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Dexrazoxane
Dexrazoxane
Dexrazoxane
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Dexrazoxane
Clinical data
Trade namesZinecard, others
AHFS/Drugs.comMonograph
MedlinePlusa609010
License data
Routes of
administration		Intravenous
ATC code
Legal status
Legal status
Identifiers
  • 4-[(2S)-2-(3,5-Dioxopiperazin-1-yl)propyl]piperazine-2,6-dione
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.163.459 Edit this at Wikidata
Chemical and physical data
FormulaC11H16N4O4
Molar mass268.273 g·mol−1
3D model (JSmol)
  • O=C2NC(=O)CN(C[C@@H](N1CC(=O)NC(=O)C1)C)C2
  • InChI=1S/C11H16N4O4/c1-7(15-5-10(18)13-11(19)6-15)2-14-3-8(16)12-9(17)4-14/h7H,2-6H2,1H3,(H,12,16,17)(H,13,18,19)/t7-/m0/s1 checkY
  • Key:BMKDZUISNHGIBY-ZETCQYMHSA-N checkY
  (verify)

Dexrazoxane hydrochloride, sold under the brand name Zinecard among others, is a cardioprotective agent. It was discovered in 1972. The IV administration of dexrazoxane is in acidic condition with HCl adjusting the pH.[3]

Medical uses

[edit]

Dexrazoxane has been used to protect the heart against the cardiotoxic side effects of chemotherapeutic drugs such as anthracyclines,[4] such as daunorubicin or doxorubicin or other chemotherapeutic agents.[5] However, in July 2011 the European Medicines Agency (EMA) released a statement restricting use only in adult patients with cancer who have received > 300 mg/m2 doxorubicin or > 540 mg/m2 epirubicin and general approval for use for cardioprotection.[6][7] That showed a possibly higher rate of secondary malignancies and acute myelogenous leukemia in pediatric patients treated for different cancers with both dexrazoxane and other chemotherapeutic agents that are associated with secondary malignancies.[8] On 19 July 2017, based on evaluation of the currently available data the European Commission issued an EU-wide legally binding decision to implement the recommendations of the Committee for Medicinal Products for Human Use (CHMP) on dexrazoxane and lifted its 2011-contraindication for primary prevention of anthracycline-induced cardiotoxicity with dexrazoxane in children and adolescents where high doses (≥ 300 mg/m3) of anthracyclines are anticipated.

Dexrazoxane was designated by the US FDA as an orphan drug for "prevention of cardiomyopathy for children and adults 0 through 16 years of age treated with anthracyclines".[9] This decision allows virtually all children to receive dexrazoxane starting with the first dose of anthracycline at the discretion of the treating provider. The label change by the agency announcing dexrazoxane as an approved cardio-oncology protectant has been followed by a review by the agency.[10] Currently, the only FDA and EMA approved cardioprotective treatment for anthracycline cardioprotection is dexrazoxane, which provides effective primary cardioprotection against anthracycline-induced cardiotoxicity without reducing anthracycline activity and without enhancing secondary malignancies.[11]

The United States Food and Drug Administration has also approved a dexrazoxane for use as a treatment of extravasation resulting from IV anthracycline chemotherapy.[12][13] Extravasation is an adverse event in which chemotherapies containing anthracylines leak out of the blood vessel and necrotize the surrounding tissue.

Mechanism

[edit]

As a derivative of EDTA, dexrazoxane chelates iron and thus reduces the number of metal ions complexed with anthracycline and, consequently, decrease the formation of superoxide radicals.[14] The exact chelation mechanism is unknown, but it has been postulated that dexrazoxane can be converted into ring-opened form intracellularly and interfere with iron-mediated free radical generation that is in part thought to be responsible for anthracycline induced cardiomyopathy.[15] It was speculated that dexrazoxane could be used for further investigation to synthesize new antimalarial drugs.[16]

