Dexrazoxane (DB00380): A Comprehensive Monograph on its Cardioprotective and Chemoprotective Roles in Oncology

Section 1: Introduction to Dexrazoxane

Executive Summary

Dexrazoxane (DrugBank ID: DB00380) is a unique, systemically administered cytoprotective agent belonging to the bisdioxopiperazine class of compounds.[1] It occupies a distinct niche in modern oncology, primarily defined by its dual, yet highly specific, roles in mitigating the toxicities of anthracycline chemotherapy. First, it serves as a cardioprotective agent, administered to reduce the incidence and severity of cumulative, dose-dependent cardiomyopathy, a major source of long-term morbidity and mortality in cancer survivors treated with drugs like doxorubicin.[4] Second, it functions as a targeted chemoprotective agent, acting as the only approved antidote for the treatment of severe local tissue damage (extravasation) that can occur when intravenous anthracyclines leak from the vein into surrounding tissues.[7] Marketed under brand names including Zinecard®, Totect®, and Cardioxane®, Dexrazoxane addresses critical unmet needs that arise directly from the use of one of the most effective and widely used classes of anticancer drugs.[4]

The Central Clinical Problem

Anthracyclines, such as doxorubicin and daunorubicin, have been a cornerstone of curative-intent therapy for a wide range of hematologic and solid tumors for over five decades.[11] However, their clinical utility is fundamentally limited by a well-characterized, dose-dependent cardiotoxicity. This cardiac damage can manifest as acute arrhythmias, but more consequentially as a chronic, progressive cardiomyopathy that can lead to irreversible congestive heart failure (HF), sometimes years or even decades after treatment completion.[4] For childhood cancer survivors, the risk is particularly stark, with at least 10% of those who receive high doses of doxorubicin experiencing heart failure by age 40.[13] This toxicity forces oncologists to adhere to strict cumulative dose limits, potentially compromising the antitumor efficacy of the regimen.[11] In parallel, anthracyclines are potent vesicants. Accidental extravasation during intravenous infusion, while uncommon, is a medical emergency that can lead to severe pain, inflammation, and progressive tissue necrosis requiring surgical debridement and reconstructive surgery.[8] Dexrazoxane was developed and approved to address these two distinct and severe complications arising from a single class of chemotherapeutic agents.

Overview of Key Controversies

Despite its established efficacy, the clinical use of Dexrazoxane is fraught with complexity and controversy, which has contributed to a significant gap between evidence and practice.[11] The scientific understanding of its primary cardioprotective mechanism has undergone a profound paradigm shift, moving from a long-held belief in simple iron chelation to a more nuanced model centered on the targeted inhibition of the enzyme topoisomerase IIβ (TOP2B).[17] Furthermore, its clinical application has been shadowed by persistent, albeit nuanced, concerns regarding its potential to interfere with the antitumor efficacy of chemotherapy or to increase the risk of secondary malignancies, particularly in pediatric populations.[18] These controversies, rooted in data from older clinical trials and evolving regulatory stances, have led to its underutilization in many clinical settings where its benefits may outweigh its risks.[11] This report seeks to provide a comprehensive synthesis of the available evidence, clarifying the drug's pharmacological profile, clinical utility, and the risk-benefit calculus that governs its use in contemporary cardio-oncology. The dual utility of Dexrazoxane in preventing systemic heart damage and treating local tissue injury is not a coincidence; rather, it reflects a sophisticated mechanism of action that directly intercepts the molecular pathways through which anthracyclines exert their toxicity. By inhibiting topoisomerase II enzymes and chelating iron, Dexrazoxane counteracts the very processes responsible for both the desired anticancer effects and the undesired collateral damage, making its study a window into the fundamental biology of chemotherapy toxicity.[1]

Section 2: Physicochemical Profile and Pharmaceutical Formulations

Chemical Identity

Dexrazoxane is the (+)-(S)-enantiomer of the racemic compound razoxane.[1] Its chemical identity is defined by a precise set of systematic names, identifiers, and codes that are critical for research, regulatory, and clinical purposes.

• Systematic Names:
• IUPAC Name: 4-piperazine-2,6-dione [1]
• Formal Name: 4,4'-bis-2,6-piperazinedione [23]
• Synonyms and Codes: The compound is known by numerous synonyms and research codes, reflecting its long history of development. These include: (+)-(S)-4,4'-Propylenedi-2,6-piperazinedione, (+)-1,2-Bis(3,5-dioxo-1-piperazinyl)propane, ICRF 187, ADR-529, and NSC 169780. Its commercial brand names include Cardioxane®, Zinecard®, Totect®, and Savene®.[1]
• Molecular Formula and Weight:
• Molecular Formula: C11​H16​N4​O4​ [4]
• Average Molecular Weight: Approximately 268.27 g/mol [1]
• Monoisotopic Mass: 268.11715502 Da [1]

Physical and Chemical Properties

Dexrazoxane is a whitish crystalline powder, though some sources describe it as ranging from white to light yellow or light orange.[1] Its solubility profile is a key determinant of its formulation and administration. It is sparingly soluble in water (approximately 10-12 mg/mL at 25 °C) and 0.1 N HCl, slightly soluble in ethanol and methanol, and is considered practically insoluble in nonpolar organic solvents.[1] Its solubility is pH-dependent, with higher solubility in acidic (35-43 mg/mL in 0.1 N HCl) and basic (25-34 mg/mL in 0.1 N NaOH) conditions compared to neutral buffers.[1] The compound has a melting point in the range of 191 °C to 197 °C.[10] Chemically, it is characterized by a pKa of 2.1 and is known to degrade rapidly in solutions with a pH above 7.0, necessitating its formulation as an acidic solution for intravenous use.[27]

Pharmaceutical Formulation and Administration

Dexrazoxane is supplied for clinical use as a sterile, pyrogen-free lyophilized powder in 250 mg and 500 mg single-dose vials.[18] The formulation contains dexrazoxane hydrochloride, with hydrochloric acid added to adjust the pH.[27]

Reconstitution of the lyophilized powder with Sterile Water for Injection, USP, yields a highly acidic solution with a pH between 1.0 and 3.0.[27] This concentrated solution (10 mg/mL) is not intended for direct injection and must be further diluted prior to administration.[27] The choice of diluent depends on the clinical indication. For cardiomyopathy prophylaxis (Zinecard®), the reconstituted solution is typically diluted with Lactated Ringer's Injection, USP.[27] For the treatment of extravasation (Totect®), the vial contents must first be mixed and diluted with a specific 50 mL volume of 0.167 M sodium lactate injection solution before being further diluted in an infusion bag containing 0.9% Sodium Chloride.[15]

