pass effect and therefore may be overcome by intravenous administration of the drug. Attempts to administer the drug intravenously have not been successful in the past...|Because it is highly lipid-soluble, altretamine is distributed to tissues with a high lipid component (e.g., omentum and subcutaneous tissues).|Protein binding: Free fractions: Altretamine: 6%; Pentamethylmelamine: 25%; Tetramethylmelamine: 50%.|For more Absorption, Distribution and Excretion (Complete) data for ALTRETAMINE (10 total), please visit the HSDB record page.

Biotransformation /is/ Hepatic. Metabolism is required for activity. Altretamine undergoes rapid and extensive demethylation, catalyzed by cytochrome P450 enzymes.|The covalent binding of hexamethylmelamine (HMM) and its metabolites was studied in liver, tumor, blood, kidney, spleen, lung, brain, heart, and small intestine after a single ip injection of 2,4,6-14C-hexamethylmelamine (50 mg/kg) to C57Bl/6J female mice bearing 20-day-old M5076/73A ovarian cancer. ... HMM metabolism was also studied. Tissue distribution of pentamethylmelamine (PMM), 2,2,4,6-tetramethylmelamine (TMM), and 2,4,6-trimethylmelamine (TriMM) was determined at the three times considered. At 2 hr the drug was already extensively metabolized, TriMM being the major metabolite among those determined.|... In all animal species, including humans, altretamine undergoes oxidative N-demethylation with the formation of hydroxymethyl derivatives as intermediates. Hydroxymethylmelamines are believed to be responsible for the cytotoxic and antitumour activity of the drug. ...|In the rat 40% of a dose of 25 mg/kg of hexamethylmelamine or pentamethylmelamine was excreted in the urine as metabolites, more than 95% of which were N2N4-dimethylmelamine and monomethylmelamine. Biliary excretion of hexamethylmelamine or pentamethylmelamine and their N-demethylated metabolites accounted for less than 2% of the administered dose. Only 3% was excreted with the feces, suggesting that there is intestinal reabsorption of a portion of the methylmelamines passing into the bile. Conjugates of methylmelamines with glucuronic acid or sulphate were found only in minute quantities in the urine or bile of rats treated with hexamethylmelamine or pentamethylmelamine. However a conjugation product of pentamethylmelamine, of as yet unknown nature, is a major metabolite after pentamethylmelamine treatment.

4.7-10.2 hours|Elimination /half-life/-Beta-phase: Range, 4.7 to 10.2 hours.

The precise mechanism by which altretamine exerts its cytotoxic effect is unknown although it is classified as an alkylating anti-neoplastic agent. Through this mechanism, the drug is metabolized into alkylating agents by N-demethylation. These alkylating species consequently damage tumor cells.|The exact mechanism of action is unknown. Although altretamine structurally resembles an alkylating agent, it has not been found to have alkylating activity in vitro. There is some evidence that it may inhibit DNA and RNA synthesis.|The hexamethylmelamine analogue trimelamol (tris-hydroxymethyl[trimethyl]melamine) and its equicytotoxic stable analogues CB 7547, CB 7639 and CB 7669 have been used to clarify the mechanism of action for the N-(hydroxymethyl)melamines as antitumour agents. Two main mechanisms have been proposed and explored: (i) formation of a reactive iminium species forming covalent adducts with DNA; and (ii) local formaldehyde release leading to cytotoxic damage. 32P-postlabelling and thermal denaturation experiments showed these compounds to be interactive with cytosine and guanine. Trimelamol gave rise to DNA-interstrand crosslinks in naked plasmid DNA and in cultured cell lines, whereas the analogues failed to do so under a variety of experimental conditions. Along with our observations that cell lines with acquired resistance to the N-(hydroxymethyl)melamines showed no significant cross-resistance to classical bifunctional alkylating agents, DNA crosslinking may play only a minor role in their mechanism of action. In cultured cell lines treatment with formaldehyde, trimelamol and CB 7639 gave rise to high levels of DNA-protein crosslinks with a gradual disappearance over a 24 hr period. Along with ... earlier observations that resistance to trimelamol coincides with cross-resistance to formaldehyde, /investigators/ conclude that formaldehyde-release may be an important factor in their cytotoxicity. Further, the cytotoxicity of trimelamol or formaldehyde towards human ovarian cancer cells was not influenced by glutathione depletion. /N-(hydroxymethyl)melamines/

