Source: FDA, National Drug Code (US) Revision Year: 2021
ZINECARD (dexrazoxane) is a cyclic derivative of EDTA which, unlike EDTA, readily penetrates cell membranes. ZINECARD was shown to be able to protect the myocardium from anthracycline-induced cardiotoxicity. The mechanism by which ZINECARD exerts its cardioprotective activity is not fully understood. Results of laboratory studies suggest that dexrazoxane is converted intracellularly to an open-ringed chelating agent which interferes with iron-mediated free radical generation thought to be responsible, in part, for anthracyclineinduced cardiotoxicity.
Pharmacokinetic studies have been performed in advanced cancer patients with normal renal and hepatic function following administration of ZINECARD as a 15 minute I.V. infusion over a dose-range of 60 to 900 mg/m² with 60 mg/m² of doxorubicin, and at a fixed dose of 500 mg/m² with 50 mg/m² doxorubicin.
The mean peak plasma concentration of dexrazoxane at the end of the 15 minute infusion was 36.5 μg/mL and was below the limit of quantitation (5 ng/mL) after 24 hours. The biphasic decay of the plasma concentration of dexrazoxane is best described by an empirical two-compartment open model.
Following a rapid distributive phase (t½,λ1: ~0.2 to 0.3 hours), dexrazoxane reached post-distributive equilibrium by two to four hours. The estimates of the mean volume of the central compartment (Vc) and the distribution volume at steady-state (Vss) were 12.9 and 25.6 L/m² , respectively. This suggests minimal tissue uptake of dexrazoxane and its confinement in a volume equal to the total body water (25 L/m²).
In vitro studies have shown that ZINECARD is not bound to plasma proteins.
Plasma clearance of ZINECARD is via both renal and nonrenal elimination. The nonrenal component is mainly metabolic. 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 means (± sd; range) of the terminal elimination half-life (t½,λz) and systemic clearance (CLs) were 2.5 (± 0.4; 1.8 to 3.3) hours and 9.56 (± 3.56; 5.93 to 16.71) L/Hr/m² , respectively. The coefficient of variation (CV) in these estimates was generally less than 42. Excellent proportionality between the area under the plasma dexrazoxane concentration-time curve (AUC) and administered dose, and no change in CLs, t½, and Vss indicate that its disposition kinetics are apparently dose-independent. The mean (± sd; range) urinary excretion (expressed as percent dose) for dexrazoxane was 37.0% (± 15.0; 17.1 to 61.2%).
The pharmacokinetics of ZINECARD were assessed following a single 15 minute IV infusion of 150 mg/m² of dexrazoxane in male and female subjects with varying degrees of renal dysfunction as determined by creatinine clearance (CLCR) based on a 24-hour urinary creatinine collection. Dexrazoxane clearance was reduced in subjects with renal dysfunction. Compared with controls, the mean AUC0-inf value was two-fold greater in subjects with moderate (CLCR 30-50 mL/min) to severe (CLCR <30 mL/min) renal dysfunction. Modeling demonstrated that equivalent exposure (AUC0-inf) could be achieved if dosing were reduced by 50% in subjects with creatinine clearance values <40 mL/min compared with control subjects (CLCR >80 mL/min).
No long-term carcinogenicity studies have been carried out with ZINECARD in animals.
Dexrazoxane was not mutagenic in the Ames test but was found to be clastogenic in human lymphocytes in vitro and to bone marrow erythrocytes in the mouse (micronucleus test). Dexrazoxane did not alter the mutagenic or the genotoxic properties of doxorubicin.
Secondary malignancies (primarily acute myeloid leukemia) have been reported in patients treated chronically with oral razoxane. Razoxane is the racemic mixture, of which dexrazoxane is the S(+)-enantiomer. In these patients, the total cumulative dose of razoxane ranged from 26 to 480 grams and the duration of treatment was from 42 to 319 weeks. One case of T-cell lymphoma, a case of B-cell lymphoma and six to eight cases of cutaneous basal cell or squamous cell carcinoma have also been reported in patients treated with razoxane.
Dexrazoxane was maternotoxic at dosages of 2 mg/kg and embryotoxic and teratogenic at 8 mg/kg when given daily to pregnant rats during the period of organogenesis. Teratogenic effects in the rat included imperforate anus, microphthalmia, and anophthalmia. In rabbits, dosages of 5 mg/kg daily during the period of organogenesis were maternotoxic and dosages of 20 mg/kg were embryotoxic and teratogenic. Teratogenic effects in the rabbit included several malformations as well as agenesis of the gallbladder and of the intermediate lobe of the lung.