Unused vials should be stored at controlled room temperature (20-25°C or 68-77°F) and protected from light.[28] The stability of the drug after reconstitution is limited. Reconstituted vials are stable for only 30 minutes at room temperature or up to 3 hours if refrigerated. Once further diluted for infusion, the solution should be used immediately, though it may be stable for up to 4 hours at room temperature or 12 hours if refrigerated.[28]

Table 1: Key Identifiers and Physicochemical Properties of Dexrazoxane

Property/Identifier	Value	Source(s)
DrugBank ID	DB00380	1
CAS Number	24584-09-6	1
IUPAC Name	4-piperazine-2,6-dione	1
Molecular Formula	C11​H16​N4​O4​	4
Average Molecular Weight	268.27 g/mol	1
Appearance	White to off-white/light yellow crystalline powder	1
Melting Point	191-197 °C	10
pKa	2.1	27
Solubility in Water (25 °C)	10-12 mg/mL	1
Solubility in DMSO	>20 mg/mL	2
Stability	Degrades rapidly at pH > 7.0	27

Section 3: Comprehensive Pharmacological Profile

3.1 Pharmacodynamics: A Re-evaluation of a Dual Mechanism

The pharmacodynamic actions of Dexrazoxane are multifaceted, and the scientific understanding of its primary protective mechanisms has evolved significantly over time. It functions through at least two distinct but related pathways: iron chelation and catalytic inhibition of topoisomerase II enzymes. The relative importance of these mechanisms differs depending on the clinical context (cardioprotection versus extravasation treatment), and recent evidence has prompted a major re-evaluation of the long-held hypothesis for its cardioprotective effects.

The Cardioprotective Mechanism - A Paradigm Shift

For decades, the cardioprotective action of Dexrazoxane was almost exclusively attributed to its function as an iron-chelating agent. This classic hypothesis is based on several key observations. Dexrazoxane is a cyclic derivative of ethylenediaminetetraacetic acid (EDTA) that, unlike EDTA itself, is lipophilic enough to readily penetrate cell membranes.[4] Once inside the cardiomyocyte, it acts as a prodrug. It is hydrolyzed by the cytosolic enzyme dihydropyrimidine amidohydrolase (DHPase) to form its principal active metabolite, a ring-opened compound known as ADR-925.[1] ADR-925 is structurally similar to EDTA and is a potent, bidentate chelating agent. The prevailing theory was that ADR-925 binds to intracellular free iron, preventing it from forming a redox-active complex with the anthracycline molecule. This anthracycline-iron complex is believed to catalyze the generation of highly damaging reactive oxygen species (ROS), such as superoxide and hydroxyl radicals, which induce lipid peroxidation, mitochondrial damage, and ultimately, cardiomyocyte apoptosis and necrosis.[1] By sequestering the iron necessary for this reaction, Dexrazoxane was thought to act as a site-specific antioxidant.

However, a more modern and compelling hypothesis has emerged, shifting the paradigm from iron chelation to the direct inhibition of topoisomerase IIβ (TOP2B).[17] This new model proposes that the critical cardiotoxic lesion induced by anthracyclines is not caused by indiscriminate ROS generation, but by a specific interaction with the TOP2B enzyme, which is highly expressed in terminally differentiated cardiomyocytes. Anthracyclines act as "topoisomerase poisons," stabilizing a transient DNA-enzyme complex, which leads to persistent DNA double-strand breaks and triggers a cascade of mitochondrial dysfunction and cell death.[11] Dexrazoxane, in this model, acts as a catalytic inhibitor of TOP2B. It binds to the enzyme in a way that prevents the anthracycline from locking it onto the DNA, thereby averting the formation of the toxic ternary complex and subsequent DNA damage.[1] This mechanistic re-evaluation is supported by powerful experimental evidence showing that the iron-chelating metabolite ADR-925 failed to protect cardiomyocytes from anthracycline toxicity, whereas the parent drug Dexrazoxane was highly protective.[17] This finding strongly suggests that the primary cardioprotective effect is mediated by the parent drug's interaction with TOP2B, not its metabolite's ability to chelate iron. This shift does not entirely discount the role of iron chelation but repositions it as a likely secondary or less critical mechanism. It provides a more specific and robust explanation for why Dexrazoxane is uniquely effective, whereas general antioxidants have consistently failed to prevent anthracycline cardiotoxicity in clinical trials.

Mechanism for Extravasation and Antineoplastic Activity - Topoisomerase IIα (TOP2A) Inhibition

In addition to its effects on TOP2B, Dexrazoxane is also a catalytic inhibitor of topoisomerase IIα (TOP2A).[1] The TOP2A isoform is highly expressed in proliferating cells and is the primary target through which anthracyclines exert their anticancer effects. When an anthracycline extravasates into subcutaneous tissue, its "poisoning" of TOP2A in local cells leads to widespread DNA damage and triggers the intense inflammatory and necrotic response that characterizes this severe adverse event.[1] By acting as a catalytic inhibitor of TOP2A, Dexrazoxane prevents the anthracycline from inducing these DNA breaks, thereby mitigating tissue damage. This same mechanism underpins the intrinsic, albeit modest, antineoplastic activity of Dexrazoxane, which was observed in early clinical trials before its development was pivoted toward cytoprotection.[1]

3.2 Pharmacokinetics: Systemic Disposition (ADME)

The pharmacokinetic profile of Dexrazoxane is well-characterized and is described by a two-compartment open model with first-order elimination.[18] Its disposition kinetics are dose-independent across a clinically relevant range of 60 to 900 mg/m².[18]

• Absorption: As it is administered exclusively via the intravenous route, bioavailability is considered 100% complete.[4]
• Distribution: Following IV infusion, Dexrazoxane undergoes a rapid initial distributive phase lasting approximately 0.2 to 0.3 hours, reaching post-distributive equilibrium within two to four hours.[18] It has a steady-state volume of distribution ( Vd​) of approximately 22.4 L/m², which suggests its distribution throughout the total body water.[4] A key feature facilitating this wide distribution is its very low binding to plasma proteins (<2%).[4]
• Metabolism: Dexrazoxane is a prodrug that undergoes intracellular hydrolysis to form several ring-opened metabolites, including the potent iron chelator ADR-925.[4] This conversion is mediated by the enzyme dihydropyrimidine amidohydrolase (DHPase), which is found in the liver and kidneys but notably not in the heart.[4] Qualitative metabolic studies have confirmed the presence of the unchanged parent drug, a diacid-diamide cleavage product, and two monoacid-monoamide ring products in the urine of both animals and humans.[18]
• Excretion: The primary route of elimination is renal. Approximately 42% of an administered dose is excreted in the urine as the parent drug and its metabolites.[4] The mean elimination half-life ( t1/2​) is approximately 2.1 to 2.5 hours.[18] The total plasma clearance is in the range of 6.25 to 7.88 L/h/m², with renal clearance accounting for about 3.35 L/h/m².[18] This significant reliance on renal excretion is a critical clinical consideration, as impaired kidney function can lead to drug accumulation.