References

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Dexrazoxane

View on Grokipedia
from Grokipedia
Dexrazoxane is a synthetic cardioprotective agent and iron chelator derived from (EDTA), with the chemical formula C₁₁H₁₆N₄O₄ and a molecular weight of 268.27 g/mol. Primarily used in , it reduces the incidence and severity of and caused by chemotherapy drugs such as , enabling higher cumulative doses of these agents in treating cancers like , , and soft tissue sarcomas. It is also approved for treating injuries from and , where it helps prevent tissue damage by neutralizing the vesicant effects. Dexrazoxane's involves intracellular to form a closed-ring chelator that binds free iron, thereby inhibiting the formation of (ROS) that damage cardiomyocytes during therapy. It may also inhibit topoisomerase II, reducing DNA damage in cardiac cells while sparing tumor cells, though this effect is less pronounced at cardioprotective doses. Administered intravenously as a salt (brand names such as Zinecard and Totect), it is typically given at a 10:1 ratio to the dose, infused over 15-30 minutes shortly before . Dosage adjustments are required for renal impairment, and it is contraindicated in due to potential embryotoxicity. First approved by the U.S. (FDA) in 1995 as Zinecard for reducing doxorubicin-induced in women with , dexrazoxane's indications expanded in 2007 with Totect's approval for anthracycline . Clinical trials, including a landmark study in pediatric patients, have demonstrated its long-term efficacy in preventing cardiac dysfunction without compromising anticancer outcomes, supporting its use in children and adults. Common adverse effects include myelosuppression, , and elevated liver enzymes, with rare risks of secondary malignancies prompting initial FDA warnings that were later revised based on evidence. Ongoing explores its potential in for conditions like , though it remains investigational for non-oncologic uses.

Medical Uses

Cardioprotection in Therapy

Dexrazoxane is indicated to reduce the incidence and severity of in women with who are receiving after a cumulative dose exceeding 300 mg/m² and for whom continued therapy is deemed beneficial by the treating physician. This primary indication stems from its FDA approval in under the brand name Zinecard specifically for cardioprotection during therapy. Although approved for , dexrazoxane's cardioprotective effects extend to other anthracyclines, such as , particularly in high-risk patients receiving cumulative doses that pose significant cardiac risk. Use is reserved for advanced disease settings where the benefits of ongoing outweigh potential risks, and it is not recommended for initial courses with cumulative doses below 300 mg/m². For cardioprotection, dexrazoxane is administered intravenously at a 10:1 dose ratio to —for instance, 500 mg/m² of dexrazoxane for every 50 mg/m² of —with infusion over 15 minutes beginning 30 minutes prior to administration. This regimen allows patients to receive higher cumulative doses while minimizing cardiac . Clinical evidence from pivotal randomized controlled trials supports dexrazoxane's , demonstrating an approximately 91% reduction in the of severe (reflected in a hazard ratio of 13.08 for cardiac events beyond 300 mg/m² without protection) and lowering the incidence of congestive from 22% in groups to 3% with dexrazoxane, without broadly compromising antitumor response rates. These trials, conducted in women with advanced , confirmed preserved oncologic outcomes alongside significant cardioprotection. Ongoing monitoring is essential, with left ventricular (LVEF) assessed via or multiple uptake gated acquisition (MUGA) scans at baseline and periodically during therapy to detect subclinical declines and guide treatment decisions.

Treatment of Extravasation

Dexrazoxane is indicated for the treatment of extravasation injuries resulting from intravenous chemotherapy, such as doxorubicin or epirubicin, to prevent or reduce severe local tissue damage including ulceration and . The U.S. approved dexrazoxane under the brand name Totect in September 2007 specifically for this indication, based on data from two prospective, multicenter, single-arm, open-label phase II/III clinical trials (TT01 and TT02) that demonstrated its efficacy in limiting tissue necrosis compared to historical controls. Treatment should begin as soon as possible, ideally within 6 hours of . The recommended dosing regimen involves intravenous administration once daily for 3 consecutive days: 1000 mg/m² (maximum 2000 mg) on day 1, 1000 mg/m² (maximum 2000 mg) on day 2, and 500 mg/m² (maximum 1000 mg) on day 3. Each dose is diluted in 1000 mL of lactated Ringer's injection and infused over 1 to 2 hours into a large distant from the site, such as the opposite arm, to avoid further local irritation. In addition to dexrazoxane, supportive local measures are essential and include immediate discontinuation of the , aspiration of any remaining from the site if possible, application of cold packs intermittently for 15 to 20 minutes every 6 hours for the first 24 to 72 hours (avoiding application within 15 minutes prior to dexrazoxane ), and of the affected limb to minimize swelling. Surgical intervention is generally avoided unless there is evidence of progressive or infection, as dexrazoxane facilitates conservative management. Clinical evidence from the TT01 and TT02 trials, involving 111 patients with biopsy-confirmed , showed that dexrazoxane prevented the need for surgical resection in 98% of evaluable cases (53 out of 54 patients), with only one patient requiring late surgical intervention for ; long-term follow-up indicated no serious sequelae such as ulceration or functional impairment in most patients. These outcomes represent a significant improvement over historical rates, where up to 46% of untreated led to surgical . Post-treatment monitoring involves regular local examination of the extravasation site for signs of pain, swelling, induration, or pigmentation changes, typically over several weeks, along with hematological assessments due to potential myelosuppression. The 3-day regimen is standard unless contraindicated by factors such as severe renal impairment, in which case dose adjustments or avoidance may be necessary.

