Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/4159
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Zinecard (Kit)
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The recommended dosage ratio of ZINECARD:doxorubicin is 10:1 (eg, 500 mg/mZINECARD:50 mg/mdoxorubicin). In patients with moderate to severe renal dysfunction (creatinine clearance values<40 mL/min), the recommended dosage ratio of ZINECARD:doxorubicin is 5:1 (eg. 250 mg/mZINECARD:50 mg/mdoxorubicin). Creatinine clearance can be determined from a 24-hour urinary creatinine collection or estimated using the Crockroft-Gault equation (assuming stable renal function): CL=[140���age (years)]��weight (kg) {��0.85 for female patients} 72��serum creatinine (mg/dL) Since a doxorubicin dose reduction is recommended in the presence of hyperbilirubinemia, the ZINECARD dosage should be proportionately reduced (maintaining the 10:1 ratio) in patients with hepatic impairment. ZINECARD must be reconstituted with 0.167 Molar (M/6) Sodium Lactate Injection, USP, to give a concentration of 10 mg ZINECARD for each mL of sodium lactate. The reconstituted solution should be given by slow I.V. push or rapid drip intravenous infusion from a bag. After completing the infusion of ZINECARD, and prior to a total elapsed time of 30 minutes (from the beginning of the ZINECARD infusion), the intravenous injection of doxorubicin should be given. Reconstituted ZINECARD, when transferred to an empty infusion bag, is stable for 6 hours from the time of reconstitution when stored at controlled room temperature, 15��to 30��C (59��to 86��F) or under refrigeration, 2��to 8��C (36��to 46��F). DISCARD UNUSED SOLUTIONS. The reconstituted ZINECARD solution may be diluted with either 0.9% Sodium Chloride Injection, USP or 5.0% Dextrose Injection, USP to a concentration range of 1.3 to 5.0 mg/mL in intravenous infusion bags. The resultant solutions are stable for 6 hours when stored at controlled room temperature, 15��to 30��C (59��to 86��F) or under refrigeration, 2��to 8��C (36��to 46��F). DISCARD UNUSED SOLUTIONS.<br/>Incompatibility: ZINECARD should not be mixed with other drugs. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.<br/>Handling and Disposal: Caution in the handling and preparation of the reconstituted solution must be exercised and the use of gloves is recommended. If ZINECARD powder or solutions contact the skin or mucosae, immediately wash thoroughly with soap and water. Procedures normally used for proper handling and disposal of anticancer drugs should be considered for use with ZINECARD. Several guidelines on this subject have been published.There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.
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ZINECARD (dexrazoxane for injection) is a sterile, pyrogen-free lyophilizate intended for intravenous administration. It is a cardioprotective agent for use in conjunction with doxorubicin. Chemically, dexrazoxane is (S)-4,4'-(1-methyl-1,2-ethanediyl)bis-2,6piperazinedione.The structural formula is as follows: CHNOM.W. 268.28 Dexrazoxane, a potent intracellular chelating agent is a derivative of EDTA. Dexrazoxane is a whitish crystalline powder which 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 pKis 2.1. Dexrazoxane has an octanol/water partition coefficient of 0.025 and degrades rapidly above a pH of 7.0. ZINECARD is available in 250 mg and 500 mg single use only vials. 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 the 25 mL vial of 0.167 Molar (M/6) Sodium Lactate Injection, USP diluent provided, each mL contains: 10 mg dexrazoxane. The pH of the resultant solution is 3.5 to 5.5. 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 the 50 mL vial of 0.167 Molar (M/6) Sodium Lactate Injection, USP diluent provided, each mL contains: 10 mg dexrazoxane. The pH of the resultant solution is 3.5 to 5.5.