Table 2: Summary of Dexrazoxane Pharmacokinetic Parameters

Parameter	Value (Mean, % Coefficient of Variation)	Conditions	Source(s)
Elimination Half-Life (t1/2​)	2.5 h (16%)	500 mg/m² Dexrazoxane + 50 mg/m² Doxorubicin	18
Plasma Clearance	7.88 L/h/m² (18%)	500 mg/m² Dexrazoxane + 50 mg/m² Doxorubicin	18
Renal Clearance	3.35 L/h/m² (36%)	500 mg/m² Dexrazoxane + 50 mg/m² Doxorubicin	18
Volume of Distribution (Vd​)	22.4 L/m² (22%)	500 mg/m² Dexrazoxane + 50 mg/m² Doxorubicin	18
Plasma Protein Binding	< 2%	In vitro studies	4
Bioavailability	100%	Intravenous administration	4

Section 4: Clinical Efficacy and Therapeutic Applications

4.1 FDA-Approved Indications and Dosing

Dexrazoxane has two distinct, FDA-approved indications, each with a specific brand name association, patient population, and dosing regimen.

Cardiomyopathy Prophylaxis (Zinecard® and Totect®)

• Indication: Dexrazoxane is indicated for reducing the incidence and severity of cardiomyopathy associated with doxorubicin administration in women with metastatic breast cancer who have already received a cumulative doxorubicin dose of 300 mg/m² and for whom continued doxorubicin therapy is planned to maintain tumor control.[4] This indication was originally approved for the brand Zinecard® and was subsequently added to the Totect® label in 2020.[19] A critical aspect of this indication is that Dexrazoxane is contraindicated for use at the initiation of a doxorubicin-containing chemotherapy regimen due to concerns, based on early trial data, that it could interfere with antitumor efficacy.[18]
• Dosing and Administration: The recommended dosage is based on a fixed ratio of 10:1 of Dexrazoxane to doxorubicin. For example, a patient receiving 50 mg/m² of doxorubicin would receive 500 mg/m² of Dexrazoxane.[30] It is administered as an intravenous infusion over 15 minutes, with the infusion completed within 30 minutes prior to the administration of doxorubicin.[30]

Anthracycline Extravasation (Totect®)

• Indication: Under the brand name Totect®, Dexrazoxane is indicated for the treatment of tissue injury resulting from the extravasation of an intravenous anthracycline chemotherapeutic agent. This includes drugs such as doxorubicin, daunorubicin, epirubicin, and idarubicin.[6] It is the only approved systemic antidote for this condition.
• Dosing and Administration: The treatment follows a specific three-day intravenous infusion schedule. The first infusion must be initiated as soon as possible and no later than six hours after the extravasation event. Any local cooling measures, such as ice packs, should be removed at least 15 minutes prior to administration to ensure adequate blood flow to the affected area.[15] The regimen is as follows:
• Day 1: 1000 mg/m² (maximum daily dose: 2000 mg)
• Day 2: 1000 mg/m² (maximum daily dose: 2000 mg)
• Day 3: 500 mg/m² (maximum daily dose: 1000 mg) Each dose is administered as an IV infusion over 1 to 2 hours. The infusions on Days 2 and 3 should be started at approximately the same time of day as the Day 1 infusion.6

Table 3: FDA-Approved Dosing Regimens for Dexrazoxane

Indication	Brand Name(s)	Dosing Regimen	Administration Details	Dose Adjustment for Renal Impairment (CrCl < 40 mL/min)
Cardiomyopathy Prophylaxis	Zinecard®, Totect®	10:1 ratio of Dexrazoxane to Doxorubicin (e.g., 500 mg/m² Dexrazoxane for 50 mg/m² Doxorubicin)	IV infusion over 15 minutes, completed within 30 minutes prior to doxorubicin administration.	Reduce Dexrazoxane dose by 50% (5:1 ratio).
Anthracycline Extravasation	Totect®	Day 1: 1000 mg/m² (max 2000 mg) Day 2: 1000 mg/m² (max 2000 mg) Day 3: 500 mg/m² (max 1000 mg)	IV infusion over 1-2 hours. First dose must start within 6 hours of the event.	Reduce all daily doses by 50%.

4.2 Off-Label and Investigational Frontiers

While the FDA-approved indications are narrow, the clinical and investigational use of Dexrazoxane extends into several other important areas, most notably pediatric cardioprotection and expanded use in adult oncology.

Pediatric Cardioprotection: An Evolving Consensus

The use of Dexrazoxane in children has been a subject of intense debate and regulatory evolution. In 2011, the European Medicines Agency (EMA) contraindicated its use in patients under 18, citing concerns about a potential increased risk of secondary malignancies and uncertain efficacy.[26] This decision created a significant barrier to its use in Europe. However, subsequent evidence from long-term follow-up studies of pediatric cancer survivors demonstrated a substantial and sustained cardioprotective benefit.[13] This new data, combined with a more nuanced understanding of the safety risks, led the EMA to conduct a formal review. In 2017, the agency lifted the blanket contraindication, instead recommending that its use be considered in children and adolescents expected to receive high cumulative doses of anthracyclines (e.g., doxorubicin >300 mg/m²).[26]

In the United States, the regulatory path was different. The FDA granted Dexrazoxane an orphan drug designation for pediatric cardioprotection in 2014, signaling its potential value in this population.[26] Reflecting the growing evidence base, clinical practice guidelines have also evolved. For example, NHS England now commissions Dexrazoxane for use in high-risk children and young people (under 25) receiving high-dose anthracyclines.[44] Ongoing research, such as the NCT01790152 (HEART) study, continues to investigate cardiac biomarkers and long-term outcomes in pediatric survivors who did or did not receive Dexrazoxane, aiming to further refine its role.[46] This entire narrative represents a powerful example of how post-marketing evidence can lead to a complete reversal of a major regulatory position, driven by the recognition that for high-risk pediatric patients, the clear and present danger of irreversible heart failure may outweigh the more uncertain, context-dependent risks of the protective agent.