Pharmacology

Mechanism of Action

Dexrazoxane functions primarily as a cardioprotective agent through its intracellular to ADR-925, a potent iron-chelating that binds free iron ions, thereby preventing the formation of -iron complexes responsible for generating (ROS). This disrupts the cycling of anthracyclines like , which otherwise catalyze the production of highly reactive hydroxyl radicals via Fenton-like reactions, leading to cellular damage. Dexrazoxane is also a catalytic inhibitor of II, particularly the β isoform (TOP2β), which prevents anthracycline-induced DNA double-strand breaks and in cardiac cells without significantly interfering with antitumor activity in cancer cells at cardioprotective doses. Recent studies (as of 2025) support TOP2β inhibition as a key mechanism, potentially independent of iron . In cardiomyocytes, these mechanisms reduce by limiting ROS-mediated of cell membranes and DNA strand breaks, while also attenuating downstream pathways such as and necroptosis involving p38MAPK/ signaling. Unlike in tumor cells, where exert their cytotoxic effects through II inhibition and DNA intercalation, dexrazoxane preserves the antineoplastic activity without significant interference. For anthracycline extravasation, dexrazoxane's local iron chelation mitigates tissue toxicity by neutralizing leaked drug-iron interactions, thereby decreasing inflammation, necrosis, and promoting wound healing through reduced ROS-induced damage. Structurally, dexrazoxane is the S-enantiomer of razoxane, a bisdioxopiperazine compound that ring-opens to form the chelating moiety analogous to EDTA, and it exhibits no direct cytotoxic effects on its own. In vitro studies demonstrate that dexrazoxane and its metabolite effectively inhibit doxorubicin-induced ROS production in isolated cardiomyocytes, with evidence of near-complete prevention of at clinically relevant concentrations. Animal models, such as chronic daunorubicin-treated rabbits, confirm dose-dependent cardioprotection, including preserved left ventricular function and reduced activation, without altering pharmacokinetics.

Pharmacokinetics

Dexrazoxane is administered exclusively via intravenous infusion, typically over 15 minutes, resulting in complete without oral absorption considerations. Following infusion, it exhibits rapid distribution, achieving peak plasma concentrations within approximately 15 minutes and reaching post-distributive equilibrium within 2-4 hours. The steady-state is approximately 22.4-30 L/m², consistent with distribution primarily into total body water. Dexrazoxane undergoes rapid intracellular hydrolysis in the cytoplasm to its active metabolite ADR-925, the chelating agent responsible for cardioprotection, via enzymes such as dihydroorotase, with facile cellular penetration of the metabolite. Metabolism occurs independently of significant cytochrome P450 involvement, producing ring-opened products including the diacid-diamide form (ADR-925). Elimination is primarily renal, with about 42% of the dose excreted in urine as metabolites; dexrazoxane and ADR-925 both display terminal elimination half-lives of approximately 2.5-3 hours. Plasma clearance is around 7.88 L/h/m² (approximately 230 mL/min total for an average adult), and renal clearance is about 3.35 L/h/m², with no accumulation observed upon repeated dosing due to the short half-life. Dexrazoxane exhibits negligible (<2%). In renal impairment ( clearance <40 mL/min), clearance is substantially reduced, necessitating a 50% dose reduction to maintain safety. Hepatic impairment has minimal impact on , with no specific dose adjustment required beyond maintaining the ratio with concomitant .