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Mechanism of Action: The mechanism by which ZINECARD 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 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.<br/>Pharmacokinetics: The pharmacokinetics of dexrazoxane have been studied in advanced cancer patients with normal renal and hepatic function. Generally, 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/mwith 60 mg/mof doxorubicin, and at a fixed dose of 500 mg/mwith 50 mg/mdoxorubicin. 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. The mean peak plasma concentration of dexrazoxane was 36.5��g/mL at the end of the 15 minute infusion of a 500 mg/mdose of ZINECARD administered 15 to 30 minutes prior to the 50 mg/mdoxorubicin dose. The important pharmacokinetic parameters of dexrazoxane are summarized in the following table. Following a rapid distributive phase (~0.2 to 0.3 hours), dexrazoxane reaches post-distributive equilibrium within two to four hours. The estimated steady-state volume of distribution of dexrazoxane suggests its distribution primarily in the total body water (25 L/m). The mean systemic clearance and steady-state volume of distribution of dexrazoxane in two Asian female patients at 500 mg/mdexrazoxane along with 50 mg/mdoxorubicin were 15.15 L/h/mand 36.27 L/m, respectively, but their elimination half-life and renal clearance of dexrazoxane were similar to those of the ten Caucasian patients from the same study. Qualitative metabolism studies with ZINECARD 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. Urinary excretion plays an important role in the elimination of dexrazoxane. Forty-two percent of the 500 mg/mdose of ZINECARD was excreted in the urine.<br/>Protein Binding: In vitro studies have shown that ZINECARD is not bound to plasma proteins.<br/>Special Populations:<br/>Pediatric: The pharmacokinetics of ZINECARD have not been evaluated in pediatric patients.<br/>Gender: Analysis of pooled data from two pharmacokinetic studies indicate that male patients have a lower mean clearance value than female patients (110 mL/min/mversus 133 mL/min/m). This gender effect is not clinically relevant.<br/>Renal insufficiency: The pharmacokinetics of ZINECARD were assessed following a single 15 minute IV infusion of 150 mg/mof dexrazoxane in male and female subjects with varying degrees of renal dysfunction as determined by creatinine clearance (CL) based on a 24-hour urinary creatinine collection. Dexrazoxane clearance was reduced in subjects with renal dysfunction. Compared with controls, the mean AUCvalue was twofold greater in subjects with moderate (CL30���50 mL/min) to severe (CL<30 mL/min) renal dysfunction. Modeling demonstrated that equivalent exposure (AUC) could be achieved if dosing were reduced by 50% in subjects with creatinine clearance values<40 mL/min compared with control subjects (CL>80 mL/min) .<br/>Hepatic insufficiency: The pharmacokinetics of ZINECARD have not been evaluated in patients with hepatic impairment. The ZINECARD dose is dependent upon the dose of doxorubicin . Since a doxorubicin dose reduction is recommended in the presence of hyperbilirubinemia, the ZINECARD dosage is proportionately reduced in patients with hepatic impairment.<br/>Drug Interactions: There was no significant change in the pharmacokinetics of doxorubicin (50 mg/m) and its predominant metabolite, doxorubicinol, in the presence of dexrazoxane (500 mg/m) in a crossover study in cancer patients.<br/>Clinical Studies: The ability of ZINECARD to prevent/reduce the incidence and severity of doxorubicin-induced cardiomyopathy was demonstrated in three prospectively randomized placebo-controlled studies. In these studies, patients were treated with a doxorubicin-containing regimen and either ZINECARD or placebo starting with the first course of chemotherapy. There was no restriction onthe cumulative dose of doxorubicin. Cardiac function was assessed by measurement of the left ventricular ejection fraction (LVEF), utilizing resting multigated nuclear medicine (MUGA) scans, and by clinical evaluations. Patients receiving ZINECARD had significantly smaller mean decreases from baseline in LVEF and lower incidences of congestive heart failure than the control group. The difference in decline from baseline in LVEF was evident beginning with a cumulative doxorubicin dose of 150 mg/mand reached statistical significance in patients who received���400 mg/mof doxorubicin. In addition to evaluating the effect of ZINECARD on cardiac function, the studies also assessed the effect of the addition of ZINECARD on the antitumor efficacy of the chemotherapy regimens. In one study (the largest of three breast cancer studies) patients with advanced breast cancer receiving fluorouracil, doxorubicin and cyclophosphamide (FAC) with ZINECARD had a lower response rate (48% vs 63%; p=0.007) and a shorter time to progression than patients who received FAC + placebo, although the survival of patients who did or did not receive ZINECARD with FAC was similar. Two of the randomized breast cancer studies evaluating the efficacy and safety of FAC with either ZINECARD or placebo were amended to allow patients on the placebo arm who had attained a cumulative dose of doxorubicin of 300 mg/m(six courses of FAC) to receive FAC with open-label ZINECARD for each subsequent course. This change in design allowed examination of whether there was a cardioprotective effect of ZINECARD even when it was started after substantial exposure to doxorubicin. Retrospective historical analyses were then performed to compare the likelihood of heart failure in patients to whom ZINECARD was added to the FAC regimen after they had