Expanded Use in Adult Oncology

The rationale for cardioprotection is not limited to breast cancer. Evidence from clinical trials and reviews supports the efficacy of Dexrazoxane in other adult cancers that often require high cumulative anthracycline doses, such as soft tissue sarcomas and small-cell lung cancer.[5] Contemporary trials like the ANNOUNCE study in soft-tissue sarcoma have provided valuable modern data on its use in this setting.[14]

A significant emerging off-label application is the upfront use of Dexrazoxane in patients with pre-existing cardiac risk factors or established, asymptomatic cardiomyopathy. These patients would traditionally be considered poor candidates for potentially curative anthracycline-based chemotherapy. A consecutive case series demonstrated that the concomitant administration of Dexrazoxane allowed such high-risk patients to receive their planned anthracycline regimens with minimal decline in cardiac function and without clinical decompensation.[12] This suggests a paradigm-shifting role for Dexrazoxane not merely as a protectant, but as a "treatment-enabling" agent, expanding access to first-line cancer therapies for a vulnerable patient population.

Furthermore, its use is being actively investigated in hematologic malignancies like acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), where anthracyclines are a critical component of induction and consolidation therapy.[48] A recruiting Phase II trial (NCT03589729) is specifically evaluating its ability to prevent heart-related side effects in patients with blood cancers receiving intensive chemotherapy.[48]

4.3 Synthesis of Clinical Evidence and Practice Guidelines

A substantial body of evidence from randomized controlled trials (RCTs) and meta-analyses supports the efficacy of Dexrazoxane. A major Cochrane Review concluded that in adults, Dexrazoxane effectively prevents or reduces anthracycline-induced cardiotoxicity without clear evidence of a negative impact on tumor response or survival.[51] Other meta-analyses have consistently shown a significant reduction in the risk of clinical congestive heart failure and other cardiac events in patients treated with Dexrazoxane.[3]

Based on this evidence, major clinical practice guidelines recommend its consideration. The American Society of Clinical Oncology (ASCO) and the European Society of Cardiology (ESC) both recommend that a cardioprotective strategy, such as Dexrazoxane or the use of liposomal anthracycline formulations, be considered for adult patients at high risk of cardiotoxicity.[11] The National Comprehensive Cancer Network (NCCN) also supports its use in appropriate settings.[39]

Despite this strong evidence and guideline support, multiple sources indicate that Dexrazoxane remains significantly underutilized in routine clinical practice.[11] This "evidence-practice gap" is likely fueled by a combination of factors, including lingering safety concerns (particularly regarding secondary malignancies), the persistence of an early, un-replicated finding of reduced tumor response, and a lack of familiarity with its use outside of the narrow FDA-approved indication. The data from comparative clinical trials, however, presents a compelling argument for its value. For instance, the LMS 04 trial in leiomyosarcoma, which prohibited Dexrazoxane use, reported a 5.4% incidence of heart failure at cumulative doxorubicin doses of 360–450 mg/m². In contrast, the ANNOUNCE trial in soft-tissue sarcoma, where Dexrazoxane was used in the majority of patients receiving high doses, reported heart failure rates of 3% or less, even at cumulative doxorubicin doses exceeding 600 mg/m².[14] This stark contrast highlights the real-world clinical benefit of cardioprotection.

Table 4: Summary of Key Clinical Trials Evaluating Dexrazoxane Cardioprotection

Trial Name / Identifier	Patient Population	Dexrazoxane Use	Cumulative Doxorubicin Dose (mg/m²)	Key Cardiac Outcome	Key Oncologic Outcome	Source(s)
LMS 04	Advanced Leiomyosarcoma	Prohibited	360–450	5.4% incidence of Heart Failure	N/A (Control Arm)	14
ANNOUNCE	Soft-Tissue Sarcoma	Yes (88.5% of pts)	450–599	3% incidence of Heart Failure	No difference in survival	14
ANNOUNCE	Soft-Tissue Sarcoma	Yes (90% of pts)	≥ 600	1.1% incidence of Heart Failure	No difference in survival	14
P9754	Pediatric Osteosarcoma	Yes (100%, upfront)	450–600	0% clinical Heart Failure; 2.1% LVEF decline	N/A (Single Arm)	14
POG 9425/9426	Pediatric Hodgkin's Disease	Randomized	Varied	Reduced cardiopulmonary toxicity	Increased risk of SMN observed	20
DFCI 95-01	Pediatric ALL	Randomized	300	Reduced markers of myocardial injury	No increased risk of SMN	21

Section 5: Safety, Tolerability, and Risk Management

5.1 Adverse Reaction Profile and Drug Interactions

The safety profile of Dexrazoxane must be interpreted in the context of its co-administration with highly toxic chemotherapy regimens. When its effects can be isolated, such as in its use for extravasation, the most common adverse reactions include nausea, vomiting, pyrexia (fever), and injection site reactions like pain and phlebitis.[15]

When used as a cardioprotectant alongside chemotherapy, the most significant and consistent adverse effect attributable to Dexrazoxane is an enhancement of the myelosuppression caused by the concomitant antineoplastic agents. This manifests as more severe leukopenia, neutropenia, and thrombocytopenia than would be seen with chemotherapy alone.[5] This necessitates careful hematological monitoring.

The primary contraindication for Dexrazoxane is its use in patients receiving chemotherapy regimens that do not contain an anthracycline.[18]

Drug interactions are primarily pharmacodynamic. There is an increased risk of additive myelosuppression when combined with other cytotoxic drugs (e.g., hydroxyurea, lomustine), radiation therapy, or certain myelosuppressive antivirals like zidovudine.[28] Pharmacokinetically, Dexrazoxane may decrease the excretion rate of a wide range of medications, potentially leading to higher serum levels. This appears to be a general, non-specific effect, and the list of potentially affected drugs is extensive, including agents like abacavir, aclidinium, and alogliptin.[4] Conversely, drugs that increase renal excretion, such as acetazolamide, could theoretically lower Dexrazoxane levels and reduce its efficacy.[4]

5.2 Critical Controversies and Warnings

Several major warnings and controversies shape the clinical use of Dexrazoxane. While it does not have a formal black box warning in the United States, the following points represent the most critical safety considerations.

