Dexrazoxane - Uses, Dosage, Side Effects, Pharmacology, and Drug Interactions

Overview:

Imagine a condition where the heart, the vital organ responsible for our very existence, battles silently against weakened muscles. This is cardiomyopathy, a complex disorder that poses a significant health challenge worldwide. Dexrazoxane hydrochloride for injection received approval from the U.S. Food and Drug Administration on September 6, 2007. It was granted approval for the treatment of extravasation caused by intravenous anthracycline chemotherapy. Despite medical advancements, effective treatment options for cardiomyopathy remain limited, necessitating innovative approaches to combat this relentless foe. In the quest for a solution, Dexrazoxane emerged as an unexpected contender. Originally developed as a cardioprotective agent for cancer patients undergoing chemotherapy, Dexrazoxane has recently captured the attention of cardiologists seeking novel therapies.

This drug, with its intriguing mechanisms of action, holds the potential to revolutionize the way in the management of not only chemotherapy-related cardiac toxicity but also the broader spectrum of cardiomyopathies. This article explores the world of Dexrazoxane and its profound impact on cardiomyopathy and unveils the secrets behind this remarkable medication, exploring how it defends the heart against oxidative stress and prevents DNA damage, thus fortifying weakened cardiac muscle. While initially celebrated for its cardioprotective effects during cancer treatment and various non-oncological cardiomyopathies as well.

Drug Group:

Dexrazoxane belongs to the class of medications known as cardioprotective agents.

Available Doses and Dosage Forms:

1. Injectable Solution: Dexrazoxane is primarily available as an injectable solution for intravenous administration. This formulation allows for precise dosing and direct delivery into the bloodstream, ensuring optimal absorption and distribution throughout the body.

2. Doses: The recommended dosage ratio of Dexrazoxane to Doxorubicin is 10:1. For example, if the prescribed dosage of Doxorubicin is 50 mg/m2 (milligrams per square), the corresponding dosage of Dexrazoxane should be 500 mg/m2.

Dexrazoxane is available in the following strengths as sterile, pyrogen-free lyophilizers:

• 250 mg (milligrams): It comes in a single-dose vial with a red flip-top seal, packaged in single vial packs. The National Drug Code (NDC) for this strength is 0013-8717-62.

• 500 mg: It comes in a single-dose vial with a blue flip-top seal, also packaged in single vial packs. The NDC for this strength is 0013-8727-89.

For Patients:

What Is Cardiomyopathy?

Cardiomyopathy is a term used to describe a group of diseases that affect the heart muscle. It is characterized by structural and functional abnormalities of the heart muscle, leading to impaired cardiac function.

There are several types of cardiomyopathy, including

1. Dilated Cardiomyopathy (DCM): In DCM, the heart chambers become enlarged, causing the heart muscle to stretch and weaken. This results in reduced pumping efficiency, leading to symptoms such as fatigue, shortness of breath, and fluid retention.

2. Hypertrophic Cardiomyopathy (HCM): HCM is a condition distinguished by the thickening of the heart muscle, particularly in the ventricles (the lower chambers). This thickening can create obstacles to the flow of blood and give rise to various symptoms, including chest pain, dizziness, and episodes of fainting.

3. Restrictive Cardiomyopathy (RCM): RCM involves the stiffening of the heart muscle, which restricts the heart's ability to stretch and fill with blood properly. This leads to decreased cardiac output and symptoms such as fatigue, swelling, and arrhythmias.

4. Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC): ARVC is a condition where fatty or fibrous tissue replaces normal heart muscle tissue, primarily in the right ventricle. This can lead to arrhythmias, heart palpitations, and in some cases, sudden cardiac arrest.

The causes of cardiomyopathy can be diverse, including genetic factors, certain infections, long-term high blood pressure, autoimmune disorders, and exposure to toxins or certain medications. Some forms of cardiomyopathy may also be idiopathic, meaning the exact cause is unknown.

Diagnosis of cardiomyopathy typically involves a combination of medical history evaluation, physical examination, imaging tests, and sometimes genetic testing. Treatment options for cardiomyopathy may include medications to manage symptoms, lifestyle changes (such as diet and exercise modifications), implantable devices (such as pacemakers or defibrillators), and in severe cases, heart transplantation.