Adverse Effects

Common Side Effects

Dexrazoxane is associated with several common side effects that are generally mild to moderate and often overlap with those from concomitant . These effects are typically manageable and do not usually lead to treatment discontinuation, with rates below 5% in pivotal trials for cardioprotection. Injection site reactions, such as pain, , and swelling, occur in approximately 5-10% of patients overall, but are more frequent in the treatment of due to local administration, with pain reported in 21% and in 6% of cases in clinical trials. These reactions are usually transient and resolve without long-term sequelae. Gastrointestinal adverse effects, including , , and , affect up to 20% of patients in cardioprotection use, though rates can reach 77% for and 59% for in trials; these are typically mild and responsive to antiemetics. In extravasation treatment, occurs in 55% and in 43% of patients, often linked to recent exposure. incidence is similar to that seen with alone. Hematologic effects involve mild myelosuppression, such as and , observed in 10-15% of patients, which is additive to the effects of co-administered but generally not dose-limiting. In cardioprotection trials, dexrazoxane was associated with more severe , granulocytopenia, and compared to . For extravasation, grade 2-4 decreases in (73%), neutrophils (61%), and platelets (26%) were reported, primarily attributable to underlying cytotoxic therapy. Other common effects include fatigue (around 61% in cardioprotection use) and alopecia (94%), with incidences comparable to therapy alone. Hair color changes have also been noted in some patients, though not uniquely severe beyond those from . No distinctive severe effects are attributed solely to dexrazoxane in these contexts.

Serious Risks and Warnings

Dexrazoxane use has been associated with an increased risk of secondary malignancies, including (AML) and (MDS), as well as solid tumors. In a of randomized controlled trials involving adults with cancer, the incidence of secondary malignant neoplasms was 2.7% in the dexrazoxane arm compared to 1.1% in the control arm, with follow-up periods typically extending up to 5 years. However, long-term follow-up studies in pediatric patients, such as the P9754 trial (as of 2025), have shown no increased risk of secondary malignant neoplasms with dexrazoxane use. This potential risk may stem from dexrazoxane's inhibition of II, a mechanism that could promote leukemogenesis when combined with or other topoisomerase inhibitors. Although not subject to a warning in the United States, regulatory authorities in some regions, such as the , have previously highlighted this concern and imposed restrictions on its use in pediatric patients, but these were lifted in 2018 based on . Cardiac monitoring is essential during dexrazoxane therapy due to the persistent risk of anthracycline-induced , despite its cardioprotective effects. Left ventricular (LVEF) should be assessed by echocardiogram or multigated acquisition scan before initiating treatment and prior to each subsequent course. Therapy should be discontinued if LVEF declines by 10% (absolute) from baseline to a level below the lower limit of normal for the institution, or if there is a 20% relative decline from baseline, whichever occurs first, to prevent progression to heart failure. Dexrazoxane is contraindicated in patients with known to the drug or its components. It should be avoided or used with extreme caution under specialist oversight in individuals with preexisting , as the underlying cardiac vulnerability may exacerbate risks despite cardioprotection. Similarly, in patients approaching or exceeding a cumulative dose of 550 mg/m² equivalent, dexrazoxane initiation requires careful evaluation, as risk escalates significantly at these levels, potentially limiting its benefit. Dexrazoxane may cause fetal harm when administered to pregnant women based on its and findings from showing embryotoxicity and teratogenicity at doses approximating clinical exposure. Women of reproductive potential should use effective contraception during treatment and for at least 6 months afterward; men should use contraception during and for 3 months post-treatment. Dexrazoxane may also impair in both males and females, as evidenced by and impaired in . No major drug interactions have been identified with dexrazoxane, but it may potentiate myelosuppression when co-administered with other chemotherapeutic agents, necessitating close monitoring of complete blood counts. In patients with renal impairment ( clearance <40 mL/min), toxicity risk increases due to reduced clearance, requiring a 50% dose reduction to mitigate accumulation and adverse effects.