Myelosuppression

This is the most well-established and clinically managed risk. By adding its own myelosuppressive effect to that of chemotherapy, Dexrazoxane can increase the depth and duration of neutropenia and thrombocytopenia. Therefore, complete blood counts (CBC) must be monitored closely before and during each course of therapy, and treatment should only proceed if hematologic parameters are adequate.[15]

Risk of Secondary Malignancies (SMN)

This is the most significant and complex controversy surrounding Dexrazoxane. The concern stems primarily from studies in pediatric Hodgkin's disease (HD), where patients randomized to receive Dexrazoxane with their chemotherapy (notably, regimens containing etoposide and alkylating agents) had a higher incidence of secondary malignancies, particularly acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS).[18] The biological plausibility for this risk is clear, as Dexrazoxane is itself a topoisomerase II inhibitor, a class of drugs known to be associated with therapy-related leukemias.[20]

However, this finding is not universal. In a starkly contrasting result, a large randomized trial in children with high-risk acute lymphoblastic leukemia (ALL) found no increased risk of SMNs in the group that received Dexrazoxane.[21] Similarly, meta-analyses of adult trials have not demonstrated a clear signal for an increased risk of secondary cancers.[11] The most likely explanation for this discrepancy is that the risk is not an independent effect of Dexrazoxane but rather a context-dependent, synergistic toxicity. The risk appears to be magnified when Dexrazoxane is combined with other known carcinogenic therapies, such as the etoposide and alkylating agents used in the HD protocols, but may be negligible when used with other chemotherapy backbones.[20] This transforms the risk assessment from a simple question of whether the drug is carcinogenic to a more sophisticated analysis of the entire treatment regimen a patient will receive.

Interference with Antitumor Efficacy

A persistent warning on the drug's label cautions against its use at the initiation of chemotherapy, based on results from a single large trial in metastatic breast cancer where patients receiving the FAC regimen (fluorouracil, doxorubicin, cyclophosphamide) plus Dexrazoxane from the start had a lower tumor response rate (48% vs. 63%) and a shorter time to progression.[18] This finding has cast a long shadow over the drug's use.

However, this result has not been consistently replicated. The majority of subsequent clinical trials and large meta-analyses have found no significant differences in tumor response rates, progression-free survival, or overall survival between patients who did and did not receive Dexrazoxane.[5] While the initial negative finding cannot be dismissed and justifies the regulatory warning, the balance of evidence today suggests that when used appropriately (i.e., not with initial cycles in certain regimens), Dexrazoxane does not compromise oncologic outcomes. This discrepancy between the label warning and the broader body of evidence contributes significantly to the evidence-practice gap, as clinicians may be hesitant to use the drug due to this "ghost of old data."

Embryo-Fetal Toxicity

Dexrazoxane is known to be teratogenic and can cause fetal harm based on its mechanism of action and findings in animal studies, which showed embryotoxicity and teratogenicity at doses well below the human equivalent.[18]

5.3 Use in Special Populations

• Pregnancy and Contraception: Dexrazoxane is contraindicated in pregnancy. Due to its potential for teratogenicity and genotoxicity, stringent contraceptive measures are required. Females of reproductive potential must use highly effective contraception during treatment and for at least 6 months after the final dose. Male patients with female partners of reproductive potential must use effective contraception during treatment and for 3 months after the final dose.[18]
• Lactation: It is not known whether Dexrazoxane is excreted in human milk. Due to the potential for serious adverse reactions in a breastfed infant, breastfeeding should be discontinued during therapy and for at least two weeks after the last dose.[1]
• Pediatric Use: While the official FDA label states that safety and efficacy have not been established in pediatric patients, this is an area of active clinical use and evolving guidelines.[18] As discussed previously, off-label use is now supported by strong evidence and recommended by some international bodies for children at high risk of cardiotoxicity from high cumulative anthracycline doses.[13]
• Geriatric Use: No specific geriatric problems have been identified in studies. However, caution is warranted as elderly patients are more likely to have age-related comorbidities, particularly renal dysfunction, which necessitates dose adjustment.[56]
• Renal Impairment: Dexrazoxane clearance is significantly reduced in patients with renal impairment. A 50% dose reduction is mandatory for patients with a creatinine clearance (CrCl) below 40 mL/min for both the cardioprotection and extravasation indications.[15]
• Hepatic Impairment: For cardiomyopathy prophylaxis, the Dexrazoxane dose should be reduced proportionally if the doxorubicin dose is reduced due to hyperbilirubinemia, thereby maintaining the 10:1 ratio.[6] For the treatment of extravasation, the use of Totect® is not recommended in patients with hepatic impairment.[28]

Section 6: Regulatory and Historical Context

Discovery and Early Development

Dexrazoxane was discovered in 1972 as part of a research program investigating bisdioxopiperazine compounds.[26] Initially, Dexrazoxane (coded as ICRF-187) and its racemic parent compound, razoxane (ICRF-159), were studied for their potential as antineoplastic agents, with early trials exploring their activity against various cancers.[1] Its potent cardioprotective properties against anthracycline toxicity were discovered subsequently, which redirected its clinical development path toward its current role as a cytoprotectant.[12]

Zinecard® Approval History

The regulatory journey for the cardioprotection indication in the United States began with an orphan drug designation.

• Orphan Designation: On December 17, 1991, the U.S. Food and Drug Administration (FDA) granted orphan drug designation to Dexrazoxane for the "prevention of cardiomyopathy associated with doxorubicin administration".[57]
• FDA Approval: Following clinical trials, the FDA granted marketing approval on May 26, 1995, to the brand Zinecard® (manufacturer: Pharmacia & Upjohn, which later became part of Pfizer). The approval was for the specific indication of reducing cardiomyopathy in women with metastatic breast cancer who had received a cumulative doxorubicin dose of 300 mg/m².[37]
• Generic Availability: The first abbreviated new drug applications (ANDAs) for generic dexrazoxane for injection were approved by the FDA in November 2011, increasing market competition.[59]

Totect® Approval History

The development of Dexrazoxane for extravasation followed a separate regulatory pathway.

