Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2012 Publisher: Novartis Pharmaceuticals UK Limited Frimley Business Park Frimley Camberley Surrey GU16 7SR
Pharmacotherapeutic group: Detoxifying agents for antineoplastic treatment
ATC code: V03AF02
The exact mechanism by which dexrazoxane exerts its cardioprotective effect has not been fully elucidated, however based on the available evidence the following mechanism has been suggested. The dose-dependent cardiotoxicity observed during anthracycline administration is due to anthracycline-induced iron-dependent free radical oxidative stress on the relatively unprotected cardiac muscle. Dexrazoxane, an analogue of EDTA (ethylene diamine tetra-acetic acid), is hydrolysed in cardiac cells to the ring-opened product ICRF-198. Both dexrazoxane (ICRF-187) and ICRF-198 are capable of chelating metal ions. It is generally thought that they can provide cardioprotection by scavenging metal ions thus preventing the Fe3+-anthracycline complex from redox cycling and forming reactive radicals.
The evidence from clinical trials to date suggests increasing cardioprotective benefit from dexrazoxane as the cumulative anthracycline dose is increased.
Dexrazoxane does not protect against non-cardiac toxicities induced by anthracyclines.
The majority of controlled clinical studies were performed in patients with advanced breast cancer. Data from adults treated in 8 controlled randomised clinical studies have been reviewed, 780 patients received dexrazoxane plus chemotherapy and 789 received chemotherapy alone. The rate of death on study was higher with the combination dexrazoxane plus chemotherapy (5.0%) compared to chemotherapy alone (3.4%). The difference was not statistically significant and no consistent cause was apparent, however a contribution of dexrazoxane to the difference cannot be ruled out.
After intravenous administration to cancer patients, serum kinetics of dexrazoxane generally follow an open two-compartment model with first-order elimination. The maximum plasma concentration observed after a 12-15 minute infusion of 1000 mg/m2 is around 80 μg/ml with area under the plasma concentration-time curve (AUC) of 130 ± 15mg.h/L. The plasma concentrations declined thereafter with an average half-life value of 2.2 ± 1.2 hours. The apparent volume of distribution is 44.0 ± 3.9L, suggesting that dexrazoxane distributes mainly in the total body water. The total body clearance of dexrazoxane in adults is estimated at 14.4 ± 1.6L/h. CARDIOXANE and its metabolites were detected in the plasma and urine of animals and man. The majority of the administered dose is eliminated in urine mainly as unchanged dexrazoxane. The total urinary excretion of unchanged dexrazoxane is in the order of 40%. Plasma protein binding of dexrazoxane is low (2%) and it does not penetrate into the cerebrospinal fluid to a clinically significant extent. Active substance clearance may be reduced in elderly patients and patients with low creatinine clearance. There is limited data on pharmacokinetic interactions with chemotherapeutic agents other than doxorubicin, epirubicin, cyclophosphamide, 5- fluorouracil and paclitaxel. No studies were conducted in the elderly and subjects with hepatic or renal impairment.
Preclinical studies indicate that, with repeated dexrazoxane administration, the primary target organs are those of rapid cell division: bone marrow, lymphoid tissue, testes and gastrointestinal mucosa. The CARDIOXANE dosing schedule is a primary factor in the degree of tissue toxicity produced. A single high dose is better tolerated than the same dose administered several times a day. Dexrazoxane has been shown to possess mutagenic activity. The carcinogenic potential of dexrazoxane has not been investigated. However prolonged administration of high doses of razoxane, the racemic mixture of which dexrazoxane is the S (+)-enantiomer, has been associated with the development of secondary malignancies (primarily acute myeloid leukaemia). Animal reproduction studies reveal that razoxane is embryotoxic to mice, rats and rabbits and also teratogenic to rats and mice, although a different dosing schedule was used compared to that used in man.
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