Dexrazoxane has been shown to be effective in ameliorating the cardiotoxicity induced by anthracyclines, in mice, rats, hamsters, guinea pigs, rabbits, dogs and miniature swine. The Bertazzoli mouse model was utilized to induce cardiomyopathy over several weeks. The anthracycline was administered I.V. to ICRF Swiss mice twice weekly during weeks 1, 2, 5, 6 and 7. Dexrazoxane administered at dose ratios of 5, 10, 15 and 20 to 1, immediately prior to doxorubicin administration (4 mg/kg) significantly reduced the incidence of cardiomyopathy, scored from a scale of 1-4. There was a significant decrease in the incidence of moderate to severe lesions (scoring >2) at 5 to 1 dose ratio (64%) and a further response at 10 to 1 dose ratio (26%). The cardioprotective effect of doxorubicin at ratios of 15 and 20 to 1 were similar to that of 10 to 1.
Similar cardioprotective activity was seen with epirubicin- and idarubicin-treated mice. Cardiotoxicity at baseline was less severe with epirubicin (5 mg/kg) than with doxorubicin. Dexrazoxane was equally cardioprotective at dose ratios of 5, 10 and 20 to 1, which were more effective compared to the 1 to 1 ratio. Notably, at a ratio of 5 to 1, cardioprotection was equal to the other dose ratios. In mice treated with 1 mg/kg idarubicin, dexrazoxane was cardioprotective at dose ratios of 5, 10 and 20 to 1.
Dexrazoxane, although less than it is against the other anthracyclines, was also effective in ameliorating the cardiotoxicity caused by mitoxantrone in the mouse. A dose of 1.5 mg/kg mitoxantrone administered I.V. per the Bertazzoli schedule, caused cardiomyopathy which was slightly less severe than that caused by doxorubicin at 4 mg/kg. At doses of 30 mg/kg and 15 mg/kg dexrazoxane, there were significant reductions in the mitoxantrone-induced cardiomyopathy.
In the foregoing mouse studies in which haematology, serum chemistry, and histopathology on major organs was performed, there were anthracycline-related non-cardiac toxicities including inhibition of weight gain and histomorphologic renal and liver changes. Dexrazoxane did not exert an appreciable effect on the other anthracycline toxicities.
Similarly, dexrazoxane exhibited a dose-dependent cardioprotective effect when administered to rats at a dose ratio of 5, 10 and 20 to 1, injected 30 minutes prior to I.V. administration of doxorubicin and epirubicin (1 mg/kg) once weekly for seven consecutive weeks.
The cardioprotective activity of dexrazoxane was convincingly demonstrated in the beagle dog. Every three weeks, beagle dogs were given dexrazoxane 25 mg/kg I.V. 15 minutes prior to a 1.75 mg/kg I.V. injection of doxorubicin. All of the dogs (n=8) given doxorubicin alone died after 7 or 8 courses.
Those given the combination of doxorubicin and dexrazoxane were still alive after 20 courses (67 weeks). Based on histological analysis, 100% of the dogs given doxorubicin alone, showed evidence of severe heart damage (score of 3+, severity scale (0-4). In dogs given the combination (n=8), no cardiac damage was observed in 50% of the animals, 25% had a score of 1 and the remainder had a score of 2.
Dogs pretreated with dexrazoxane received much higher cumulative doses of doxorubicin (35-43.75 mg/kg) than those receiving doxorubicin alone (12.25-14 mg/kg) and had significantly lower mean cardiomyopathy severity scores (0.75 versus 3.0).
Dexrazoxane appears to be highly schedule dependent, and the optimal cardioprotection is observed when dexrazoxane is given in a time span of 30 minutes prior to and 15 minutes after doxorubicin administration. However, studies in mice showed that dexrazoxane given I.V. as early as 2 hours prior to or as long as 1 hour after doxorubicin administration is cardioprotective. Simultaneous dosing of dexrazoxane also provided optimal protection in doxorubicin treated mice.
Dexrazoxane is intended for use with anthracycline chemotherapy or anthracycline containing combinations of cytotoxic drugs.