• Indication and Approval: On September 6, 2007, the FDA approved Totect® (manufacturer: TopoTarget A/S, later acquired by Clinigen) for the treatment of extravasation resulting from intravenous anthracycline chemotherapy.[16] The approval was based on data from two open-label, non-controlled studies that demonstrated a dramatic reduction in the need for surgical debridement in patients treated with the three-day regimen.[16]
• Label Expansion: In a significant regulatory harmonization, the FDA approved a label expansion for Totect® on November 2, 2020. This expansion added the cardiomyopathy prophylaxis indication, making the approved uses of Totect® and Zinecard® consistent.[19]

European Regulatory History

In Europe, Dexrazoxane has been approved by the European Medicines Agency (EMA) under brand names such as Cardioxane® and Savene®.[26] The European regulatory history is particularly notable for its dynamic handling of the pediatric use controversy. The initial contraindication in children in 2011, followed by a formal review and subsequent reversal of this decision in 2017 for high-risk patients, serves as a key example of how regulatory bodies adapt to new, long-term clinical evidence.[26]

Table 5: Regulatory Approval History of Dexrazoxane Formulations (Zinecard & Totect)

Brand Name	Manufacturer	Date	Regulatory Body	Action	Approved Indication	Source(s)
Zinecard®	Pharmacia & Upjohn	Dec 17, 1991	FDA	Orphan Designation	Prevention of doxorubicin-associated cardiomyopathy	57
Zinecard®	Pharmacia & Upjohn	May 26, 1995	FDA	Initial Approval	Cardiomyopathy prophylaxis in metastatic breast cancer	37
Totect®	TopoTarget A/S	Sep 6, 2007	FDA	Initial Approval	Treatment of anthracycline extravasation	16
Generic	Mylan Inc.	Nov 28, 2011	FDA	Generic Approval	Cardiomyopathy prophylaxis (Zinecard equivalent)	59
Totect®	Clinigen	Nov 2, 2020	FDA	Label Expansion	Addition of cardiomyopathy prophylaxis indication	19

Section 7: Conclusion and Future Directions

Summary of Findings

Dexrazoxane is a pharmacologically unique agent with proven efficacy in two distinct oncologic settings. It stands as the only approved therapy for mitigating the dose-limiting cardiotoxicity of anthracyclines and for treating the severe tissue damage caused by their extravasation. The scientific understanding of its mechanism of action has matured significantly, with compelling evidence now pointing to the inhibition of topoisomerase IIβ (TOP2B) as the primary driver of its cardioprotective effects. This represents a critical paradigm shift away from the classic, simpler model of iron chelation and provides a more robust explanation for its specific efficacy. Decades of clinical trials and multiple meta-analyses have firmly established its ability to reduce the incidence of congestive heart failure in patients receiving high cumulative doses of anthracyclines, generally without compromising oncologic outcomes.

The Central Paradox

Despite this wealth of positive data and support from major international clinical practice guidelines, Dexrazoxane remains a profoundly underutilized drug. This report has detailed the central paradox of Dexrazoxane: a significant and persistent gap between the evidence supporting its use and its actual implementation in clinical practice. This gap is fueled by a confluence of factors, including the persistence of warnings on its label that are rooted in early, un-replicated trial data, and a complex and often misunderstood safety profile. The lingering concerns about its potential to cause secondary malignancies or interfere with antitumor efficacy, while valid points for consideration, are highly context-dependent and may be overstated in many clinical scenarios where the risk of permanent cardiac damage is high and immediate.

Future Research Directions

To bridge the evidence-practice gap and optimize the clinical utility of Dexrazoxane, future research should focus on addressing the remaining areas of uncertainty. Based on the evidence gaps identified in this report, key priorities for future investigation include:

• Prospective Trials in Modern Regimens: There is a pressing need for well-designed, prospective, randomized trials evaluating the efficacy and safety of Dexrazoxane in the context of modern adult oncologic regimens. This includes its combination with newer targeted therapies and immunotherapies for hematologic malignancies (e.g., AML, lymphoma) and solid tumors beyond breast cancer and sarcoma, where anthracyclines remain a standard of care.[11]
• Use in High-Risk Cardiac Patients: More robust data is required to confirm the safety and efficacy of upfront Dexrazoxane use in patients with pre-existing cardiac dysfunction (e.g., low LVEF) or multiple cardiac risk factors who require anthracycline therapy. Moving beyond case series to larger, prospective studies would provide the evidence needed to confidently use Dexrazoxane as a treatment-enabling agent in this vulnerable population.[11]
• Clarification of SMN Risk: Further research is needed to definitively elucidate the mechanisms behind the potential synergistic risk of secondary malignancies. This would involve preclinical and clinical studies designed to understand the interaction between Dexrazoxane and other specific classes of carcinogenic agents (e.g., etoposide, alkylating agents), which could lead to more nuanced, regimen-specific guidelines for its use in pediatrics and young adults.
• Exploration of Novel Applications: The protective effects of Dexrazoxane against ischemia-reperfusion injury, which are central to its action in both cardiotoxicity and extravasation, suggest potential applications beyond oncology. The pilot trial exploring its use in congenital heart surgery is an intriguing first step, and further investigation into its utility in other clinical settings characterized by ischemia-reperfusion injury may be warranted.[64]

Final Expert Perspective

The decision to incorporate Dexrazoxane into a patient's treatment plan is a sophisticated clinical judgment that demands an individualized risk-benefit calculation. Clinicians must weigh the known, substantial, and often irreversible risk of anthracycline-induced cardiotoxicity against the lower, context-dependent, and in some cases, theoretical risks associated with the protectant. The evidence strongly suggests that for many patients—particularly those with advanced cancers requiring high cumulative anthracycline doses, children with cancers where anthracyclines are critical, and adults with pre-existing cardiac risk—the balance tips decisively in favor of cardioprotection. Overcoming the inertia that limits its current use will require a concerted effort in provider education to disseminate the contemporary understanding of its mechanisms and risk profile, alongside the generation of new, targeted clinical data to finally resolve the lingering questions from a previous era of research.

