Dexrazoxane

268.27

268.27

048L81261F

169780

DTXSID3040647

C1333

Crystals from aqueous methanol/ether|Whitish crystalline powder

V03AF02|V - Various

2933599090

98.8

-1.4

white to off-white

1.3±0.1 g/cm3

193 °C

531.5°C at 760 mmHg

275.3±30.1 °C

1.540

H2O: Sparingly soluble ;DMSO: >20mg/mL

Desiccate at RT

2.0X10-15 mm Hg at 25 deg C /Estimated/

D +11.35° (c = 5 in DMF)

2.1None

Henry's law constant = 2.1X10-19 atm-cu m/mole at 25 °C /Estimated/

2.1|pKa = 2.1

Hydroxyl radical reaction rate constant = 2.0X10-10 cu cm/molec-sec at 25 °C /Estimated/

UN 2811 6.1 / PGIII

3

36/37/38

26-36

TL6390000

Xi

Bulk: A sample stored at 60 °C showed less than 1% decomposition after seven days (HPLC). Solution: A 10 mg/mL solution in water at 28 °C showed 10% and 42% decomposition in 1 day and 6 days respectively (HPLC).

P261-P305 + P351 + P338

H315-H319-H335

SRP: The most favorable course of action is to use an alternative chemical product with less inherent propensity for occupational exposure or environmental contamination. Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in soil or water; effects on animal, aquatic, and plant life; and conformance with environmental and public health regulations.

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

|Warning|H315 (97.67%): Causes skin irritation [Warning Skin corrosion/irritation]|P261, P264, P271, P280, P302+P352, P304+P340, P305+P351+P338, P312, P321, P332+P313, P337+P313, P362, P403+P233, P405, and P501|Aggregated GHS information provided by 43 companies from 5 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Exercise caution in the handling nad preparation of the reconstituted solution; the use of the gloves is recommended. If dexrazoxane powder or solutions contact the skin or mucosa, immediately wash with soap and water.|The usual precautions of handling antineoplastic agents should be observed with dexrazoxane hydrochloride. The manufacturer recommends that protective gloves be used during the handling and preparation of dexrazoxane hydrochloride injection. If contact with skin or mucous membranes occurs, the affected area should be washed immediately and thoroughly with soap and water.

Intraperitoneal, mouse LD10 = 500 mg/kg. Intravenous, dog LD10 = 2 gm/kg.

There was no significant change in the pharmacokinetics of doxorubicin (50 mg/sq m ) and its predominant metabolite, doxorubicinol, in the presence of dexrazoxane (500 mg/sq m ) in a crossover study in cancer patients.

Very low (< 2%)

Dexrazoxane's production and use as a cardioprotective agent(1) may result in its release to the environment through various waste streams(SRC).

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 24(SRC), determined from a log Kow of 0.025(2) and a regression-derived equation(3), indicates that dexrazoxane is expected to have very high mobility in soil(SRC). Volatilization of dexrazoxane from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 2.1X10-19 atm-cu m/mole(SRC), using a fragment constant estimation method(4). Dexrazoxane is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 2.0X10-15 mm Hg(SRC), determined from a fragment constant method(5). Biodegradation data were not available(SRC, 2005).|AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 24(SRC), determined from a log Kow of 0.025(2) and a regression-derived equation(3), indicates that dexrazoxane 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 2.1X10-19 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 3.2(SRC), from an estimated log Kow(2) and a regression-derived equation(6), suggests the potential for bioconcentration in aquatic organisms is low (SRC). Biodegradation data were not available(SRC, 2005).|ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), dexrazoxane, which has an estimated vapor pressure of 2.0X10-15 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase dexrazoxane may be removed from the air by wet and dry deposition(SRC). Dexrazoxane does not contain chromophores that absorb light at wavelengths >290 nm and would not be expected to be susceptible to direct photolysis by sunlight(SRC).

Dexrazoxane is not expected to undergo hydrolysis in the environment due to the lack of hydrolyzable functional groups(1). Dexrazoxane does not contain chromophores that absorb light at wavelengths >290 nm and would not be expected to be susceptible to direct photolysis by sunlight(SRC).

An estimated BCF of 3.2 was calculated for dexrazoxane(SRC), using a log Kow of 0.025(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).

The Koc of dexrazoxane is estimated as 24(SRC), using a log Kow of 0.025(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that dexrazoxane is expected to have very high mobility in soil.

The Henry's Law constant for dexrazoxane is estimated as 2.1X10-19 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that dexrazoxane is expected to be essentially nonvolatile from water surfaces(2). Dexrazoxane is not expected to volatilize from dry soil surfaces(SRC) based upon a an estimated vapor pressure of 2.0X10-15mm Hg(SRC), determined from a fragment constant method(3).