received six (6) courses of FAC (and who then continued treatment with FAC therapy) with the heart failure rate in patients who had received six (6) courses of FAC and continued to receive this regimen without added ZINECARD. These analyses showed that the risk of experiencing a cardiac event (see Table 1 for definition) at a given cumulative dose of doxorubicin above 300 mg/mwas substantially greater in the 99 patients who did not receive ZINECARD beginning with their seventh course of FAC than in the 102 patients who did receive ZINECARD (See Figure 1). Figure 1 displays the risk of developing congestive heart failure by cumulative dose of doxorubicin in patients who received ZINECARD starting with their seventh course of FAC compared to patients who did not. Patients unprotected by ZINECARD had a 13 times greater risk of developing congestive heart failure. Overall, 3% of patients treated with ZINECARD developed CHF compared with 22% of patients not receiving ZINECARD. Because of its cardioprotective effect, ZINECARD permitted a greater percentage of patients to be treated with extended doxorubicin therapy. Figure 2 shows the number of patients still on treatment at increasing cumulative doses. Figure 2 Cumulative Number of Patients On Treatment
FAC vs. FAC/ZINECARD Patients Patients Receiving at Least Seven Courses of Treatment In addition to evaluating the cardioprotective efficacy of ZINECARD in this setting, the time to tumor progression and survival of these two groups of patients were also compared. There was a similar time to progression in the two groups and survival was at least as long for the group of patients that received ZINECARD starting with their seventh course, i.e., starting after a cumulative dose of doxorubicin of 300 mg/m. These time to progression and survival data should be interpreted with caution, however, because they are based on comparisons of groups entered sequentially in the studies and are not comparisons of prospectively randomized patients.
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ZINECARD should not be used with chemotherapy regimens that do not contain an anthracycline.
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ZINECARD (dexrazoxane for injection) is available in the following strengths as sterile, pyrogen-free lyophilizates. NDC 0013-8715-62 250 mg single dose vial with a red flip-top seal, packaged in single vial packs. (This package also contains a 25 mL vial of 0.167 Molar (M/6) Sodium Lactate Injection, USP.) NDC 0013-8725-89 500 mg single dose vial with a blue flip-top seal, packaged in single vial packs. (This package also contains a 50 mL vial of 0.167 Molar (M/6) Sodium Lactate Injection, USP.) Store at 25��C (77��F); excursions permitted to 15��to 30��C (59��to 86��F) [see USP Controlled Room Temperature]. Reconstituted solutions of ZINECARD are stable for 6 hours at controlled room temperature or under refrigeration, 2��to 8��C (36��to 46��F). DISCARD UNUSED SOLUTIONS. Rx only
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There have been no instances of drug overdose in the clinical studies sponsored by either Pharmacia&Upjohn Company or the National Cancer Institute. The maximum dose administered during the cardioprotective trials was 1000 mg/mevery three weeks. Disposition studies with ZINECARD have not been conducted in cancer patients undergoing dialysis, but retention of a significant dose fraction (>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.
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dexrazoxane
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Zinecard (Kit)
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ZINECARD at a dose of 500 mg/mhas been administered in combination with FAC in randomized, placebo-controlled, double-blind studies to patients with metastatic breast cancer. The dose of doxorubicin was 50 mg/min each of the trials. Courses were repeated every three weeks, provided recovery from toxicity had occurred. Table 2 below lists the incidence of adverse experiences for patients receiving FAC with either ZINECARD or placebo in the breast cancer studies. Adverse experiences occurring during courses 1 through 6 are displayed for patients receiving ZINECARD or placebo with FAC beginning with their first course of therapy (column 1&3, respectively). Adverse experiences occurring at course 7 and beyond for patients who received placebo with FAC during the first six courses and who then received either ZINECARD or placebo with FAC are also displayed (column 2&4, respectively). The adverse experiences listed above are likely attributable to the FAC regimen with the exception of pain on injection that was observed mainly on the ZINECARD arm.<br/>Myelosuppression: Patients receiving FAC with ZINECARD experienced more severe leucopenia, granulocytopenia and thrombocytopenia at nadir than patients receiving FAC without ZINECARD, but recovery counts were similar for the two groups of patients.<br/>Hepatic and Renal: Some patients receiving FAC + ZINECARD or FAC + placebo experienced marked abnormalities in hepatic or renal function tests, but the frequency and severity of abnormalities in bilirubin, alkaline phosphatase, BUN, and creatinine were similar for patients receiving FAC with or without ZINECARD.
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ZINECARD is 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 of 300 mg/mand who will continue to receive doxorubicin therapy to maintain tumor control. It is not recommended for use with the initiation of doxorubicin therapy .
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Zinecard
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