Works cited

1. Dexrazoxane | C11H16N4O4 | CID 71384 - PubChem, accessed August 12, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Dexrazoxane
2. Dexrazoxane = 95 HPLC 24584-09-6 - Sigma-Aldrich, accessed August 12, 2025, https://www.sigmaaldrich.com/US/en/product/sigma/d1446
3. Dexrazoxane for the treatment of chemotherapy-related side effects - Dove Medical Press, accessed August 12, 2025, https://www.dovepress.com/dexrazoxane-for-the-treatment-of-chemotherapy-related-side-effects-peer-reviewed-fulltext-article-CMAR
4. Dexrazoxane: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed August 12, 2025, https://go.drugbank.com/drugs/DB00380
5. Dexrazoxane : a review of its use for cardioprotection during anthracycline chemotherapy, accessed August 12, 2025, https://pubmed.ncbi.nlm.nih.gov/15892593/
6. Dexrazoxane - StatPearls - NCBI Bookshelf, accessed August 12, 2025, https://www.ncbi.nlm.nih.gov/books/NBK560559/
7. Dexrazoxane - brand name list from Drugs.com, accessed August 12, 2025, https://www.drugs.com/ingredient/dexrazoxane.html
8. Definition of dexrazoxane hydrochloride - NCI Dictionary of Cancer Terms, accessed August 12, 2025, https://www.cancer.gov/publications/dictionaries/cancer-terms/def/dexrazoxane-hydrochloride
9. Dexrazoxane Injection: MedlinePlus Drug Information, accessed August 12, 2025, https://medlineplus.gov/druginfo/meds/a609010.html
10. CAS 24584-09-6 Dexrazoxane ((S)-Razoxane) - BOC Sciences, accessed August 12, 2025, https://www.bocsci.com/product/dexrazoxane-s-razoxane-cas-24584-09-6-63948.html
11. Dexrazoxane to Prevent Cardiotoxicity in Adults Treated with Anthracyclines: JACC: CardioOncology Controversies in Cardio-Oncology, accessed August 12, 2025, https://www.jacc.org/doi/10.1016/j.jaccao.2024.02.004
12. Upfront dexrazoxane for the reduction of anthracycline-induced cardiotoxicity in adults with preexisting cardiomyopathy and cancer: a consecutive case series, accessed August 12, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC7048095/
13. Dexrazoxane Protects Kids' Hearts from Doxorubicin - NCI - National Cancer Institute, accessed August 12, 2025, https://www.cancer.gov/news-events/cancer-currents-blog/2023/childhood-cancer-dexrazoxane-protects-heart-doxorubicin
14. Dexrazoxane makes doxorubicin-induced heart failure a rare event in sarcoma patients receiving high cumulative doses - PMC, accessed August 12, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11921489/
15. Totect (dexrazoxane) for injection - accessdata.fda.gov, accessed August 12, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/022025s015lbl.pdf
16. Dexrazoxane (Totect): FDA review and approval for the treatment of accidental extravasation following intravenous anthracycline chemotherapy - PubMed, accessed August 12, 2025, https://pubmed.ncbi.nlm.nih.gov/18448560/
17. Clinically Translatable Prevention of Anthracycline Cardiotoxicity by Dexrazoxane Is Mediated by Topoisomerase II Beta and Not Metal Chelation | Circulation: Heart Failure, accessed August 12, 2025, https://www.ahajournals.org/doi/10.1161/CIRCHEARTFAILURE.120.008209
18. ZINECARD® (dexrazoxane) for injection - accessdata.fda.gov, accessed August 12, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/020212s017lbl.pdf
19. Totect® (dexrazoxane) – New indication, accessed August 12, 2025, https://professionals.optumrx.com/content/dam/optum3/professional-optumrx/news/rxnews/clinical-updates/clinicalupdates_totect_2020-1106.pdf
20. Dexrazoxane-Associated Risk for Acute Myeloid Leukemia/Myelodysplastic Syndrome and Other Secondary Malignancies in Pediatric Hodgkin's Disease | Journal of Clinical Oncology - ASCO Publications, accessed August 12, 2025, https://ascopubs.org/doi/10.1200/JCO.2005.02.3879
21. Absence of Secondary Malignant Neoplasms in Children With High-Risk Acute Lymphoblastic Leukemia Treated With Dexrazoxane | Journal of Clinical Oncology - ASCO Publications, accessed August 12, 2025, https://ascopubs.org/doi/10.1200/JCO.2007.12.2481
22. Dexrazoxane to Prevent Cardiotoxicity in Adults Treated with Anthracyclines: JACC: CardioOncology Controversies in Cardio-Oncology - PMC, accessed August 12, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11103024/
23. Dexrazoxane (ICRF 187, NSC 169780, CAS Number: 24584-09-6) | Cayman Chemical, accessed August 12, 2025, https://www.caymanchem.com/product/14632/dexrazoxane
24. Dexrazoxane 24584-09-6 | TCI AMERICA - TCI Chemicals, accessed August 12, 2025, https://www.tcichemicals.com/US/en/p/D4227
25. Dexrazoxane | CAS 24584-09-6 | SCBT - Santa Cruz Biotechnology, accessed August 12, 2025, https://www.scbt.com/p/dexrazoxane-24584-09-6
26. en.wikipedia.org, accessed August 12, 2025, https://en.wikipedia.org/wiki/Dexrazoxane
27. Zinecard (dexrazoxane for injection) - accessdata.fda.gov, accessed August 12, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020212s013lbl.pdf
28. Totect, Zinecard (dexrazoxane) dosing, indications, interactions, adverse effects, and more, accessed August 12, 2025, https://reference.medscape.com/drug/totect-zinecard-dexrazoxane-342250
29. Dexrazoxane: Side Effects, Uses, Dosage, Interactions, Warnings - RxList, accessed August 12, 2025, https://www.rxlist.com/dexrazoxane/generic-drug.htm
30. Clinical Policy: Dexrazoxane (Zinecard, Totect) - Ambetter Health, accessed August 12, 2025, https://www.ambetterhealth.com/content/dam/centene/Superior/policies/pharmacy-policies/Dexrazoxane%20(Zinecard,%20Totect)%20(CP.PHAR.418)%20(PDF).pdf
31. What is Dexrazoxane Hydrochloride used for? - Patsnap Synapse, accessed August 12, 2025, https://synapse.patsnap.com/article/what-is-dexrazoxane-hydrochloride-used-for
32. Dexrazoxane supplier | CAS 24584-09-6 | Focus Biomolecules, accessed August 12, 2025, https://focusbiomolecules.com/dexrazoxane-iron-chelator-ferroptosis-inhibitor/
33. In Brief: Dexrazoxane for Anthracycline Extravasation | The Medical Letter Inc., accessed August 12, 2025, https://secure.medicalletter.org/TML-article-1275c
34. Phase I Trial of 96-Hour Continuous Infusion of Dexrazoxane in Patients with Advanced Malignancies1 - AACR Journals, accessed August 12, 2025, https://aacrjournals.org/clincancerres/article/7/6/1569/288865/Phase-I-Trial-of-96-Hour-Continuous-Infusion-of
