truely [40:0.4) of the unchanged drug in the plasma pool, minimal tissue partitioning or binding, and availability of greater than 90% of the systemic drug levels in the unbound form suggest that it could be removed using conventional peritoneal or hemodialysis. 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. Dexrazoxane Description Dexrazoxane for Injection, a cardioprotective agent for use in conjunction with doxorubicin, is a sterile, pyrogen-free lyophilizate intended for intravenous administration. Chemically, Dexrazoxane is (+)-( S )-4,4 -Propylenedi-2,6-piperazinedione. The structural formula is as follows: Structural Formula C 11 H 16 N 4 O 4 M.W. 268.27 Dexrazoxane, an intracellular chelating agent, is a derivative of EDTA. Dexrazoxane is a whitish crystalline powder that melts at 191 to 197 C. It is sparingly soluble in water and 0.1 N HCl, slightly soluble in ethanol and methanol, and practically insoluble in nonpolar organic solvents. The pK a is 2.1. Dexrazoxane has an octanol/water partition coefficient of 0.025 and degrades rapidly above a pH of 7.0. Each 250 mg vial contains Dexrazoxane hydrochloride equivalent to 250 mg Dexrazoxane. Hydrochloric Acid, NF is added for pH adjustment. When reconstituted as directed with 25 mL of Sterile Water for Injection, USP, each mL contains: 10 mg Dexrazoxane. The pH of the resultant solution is 1.0 to 3.0. Each 500 mg vial contains Dexrazoxane hydrochloride equivalent to 500 mg Dexrazoxane. Hydrochloric Acid, NF is added for pH adjustment. When reconstituted as directed with 50 mL of Sterile Water for Injection, USP, each mL contains: 10 mg Dexrazoxane. The pH of the resultant solution is 1.0 to 3.0. The reconstituted Dexrazoxane for injection solutions prepared from Sterile Water for Injection, USP, are intended for further dilution with Lactated Ringer s Injection, USP, for rapid intravenous drip infusion. DO NOT ADMINISTER VIA AN INTRAVENOUS PUSH [see Dosage and Administration (2.1 , 2.3)] . Dexrazoxane - Clinical Pharmacology Mechanism of Action The mechanism by which Dexrazoxane for injection exerts its cytoprotective activity is not fully understood. Dexrazoxane is a cyclic derivative of EDTA that penetrates cell membranes. Results of 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. Pharmacokinetics The pharmacokinetics of Dexrazoxane have been studied in advanced cancer patients with normal renal and hepatic function. The pharmacokinetics of Dexrazoxane can be adequately described by a two-compartment open model with first-order elimination. Dexrazoxane has been administered as a 15 minute infusion over a dose range of 60 to 900 mg/m 2 with 60 mg/m 2 of doxorubicin, and at a fixed dose of 500 mg/m 2 with 50 mg/m 2 doxorubicin. The disposition kinetics of Dexrazoxane are dose-independent, as shown by linear relationship between the area under plasma concentration-time curves and administered doses ranging from 60 to 900 mg/m 2 . The mean peak plasma concentration of Dexrazoxane was 36.5 mcg/mL at 15- minute after intravenous administration of 500 mg/m 2 dose of Dexrazoxane for injection over 15 to 30 minutes prior to the 50 mg/m 2 doxorubicin dose. The important pharmacokinetic parameters of Dexrazoxane are summarized in Table 2: Table 2: SUMMARY OF MEAN (%CV a ) Dexrazoxane PHARMACOKINETIC PARAMETERS AT A DOSAGE RATIO OF 10:1 OF Dexrazoxane FOR INJECTION:DOXORUBICIN Dose Dose Number of Elimination Plasma Renal bVolume of Doxorubicin (mg/m2) Dexrazoxane (mg/m2) Subjects Half-Life (h) Clearance (L/h/m2) Clearance (L/h/m2) Distribution (L/m2) 50 500 10 2.5 (16) 7.88 (18) 3.35 (36) 22.4 (22) 60 600 5 2.1 (29) 6.25 (31) 22.0 (55) a Coefficient of variation b Steady-state volume of distribution Distribution Following a rapid distributive phase (0.2 to 0.3 hours), Dexrazoxane reaches post-distributive equilibrium within two to four hours. The estimated mean steady-state volume of distribution of Dexrazoxane is 22.4 L/m 2 after 500 mg/m 2 of Dexrazoxane for injection dose followed by 50 mg/m 2 of doxorubicin, suggesting distribution throughout total body water (25 L/m 2 ). In vitro studies have shown that Dexrazoxane is not bound to plasma proteins. Metabolism Qualitative metabolism studies with Dexrazoxane have confirmed the presence of unchanged drug, a diacid-diamide cleavage product, and two monoacid-monoamide ring products in the urine of animals and man. The metabolite levels were not measured in the pharmacokinetic studies. Excretion Urinary excretion plays an important role in the elimination of Dexrazoxane. Forty-two percent of a 500 mg/m 2 dose of Dexrazoxane for injection was excreted in the urine. Renal clearance averages 3.35 L/h/m 2 after the 500 mg/m 2 Dexrazoxane for injection dose followed by 50 mg/m 2 of doxorubicin. Specific Populations Pediatric Pharmacokinetics following Dexrazoxane for injection administration have not been evaluated in pediatric patients. Effect of Renal Impairment The pharmacokinetics of Dexrazoxane were assessed following a single 15-minute IV infusion of 150 mg/m 2 of Dexrazoxane for injection. Dexrazoxane clearance was reduced in subjects with renal dysfunction. Compared with controls, the mean AUC 0-inf value was two-fold greater in subjects with moderate (CL CR 30-50 mL/min) to severe (CL CR] FEATURED: CAR-T Cell Therapy Overview Mechanism of Action KTE-C19 Studies KTE-C19 Cancer Targets Adverse Events Manufacturing Drug Status Rx Availability Prescription only D Pregnancy Category Positive evidence of risk N/A CSA Schedule Not a controlled drug Approval History Drug history at FDA Manufacturer Mylan Pharmaceuticals Inc. Drug Class Miscellaneous uncategorized agents Related Drugs miscellaneous uncategorized agents Accutane , isotretinoin , anagrelide , Esbriet , Claravis Cardiomyopathy Prophylaxis Zinecard , More... Extravasation hyaluronidase , Hylenex , Amphadase , Totect , Vitrase , More... Dexrazoxane Rating No Reviews - Be the first! No Reviews - Be the first! Not Rated - Be the first! music
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