How Does Dexrazoxane Work?

Dexrazoxane, a medication with cardioprotective properties, works through several mechanisms to protect the heart from damage caused by certain treatments, particularly anthracycline chemotherapy drugs. While the exact details of its action are not fully understood, the following mechanisms are believed to contribute to Dexrazoxane's cytoprotective effects:

1. Chelation of Iron: Dexrazoxane has chelating properties, meaning it can bind to and sequester iron ions. Iron contributes to the generation of free radicals, which can lead to oxidative harm to cells, including the cardiac muscle. By chelating iron, Dexrazoxane helps reduce the availability of iron for free radical formation, thus decreasing oxidative stress and potential cardiac injury.

2. Inhibition of Topoisomerase II: Dexrazoxane has been found to inhibit the activity of the enzyme topoisomerase II, which plays a role in DNA (Deoxyribonucleic acid) replication and repair. By inhibiting this enzyme, Dexrazoxane may help prevent or minimize DNA damage caused by chemotherapy drugs.

3. Reduction of Reactive Oxygen Species (ROS): Dexrazoxane has been shown to reduce the levels of reactive oxygen species (ROS) in cardiac cells. ROS are highly reactive molecules that can cause cellular damage, including oxidative stress. By reducing ROS levels, Dexrazoxane helps maintain the redox balance within cardiac cells, reducing the risk of oxidative damage and preserving their function.

4. Preservation of Mitochondrial Function: Dexrazoxane has been found to protect mitochondria, the energy-producing structures within cells. It helps maintain mitochondrial membrane integrity and function, which is crucial for the heart's energy supply and overall cardiac performance.

What Is the Dosage of Dexrazoxane?

The recommended dosage ratio of Dexrazoxane to Doxorubicin is often 10:1. This means that if the prescribed dosage of Doxorubicin is 50 mg/m2, the corresponding dosage of Dexrazoxane would be 500 mg/m2.

How Effective Is Dexrazoxane?

Dexrazoxane is a cardioprotective agent that has proven effective in various clinical settings, particularly in mitigating the cardiotoxic effects of certain treatments like anthracycline chemotherapy. Extensive research supports its use in cancer treatment to protect the heart from anthracycline-induced cardiomyopathy. Clinical trials have shown that Dexrazoxane significantly reduces the incidence and severity of cardiotoxicity without compromising cancer treatment efficacy. It is recommended for patients receiving high cumulative doses of anthracyclines or those with pre-existing cardiac risk factors. Dexrazoxane has also shown promise in managing non-oncological cardiomyopathies by improving cardiac function, reducing symptoms, and enhancing quality of life. Its mechanisms of action, including reducing oxidative stress and preserving mitochondrial function, contribute to its effectiveness in supporting cardiac health.

What Are the Things to Inform the Doctor Before Taking the Drug?

Before receiving a Dexrazoxane injection, it is important to:

• Inform the doctor about allergies to Dexrazoxane or other medications.

• Provide a list of current medications, including topical products with DMSO (Dimethyl sulfoxide).

• Disclose any history of heart, kidney, or liver disease.

• Discuss pregnancy plans and use appropriate birth control during treatment. Avoid breastfeeding while using Dexrazoxane.

• Understand that Dexrazoxane may affect male fertility.

• Notify the doctor of any scheduled surgeries, including dental procedures.

• Regular monitoring by the doctor is necessary to assess heart impact despite Dexrazoxane's protective effects.

How Is Dexrazoxane Administered?

Dexrazoxane should be administered through intravenous (IV) infusion over a period of 15 minutes. It is important to note that intravenous push administration should be avoided. Dexrazoxane should be administered before Doxorubicin. It is advised not to administer Doxorubicin prior to the completion of the Dexrazoxane infusion. After the Dexrazoxane infusion is completed, Doxorubicin should be administered within 30 minutes. This sequential administration ensures the appropriate timing for both medications. To prepare and handle the infusion solution for Dexrazoxane, follow these guidelines:

• Reconstitution: Reconstitute Dexrazoxane with sterile water for injection, USP. Use 25 mL of sterile water for injection for a Dexrazoxane 250 mg vial and 50 mL for a Dexrazoxane 500 mg vial. This will result in a concentration of 10 mg/mL.