Occupational exposure to dexrazoxane may occur through inhalation and dermal contact with this compound at workplaces where dexrazoxane is produced or used. Exposure to the drug among the general population may be limited to those being administered dexrazoxane (a cardioprotective agent). (SRC)

For reducing the incidence and severity of cardiomyopathy associated with doxorubicin administration in women with metastatic breast cancer who have received a cumulative doxorubicin hydrochloride dose of 300 mg/m^2 and would benefit from continued doxorubicin therapy. Also approved for the treatment of extravasation from intravenous anthracyclines.|FDA Label|Savene is indicated for the treatment of anthracycline extravasation.|Drug: Dexrazoxanehydrochloride

Cardioprotectant|Dexrazoxane is indicated for reducing the incidence and severity of cardiomyopathy associated with the administration of doxorubicin in women with metastatic breast cancer who have received a cumulative doxorubicin dose of 300 mg/sq m of body surface and who would benefit from continued therapy with doxorubicin. /Included in US product labeling/|/Exptl Ther:/ Accidental extravasation of chemotherapy containing anthracycline often causes mutilating complications as a result of extensive tissue necrosis. Treatment therefore consists of extensive surgical debridement. We present the case of a 41-year-old woman with breast cancer who experienced extravasation of epirubicin. She was treated with an intravenous infusion of dexrazoxane for three successive days and recovered without surgical treatment and only slightly dysaesthesia in the surrounding tissue. Although infusion of dexrazoxane for this indication is still experimental we consider it a promising treatment for patients who have accidental extravasation of anthracyclines.

Dexrazoxane is not indicated for use at the time of initiation of doxorubicin therapy. Cconcurrent use of dexrazoxane with the initiation of fluorouracil, doxorubicin, and cyclophosphamide (FAC) therapy is not recommended because of possible interference with the antitumor efficacy of the regimen.|FDA Pregnancy Risk Category: C /RISK CANNOT BE RULED OUT. Adequate, well controlled human studies are lacking, and animal studies have shown risk to the fetus or are lacking as well. There is a chance of fetal harm if the drug is given during pregnancy; but the potential benefits may outweigh the potential risk./|Dexrazoxane may add to the myelosuppression caused by chemotherapeutic agents.|Do not use with chemotherapy regimens that do not contain anthracycline.|For more Drug Warnings (Complete) data for DEXRAZOXANE (8 total), please visit the HSDB record page.

Dexrazoxane is a cardioprotective agent for use in conjunction with doxorubicin indicated for reducing the incidence and severity of cardiomyopathy associated with doxorubicin administration in women with metastatic breast cancer who have received a cumulative doxorubicin dose. Patients receiving anthracycline-derivative antineoplastic agents may experience three types of cardiotoxicity: acute transient type; chronic, subacute type (related to cumulative dose and has a more indolent onset later on); and a late-onset type that manifests years after therapy, mainly in patients that have been exposed to the drug as a child. Although the exact mechanism of anthracycline-induced cardiotoxicity is not known, it has shown to exert a variety of actions that may result in the development of cardiotoxicity. In animals, anthracyclines cause a selective inhibition of cardiac muscle gene expression for α-actin, troponin, myosin light-chain 2, and the M isoform of creatine kinase. This may lead to myofibrillar loss associated with anthracycline-induced cardiotoxicity. Anthracyclines may also cause myocyte damage via calcium overload, altered myocardial adrenergic function, release of vasoactive amines, and proinflammatory cytokines. Furthermore, it has been suggested that the main cause of anthracycline-induced cardiotoxicity is associated with free-radical damage to DNA. The drugs intercalate DNA, chelate metal ions to produce drug-metal complexes, and generate superoxide radicals via oxidation-reduction reactions. Anthracyclines also contain a quinone structure that can undergo reduction via NADPH-dependent reactions to produce a semiquinone free radical that initiates a cascade of superoxide and hydroxide radical generation. Chelation of metal ions, particularly iron, by anthracyclines results in an anthracycline-metal complex that catalyzes the generation of reactive oxygen free radicals. This complex is a powerful oxidant that can initiate lipid peroxidation in the absence of oxygen free radicals. The toxicity induced by antrhacyclines may be exacerbated in cardiac cells, as these cells do not possess sufficient amounts of certain enzymes (e.g., superoxide dismutase, catalase, glutathione peroxidase) involved in detoxifying free radicals and protecting the cells from subsequent damage.

Substances that inhibit or prevent the proliferation of NEOPLASMS. (See all compounds classified as Antineoplastic Agents.)|Agents that have a strengthening effect on the heart or that can increase cardiac output. They may be CARDIAC GLYCOSIDES; SYMPATHOMIMETICS; or other drugs. They are used after MYOCARDIAL INFARCT; CARDIAC SURGICAL PROCEDURES; in SHOCK; or in congestive heart failure (HEART FAILURE). (See all compounds classified as Cardiotonic Agents.)|Compounds that inhibit the activity of DNA TOPOISOMERASE II. Included in this category are a variety of ANTINEOPLASTIC AGENTS which target the eukaryotic form of topoisomerase II and ANTIBACTERIAL AGENTS which target the prokaryotic form of topoisomerase II. (See all compounds classified as Topoisomerase II Inhibitors.)