In several experimental tumour assays in the mouse, including leukemias and solid tumours, dexrazoxane was found to possess weak or no antitumour activity, in combination with such cytotoxic agents as doxorubicin, epirubicin, daunorubicin, mitoxantrone, 5-fluoruracil, cyclophosphamide, bleomycin, cisplatin, cytarabine, vincristine and methotrexate. In the P388 murine leukemia, L1210 leukemia models and Lewis lung carcinoma, dexrazoxane enhanced the antitumoural activity of doxorubicin as seen in the form of increased median survival time (MST) of mice. Dexrazoxane did not affect the antitumoural activity of optimal doxorubicin dosages in the Gross leukemia, B16 melanoma, Madison 109 lung tumour in the mouse. At optimally efficacious doses of doxorubicin, dexrazoxane has no effect on the antitumoural activity of doxorubicin. At suboptimal doses, dexrazoxane may enhance the efficacy due to slight antitumoural activity it may possess.
The effect of dexrazoxane on the antitumoural efficacy of doxorubicin against human tumour xenografts was also investigated. At ratios of from 5:1 to 20:1 of dexrazoxane to doxorubicin, there was no interference with the efficacy of doxorubicin against fresh human tumour explants, the BL/LX5 human lung tumour cell line, or of the MX-1 breast cancer cell line implanted in the subrenal capsule of the mouse. However, at a ratio of 10:1, there was evidence of interference with the activity of doxorubicin against the BL/BX7 human mammary tumour (a subline of MX-1), implanted subcutaneously in the athymic mouse. Since this inhibitory effect was not seen at ratios of 5:1, 15:1 or 20:1, the significance of this observation is unclear.
In in vitro studies, there were additive or synergistic cytotoxic effects when combinations of dexrazoxane and doxorubicin were added to murine sarcoma 180 cells or HL-60 human leukemia cells.
Dexrazoxane was devoid of central nervous system activity (general behaviour, body and skin temperature) The acute hemodynamic effects of I.V. dexrazoxane were measured in anesthetized Beagle dogs. Dexrazoxane (80 and 200 mg/kg) had no consistent effects on mean arterial pressure, left ventricular pressure, contractility or heart rate.
In vitro studies in the rat, proved that dexrazoxane was devoid of effects on the autonomic nervous system. Intravenously in the rat, dexrazoxane reduce urinary K+ and Ca++ at doses of 100 mg/kg and above, and decreased urinary volume at 120 mg/kg.
With regard to immunological activity, dexrazoxane at doses of 100 mg/kg and above produced immunosuppression and can increase the immunosuppressive effects of doxorubicin in mice when given at 10 or 20 times the doxorubicin dose.
Toxicology studies were carried out in the mouse, rat and dog, with dexrazoxane alone and in combination with either doxorubicin or epirubicin, two of the most widely used antineoplastic anthracyclines, as well as with other antineoplastic drugs likely to be used in anthracyclinecontaining chemotherapeutic regimens.
Single I.V. doses of dexrazoxane of up to 1000 mg/kg in either saline or sodium lactate, were well tolerated in the mouse. In the rat, the LD50 of dexrazoxane was estimated to be greater than 1000 mg/kg. Acute toxic effects of single infusions of dexrazoxane at doses of 250, 500, 1000 or 2000 mg/kg were examined in the beagle dog. The 250 and 500 mg/kg doses were considered well tolerated in the dog. Cytoplasmic alterations were observed in the liver at the two highest doses and hemorrhage was noted in several tissues of the high dose dog. There was some evidence of granulocyte hypoplasia or erythroid hyperplasia in the high dose male.
In the mouse, the LD50 for doxorubicin alone was 16 and 23 mg/kg in males and females, respectively, whereas the LD50 for doxorubicin given in combination with dexrazoxane (20 to 1, dexrazoxane:doxorubicin) was 25 and 26 mg/kg in males and females, respectively. The LD50 of epirubicin alone in male and female mice, were 26 and 28 mg/kg, respectively, whereas in combination with dexrazoxane, the LD50 were 30 and 34 mg/kg, respectively.
The pathologic changes found in the dexrazoxane:epirubicin treatment groups were consistent with anthracycline toxicity. Dexrazoxane had no appreciable effect on the acute toxicity of vincristine or cisplatin in the mouse.