35. Dexrazoxane | Davis's Drug Guide for Rehabilitation Professionals, accessed August 12, 2025, https://fadavispt.mhmedical.com/content.aspx?bookid=1873§ionid=139007944
36. Dexrazoxane Hydrochloride - NCI, accessed August 12, 2025, https://www.cancer.gov/about-cancer/treatment/drugs/dexrazoxanehydrochloride
37. Generic Zinecard Availability - Drugs.com, accessed August 12, 2025, https://www.drugs.com/availability/generic-zinecard.html
38. Dexrazoxane Dosage Guide + Max Dose, Adjustments - Drugs.com, accessed August 12, 2025, https://www.drugs.com/dosage/dexrazoxane.html
39. Clinical Policy: Dexrazoxane (Zinecard, Totect) - Ambetter Health, accessed August 12, 2025, https://www.ambetterhealth.com/content/dam/centene/Superior/policies/pharmacy-policies/CPPHAR418.pdf
40. Dexrazoxane Uses, Side Effects & Warnings - Drugs.com, accessed August 12, 2025, https://www.drugs.com/mtm/dexrazoxane.html
41. Totect (dexrazoxane) FDA Approval History - Drugs.com, accessed August 12, 2025, https://www.drugs.com/history/totect.html
42. Safety Evaluation of the Combination with Dexrazoxane and Anthracyclines: A Disproportionality Analysis Based on the Food and Drug Administration Adverse Event Reporting System Database - PMC - PubMed Central, accessed August 12, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11678267/
43. Safety Evaluation of the Combination with Dexrazoxane and Anthracyclines: A Disproportionality Analysis Based on the Food and Drug Administration Adverse Event Reporting System Database - MDPI, accessed August 12, 2025, https://www.mdpi.com/1424-8247/17/12/1739
44. NHS England Evidence review: Dexrazoxane for preventing cardiotoxicity in people aged under 25 years receiving high-dose, accessed August 12, 2025, https://www.england.nhs.uk/wp-content/uploads/2020/03/1825-Evidence-Review-Jan-2019.pdf
45. Clinical Commissioning Policy: Dexrazoxane for preventing cardiotoxicity in children and young people (under 25 years) receiving high - NHS England, accessed August 12, 2025, https://www.england.nhs.uk/wp-content/uploads/2020/03/Dexrazoxane-for-preventing-cardiotoxicity-in-children-and-young-people.pdf
46. Study Details | Effects of Dexrazoxane Hydrochloride on Biomarkers Associated With Cardiomyopathy and Heart Failure After Cancer Treatment | ClinicalTrials.gov, accessed August 12, 2025, https://www.clinicaltrials.gov/study/NCT01790152?term=DEXRAZOXANE&rank=10
47. Effects of Dexrazoxane Hydrochloride on Biomarkers Associated With Cardiomyopathy and Heart Failure After Cancer Treatment (HEART) > Clinical Trials > Yale Medicine, accessed August 12, 2025, https://www.yalemedicine.org/clinical-trials/alte11c2-heart
48. Dexrazoxane Recruiting Phase 2 Trials for Granulocytic Sarcoma / Philadelphia Chromosome Positive (Ph+) / High-risk Myelodysplastic Syndrome (MDS) / Myeloproliferative Neoplasms (MPNs) Supportive Care - DrugBank, accessed August 12, 2025, https://go.drugbank.com/drugs/DB00380/clinical_trials?conditions=DBCOND0077483%2CDBCOND0071603%2CDBCOND0133605%2CDBCOND0047040&phase=2&purpose=supportive_care&status=recruiting
49. Dexrazoxane for cardioprotection in older adults with acute myeloid leukemia - PMC, accessed August 12, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC5402627/
50. Dexrazoxane Hydrochloride in Preventing Heart-Related Side Effects of Chemotherapy in Participants With Blood Cancers | ClinicalTrials.gov, accessed August 12, 2025, https://clinicaltrials.gov/study/NCT03589729
51. Can the medicine dexrazoxane prevent or reduce heart damage in adults and children with cancer receiving anthracyclines? | Cochrane, accessed August 12, 2025, https://www.cochrane.org/evidence/CD014638_can-medicine-dexrazoxane-prevent-or-reduce-heart-damage-adults-and-children-cancer-receiving
52. Dexrazoxane. A review of its use as a cardioprotective agent in patients receiving anthracycline-based chemotherapy - PubMed, accessed August 12, 2025, https://pubmed.ncbi.nlm.nih.gov/9777314/
53. Cardioprotective effect and safety of dexrazoxane in all breast cancer stages in patients treated with anthracyclines with or without trastuzumab: A systematic review and meta-analysis. - ASCO Publications, accessed August 12, 2025, https://ascopubs.org/doi/10.1200/JCO.2018.36.15_suppl.10072
54. Preventing Anthracycline-Associated Heart Failure: What Is the Role of Dexrazoxane?: JACC: CardioOncology Controversies in Cardio-Oncology, accessed August 12, 2025, https://www.jacc.org/doi/10.1016/j.jaccao.2024.01.004
55. Cardioprotection and Second Malignant Neoplasms Associated With Dexrazoxane in Children Receiving Anthracycline Chemotherapy: A Systematic Review and Meta-Analysis | JNCI: Journal of the National Cancer Institute | Oxford Academic, accessed August 12, 2025, https://academic.oup.com/jnci/article/108/4/djv357/2412399
56. Dexrazoxane (intravenous route) - Side effects & uses - Mayo Clinic, accessed August 12, 2025, https://www.mayoclinic.org/drugs-supplements/dexrazoxane-intravenous-route/description/drg-20063392
57. Search Orphan Drug Designations and Approvals - FDA, accessed August 12, 2025, https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=63291
58. Zinecard Uses, Side Effects & Warnings - Drugs.com, accessed August 12, 2025, https://www.drugs.com/mtm/zinecard.html
59. Mylan Receives Approval for Generic Version of Zinecard® for Injection, accessed August 12, 2025, https://investor.mylan.com/news-releases/news-release-details/mylan-receives-approval-generic-version-zinecardr-injection
60. Generic Totect Availability - Drugs.com, accessed August 12, 2025, https://www.drugs.com/availability/generic-totect.html
61. center for drug evaluation and - accessdata.fda.gov, accessed August 12, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022025s000_MedR.pdf
62. dexrazoxane | Ligand page - IUPHAR/BPS Guide to PHARMACOLOGY, accessed August 12, 2025, https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?tab=biology&ligandId=7330
63. dexrazoxane | Ligand page - IUPHAR/BPS Guide to PHARMACOLOGY, accessed August 12, 2025, https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=7330
64. Study Details | Use of the Cardioprotectant Dexrazoxane During Congenital Heart Surgery: Proposal for Pilot Investigation, accessed August 12, 2025, https://www.clinicaltrials.gov/study/NCT02519335?term=DEXRAZOXANE&rank=4