History

Development and Discovery

Dexrazoxane was developed in the 1970s and 1980s as the S-(+)- of razoxane (also known as ICRF-159), a bisdioxopiperazine compound originally synthesized at the Imperial Cancer Research Fund Laboratories in as a potential anticancer agent. Razoxane, initially explored for its antitumor properties in preclinical models, demonstrated limited efficacy as a standalone antineoplastic , prompting further investigation into structural analogs like dexrazoxane for alternative therapeutic applications. The key discovery of dexrazoxane's cardioprotective potential occurred in the late 1970s and early 1980s through research led by Edward H. Herman and colleagues at the . In a seminal 1979 study, pretreatment with dexrazoxane (then ICRF-187) significantly reduced daunorubicin-induced lethality and myocardial cellular damage in Syrian golden hamsters, without compromising the anthracycline's antitumor effects in tumor-bearing models. Subsequent work by Herman et al. in the 1980s extended these findings to , using , , and miniature swine models to demonstrate decreased cardiac lesions, such as myofibrillar loss and vacuolization, following dexrazoxane administration. These preclinical investigations were grounded in the emerging theory that like form toxic iron complexes in cardiac tissue, generating (ROS) that cause oxidative damage; studies confirmed dexrazoxane's ability to chelate iron and scavenge ROS, thereby mitigating this pathway. During its development by Laboratories, dexrazoxane was designated as ADR-529, reflecting its role as a cardioprotectant rather than an anticancer agent. By the late 1980s, these promising preclinical results facilitated the transition to human studies, with initial phase I clinical trials commencing in 1987 to evaluate safety and dosing in patients receiving therapy. Early trials confirmed dexrazoxane's tolerability and lack of independent antitumor activity, solidifying its focus as an adjunctive cardioprotectant that preserved anthracycline efficacy while reducing cardiac toxicity risks.

Regulatory Approvals

Dexrazoxane received its initial U.S. (FDA) approval on May 26, 1995, under the brand name Zinecard (NDA 20-212) for reducing the incidence and severity of induced by in women with who have received a cumulative doxorubicin dose of 300 mg/m² and who, in the opinion of the treating physician, would benefit from continued doxorubicin therapy. In 2007, the FDA expanded approval to a new formulation, Totect (NDA 22-025), on September 6, for treating resulting from intravenous , based on clinical studies demonstrating reduced tissue damage. In 2020, the FDA further expanded the indication for Totect via a supplemental NDA approved on November 10, allowing its use for reducing the incidence and severity of associated with administration in women with who have received a cumulative doxorubicin dose of 300 mg/m² and would benefit from continuing therapy, aligning the product's indications with those of Zinecard. Internationally, dexrazoxane was first licensed in in as Cardioxane for cardioprotection in adults with advanced or receiving high cumulative doses of or epirubicin. The (EMA) granted centralized marketing authorization for Savene (dexrazoxane) on July 27, 2006, specifically for treating injuries. Following a 2017 review under Article 13 of Directive 2001/83/EC, the EMA revised the labeling for Cardioxane on July 19, expanding its indication to adult patients with cancer (beyond only) receiving and permitting use from the start of therapy rather than after a cumulative dose threshold, based on evidence of cardioprotective benefits outweighing risks. The drug is authorized in multiple European countries through mutual recognition and decentralized procedures and is marketed globally under names such as Cardaxane and Cardioxane. The FDA awarded designation to dexrazoxane on December 17, 1991, for preventing doxorubicin-associated in patients. Additional orphan designations followed, including on March 25, 2004, for extravasation treatment, and on August 19, 2014, for preventing in children and adolescents aged 0-16 years treated with . Labeling for Zinecard was revised in to clarify monitoring requirements and reinforce its use in conjunction with , while maintaining restrictions to advanced disease settings due to concerns over potential interference with antitumor efficacy in early-stage cancers. Warnings for secondary malignancies, particularly , were added to the product labeling in the early based on post-approval reports, though no warning was implemented; these risks are noted as rare and primarily associated with long-term razoxane use. Post-marketing surveillance, including reports and observational studies, has generally confirmed dexrazoxane's safety profile consistent with data, with no major product withdrawals. Use remains restricted in early-stage cancers per guidelines from organizations like the (NCCN), which recommend it primarily for high-risk advanced cases to balance cardioprotection against potential oncologic impacts.

References

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