The effects of dexrazoxane on the acute toxicity of doxorubicin were examined in the rat using doses of 3 to 12 mg/kg doxorubicin at ratios of 20 to 1, dexrazoxane:doxorubicin. The LD50 for doxorubicin alone were 12.5 and 15 mg/kg in males and females, respectively, and for the combination, 12 and 11.3 mg/kg. Dexrazoxane tended to exacerbate the lethality of doxorubicin at the higher doses (>9 mg/kg doxorubicin), but exhibited some protection against the gross pathologic effect of doxorubicin (small thymus, fluid in abdominal and thoracic cavities).
In the dog, the acute toxicity of dexrazoxane given 30 minutes prior to doxorubicin was studied at doses of 5, 10, 20 and 40 mg/kg dexrazoxane and 0.25, 0.5, 1.0 and 2.0 mg/kg doxorubicin. Doses up to 20 mg/kg were well tolerated with slight transient changes in haematology and clinical chemistry, but the highest dose was toxic. In combination with epirubicin or cisplatin, dexrazoxane did not affect the toxicity profile commonly seen with these two agents administered alone. Chronic toxicity studies were carried out in the, rat and beagle dog after I.V. courses of dexrazoxane both alone or in combination with doxorubicin or epirubicin for a total of 6 and 13 weeks.
Results showed that in the rat and dog, dexrazoxane (administered at 20 to 1 dose ratios) exhibited protection against doxorubicin-induced cardiotoxicity and epirubicin-induced renal tubulonephrosis, but did not affect the other commonly associated toxicities. Dexrazoxane was given IV at doses of 10, 20 and 40 mg/kg approximately 25 minutes before an I.V. dose of doxorubicin at 0.5, 1.0 and 2.0 mg/kg, respectively. Controls included dexrazoxane alone (40 mg/kg) and doxorubicin alone (2.0 mg/kg). Dexrazoxane alone had minimal effects, the most important of which was a decrease in testes and thymus weights which were not associated with histomorphological changes. Doxorubicin, either alone or together with dexrazoxane, caused anaemia, leukopenia, bone marrow depletion, thymus atrophy, hyperplasia of immature lymphocytes and lymphoid depletion of mesenteric lymph nodes. Doxorubicin caused renal tubulonephrosis which was prevented to a significant degree by dexrazoxane. Changes in serum chemistry in doxorubicin-treated rats were less severe in the rats given dexrazoxane with doxorubicin. Dexrazoxane also exhibited protection against doxorubicin-induced cardiotoxicity.
Epirubicin given at doses of 0.6, 1.2, and 2.4 mg/kg IV, caused anaemia, leukopenia, bone marrow depletion, testicular atrophy, renal tubulonephrosis and cardiotoxicity in the rat. Dexrazoxane (12, 24, and 48 mg/kg) exhibited some protection against the renal tubulonephrosis and cardiotoxicity induced by epirubicin, but did not affect the other toxicities of epirubicin appreciably.
The efficacy of ZINECARD in preventing/reducing the incidence and severity of doxorubicininduced cardiomyopathy was demonstrated in a series of prospective studies. In these studies, patients were treated with a doxorubicin-containing regimen and either ZINECARD or placebo starting with the first course of chemotherapy. 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/m² and reached statistical significance in patients who received >400 mg/m² of doxorubicin. The studies also assessed the effect of the addition of ZINECARD on the antitumour efficacy of the chemotherapy regimens.
In one of the studies (the largest of the breast cancer studies) patients with advanced breast cancer receiving fluorouracil, Adriamycin and cyclophosphamide (FAC) with ZINECARD had a lower response rate and a shorter time to progression than patients on the control arm although the survival of the patients who did or did not receive ZINECARD with FAC was similar. More non-responders dropped out by course three in the ZINECARD arm. The non-responders correlated to dose delays due to additive myelotoxicity. It appears that ZINECARD may potentiate doxorubicin toxicity in some patients, thus causing increased early dropout rate or decreased dose-intensity.
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/m² (six (6) courses of FAC) to receive FAC with open-label ZINECARD for each subsequent course. Most of these patients had already experienced a partial or complete response or had stable disease. Analyses of these amended studies indicate that significant though not complete cardioprotection can be obtained with the administration of ZINECARD only after the accumulated dose of 300 mg/m² of doxorubicin. In addition, the time to tumour progression and survival of these two groups of patients were also compared. Results demonstrate significantly longer overall survival for the group of patients who received ZINECARD starting with the seventh course of FAC treatment.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