SYMPTOMS: Nausea and vomiting, possibly parathesia, numbness, depression, confusion, drowsiness and hallucinations. ACUTE/CHRONIC HAZARDS: This chemical is toxic. (NTP, 1992)

EYES: First check the victim for contact lenses and remove if present. Flush victim's eyes with water or normal saline solution for 20 to 30 minutes while simultaneously calling a hospital or poison control center. Do not put any ointments, oils, or medication in the victim's eyes without specific instructions from a physician. IMMEDIATELY transport the victim after flushing eyes to a hospital even if no symptoms (such as redness or irritation) develop. SKIN: IMMEDIATELY flood affected skin with water while removing and isolating all contaminated clothing. Gently wash all affected skin areas thoroughly with soap and water. If symptoms such as redness or irritation develop, IMMEDIATELY call a physician and be prepared to transport the victim to a hospital for treatment. INHALATION: IMMEDIATELY leave the contaminated area; take deep breaths of fresh air. If symptoms (such as wheezing, coughing, shortness of breath, or burning in the mouth, throat, or chest) develop, call a physician and be prepared to transport the victim to a hospital. Provide proper respiratory protection to rescuers entering an unknown atmosphere. Whenever possible, Self-Contained Breathing Apparatus (SCBA) should be used; if not available, use a level of protection greater than or equal to that advised under Protective Clothing. INGESTION: DO NOT INDUCE VOMITING. If the victim is conscious and not convulsing, give 1 or 2 glasses of water to dilute the chemical and IMMEDIATELY call a hospital or poison control center. Be prepared to transport the victim to a hospital if advised by a physician. If the victim is convulsing or unconscious, do not give anything by mouth, ensure that the victim's airway is open and lay the victim on his/her side with the head lower than the body. DO NOT INDUCE VOMITING. IMMEDIATELY transport the victim to a hospital. (NTP, 1992)

Emergency and supportive measures. Maintain an open airway and assist ventilation if necessary. Treat coma, seizures, hypotensin, and arrhythmias if they occur. Treat nausea and vomiting with metoclopramide and fluid loss caused by gastroenteritis with intravenous crystalloid fluids. /Antineoplastic agents/|Bone marrow depression should be treated with the assistance of an experienced hematologist or oncologist. /Antineoplastic agents/|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. /Antineoplastic agents/|Enhanced elimination. Because of the rapid intracellular incorporation of most of these agents, dialysis and other extracorporeal removal procedures are generally not effective. /Antineoplastic agents/

/CASE REPORTS/ This case report describes a 76-year-old white woman who was found to have ovarian cancer and underwent chemotherapy with hexamethylmelamine. After 34 months of therapy, she developed an acute myelocytic leukemia.

Altretamine

U.S.: 50 mg (Rx) [Hexalen (lactose)]. Canada: 50 mg (Rx) [Hexalen].

Analyte: altretamine; matrix: chemical identification; procedure: infrared absorption spectrophotometry with comparison to standards|Analyte: altretamine; matrix: chemical identification; procedure: retention time of the major peak of the liquid chromatogram with comparison to standards|Analyte: altretamine; matrix: chemical purity; procedure: liquid chromatography with detection at 227 nm and comparison to standards|Analyte: altretamine; matrix: pharmaceutical preparation (capsule); procedure: infrared absorption spectrophotometry with comparison to standards (chemical identification)|For more Analytic Laboratory Methods (Complete) data for ALTRETAMINE (6 total), please visit the HSDB record page.

Analyte: altretamine; matrix: blood (plasma, serum); procedure: high-performance liquid chromatography with ultraviolet detection at 230 nm; limit of quantitation: 150 ng/mL|Analyte: altretamine; matrix: blood (whole), urine; procedure: high-performance liquid chromatography with ultraviolet detection at 229.9 nm; limit of quantitation: 150 ng/mL

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