IV administration results in complete bioavailability.|Urinary excretion plays an important role in the elimination of dexrazoxane. Forty-two percent of the 500 mg/m2 dose of dexrazoxane was excreted in the urine.|9 to 22.6 L/m^2|7.88 L/h/m2 [dose of 50 mg/m2 Doxorubicin and 500 mg/m2 Dexrazoxane]|After intravenous administration, the drug is rapidly distributed into tissue fluids, the highest concentrations of the parent drug and its hydrolysis product being found in hepatic and renal tissues.|The mean peak plasma concentration of dexrazoxane was 36.5 mcg/mL at the end of the 15-minute infusion of a 500 mg/sq m doxorubicin dose. Following a rapid distributive phase, dexrazoxane reaches post-distributive equilibrium within 2 to 4 hours.|The estimated steady-state volume of distribution of dexrazoxane suggests its distribution primarily in the total body water (25 L/sq m ).|In vitro studies have shown that /dexrazoxane/ is not bound to plasma proteins.|For more Absorption, Distribution and Excretion (Complete) data for DEXRAZOXANE (9 total), please visit the HSDB record page.

Dexrazoxane is hydrolysed by the enzyme dihydropyrimidine amidohydrolase in the liver and kidney to active metabolites that are capable of binding to metal ions.|Metabolic products include the unchanged drug, a diacid-diamide cleavage product, and two monoacid-monoamide ring products of unknown concentrations.|In vitro studies have shown dexrazoxane to be hydrolysed by DHPase in liver and kidney, but not heart extracts.|/This/ study was undertaken to determine the metabolism of dexrazoxane (ICRF-187) to its one-ring open hydrolysis products and its two-rings opened metal-chelating product ADR-925 in cancer patients with brain metastases treated with high-dose etoposide. In this phase I/II trial dexrazoxane was used as a rescue agent to reduce the extracerebral toxicity of etoposide. Dexrazoxane and its one-ring open hydrolysis products were determined by HPLC and ADR-925 was determined by a fluorescence flow injection assay. The two one-ring open hydrolysis intermediates of dexrazoxane appeared in the plasma at low levels upon completion of dexrazoxane infusion and then rapidly decreased with half-lives of 0.6 and 2.5 hr. A plasma concentration of 10 micro M ADR-925 was also detected at the completion of the dexrazoxane i.v. infusion period, indicating that dexrazoxane was rapidly metabolized in vivo. A plateau level of 30 micro M ADR-925 was maintained for 4 hr and then slowly decreased. The pharmacokinetics of dexrazoxane were found to be similar to other reported data in other settings and at lower doses. The rapid appearance of ADR-925 in plasma may make ADR-925 available to be taken up by heart tissue and bind free iron. These results suggest that the dexrazoxane intermediates are enzymatically metabolized to ADR-925 and provide a pharmacodynamic basis for the antioxidant cardioprotective activity of dexrazoxane.

2.5 hours|The distribution half-life has ranged from about 12 to 60 minutes ...|Elimination - 2.5 hours.

The mechanism by which dexrazoxane exerts its cardioprotective activity is not fully understood. Dexrazoxane is a cyclic derivative of EDTA that readily penetrates cell membranes. Results of laboratory studies suggest that dexrazoxane (a prodrug) is converted intracellularly to a ring-opened bidentate chelating agent that chelates to free iron and interferes with iron-mediated free radical generation thought to be responsible, in part, for anthracycline-induced cardiomyopathy. It should be noted that dexrazoxane may also be protective through its inhibitory effect on topoisomerase II.|The mechanism of action of dexrazoxane's cardioprotective activity is not fully understood. Dexrazoxane is a cyclic derivative of ethylenediamine tetra-acetic acid (EDTA) that readily penetrates cell membranes. Laboratory studies suggest that dexrazoxane is converted intracellularly to a ring-opened chelating agent that interferes with iron-mediated free radical generation thought to be responsible, in part, for anthracycline-induced cardiomyopathy.

There is no known antidote for dexrazoxane. Instances of suspected overdose should be managed with good supportive care until resolution of myelosuppression and related conditions is complete. Management of overdose should include treatment of infections, fluid regulation, and maintenance of nutritional requirements.|Basic treatment: Establish a patent airway. 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 normal saline 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 ... . /Poison A and B/|Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in respiratory arrest. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poison A and B/

/HUMAN EXPOSURE STUDIES/ There have been no instances of drug overdose in the clinical studies ... The maximum dose administered during the cardioprotective trials was 1000 mg/m 2 every three weeks.

ADR 529

(+)-form of razoxane|Information available in 2005 indicated that Dexrazoxane was used in the manufacture of pharmaceutical preparations in the following countries: Austria, Brazil, Canada, Czech Republic, Denmark, France, Hungary, Israel, Italy, Mexico, Poland, USA (1,2)|Information available in 2005 indicated that Dexrazoxane hydrochloride was used in the manufacture of pharmaceutical preparations in the following countries: Argentina, Brazil, Denmark, France, Hungary, Italy, Poland, Romania, Russian Federation, United States (1) /Dexrazoxane Hydrochloride/

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