• Further Dilution: To achieve a concentration of 1.3 to 3.0 mg/mL (milligrams per milliliter), it is advised to dilute the reconstituted solution with lactated Ringer's injection, USP. This dilution is done in intravenous infusion bags for administration via intravenous infusion.

• Stability: Once reconstituted with sterile water for injection, USP, the reconstituted solution of Dexrazoxane is stable for 30 minutes at room temperature. If there is a need for storage, the reconstituted solution can be refrigerated around a temperature of two degrees Celsius to eight degrees Celsius (36 degrees Fahrenheit to 46 degrees Fahrenheit) for a maximum duration of three hours. The pH of the resultant solution should be in the range of 1.0 to 3.0. Unused solutions should be discarded.

• Diluted Infusion Solutions: The diluted infusion solutions are stable for one hour at room temperature. If storage is necessary, the recommended method is refrigeration at a temperature range of two to eight degrees Celsius (36 to 46 degrees Fahrenheit) for a maximum duration of four hours. The pH of the infusion solutions should be in the range of 3.5 to 5.5. Unused solutions should be discarded.

• Visual Inspection: Prior to administration, visually inspect the infusion solution for any particulate matter or discoloration. If a solution contains a precipitate, it should be discarded.

• Handling Precautions: Exercise caution when handling and preparing the reconstituted solution. It is recommended to use gloves. In the event of Dexrazoxane powder or solutions coming into contact with the skin or mucous membranes, it is crucial to promptly and thoroughly cleanse the affected area with soap and water. Follow specific handling and disposal procedures.

What Are the Side Effects of Dexrazoxane?

The following symptoms are seen after receiving a Dexrazoxane injection. It is important to inform the doctor as they may be signs of side effects:

• Pain or swelling at the injection site.

• Nausea.

• Vomiting.

• Diarrhea.

• Constipation.

• Stomach pain.

• Loss of appetite.

• Dizziness.

• Headache.

• Excessive tiredness.

• Difficulty sleeping.

• Depressive symptoms.

• Swelling in the arms, hands, feet, ankles, or lower legs.

Some side effects may require immediate medical attention. Contact the doctor promptly or seek emergency medical treatment if one experiences any of the following:

• Symptoms indicating infection, such as a scratchy throat, elevated body temperature, shivering, and respiratory cough.

• Unusual bruising or bleeding.

• Pale skin.

• Weakness.

• Shortness of breath.

• Rash.

• Itching.

• Hives.

• Difficulty breathing or swallowing.

• Swelling of the eyes, face, mouth, lips, tongue, or throat.

• Dizziness.

• Fainting.

It is important to note that there have been reports of new forms of cancer in some individuals who have taken medications similar to Dexrazoxane.

Dietary Considerations:

There are no specific dietary restrictions associated with Dexrazoxane use. However, it is always important to maintain a balanced and healthy diet to support overall well-being, including cardiovascular health. In general, it is advisable to follow a nourishing diet that encompasses a diverse range of whole grains, fruits, vegetables, lean proteins, and healthy fats.

Missed Dose:

If the patient forgets to take a dose of Dexrazoxane, it is crucial to contact the healthcare provider promptly. The doctor will provide guidance on what to do next, such as rescheduling the missed dose or making adjustments to future doses. It is important not to take a double dose without consulting the healthcare provider. Simply resume the regular dosing schedule as directed. Consistently following the prescribed treatment schedule is essential to ensure the treatment's effectiveness and safety.

Overdose:

An overdose of Dexrazoxane may lead to the following symptoms:

• Sore throat, elevated body temperature, chills, and other related symptoms.

• Unusual bruising or bleeding.

• Pale skin.

• Shortness of breath.

• Excessive tiredness.

If an overdose of Dexrazoxane occurs, it is important to seek immediate medical assistance or get in touch with a poison control center without delay.

Storage

Dexrazoxane should be stored under the following conditions:

• Temperature: Store Dexrazoxane at a controlled room temperature of 25 degrees Celsius (77 degrees Fahrenheit).

• Excursions: Temporary excursions in temperature are allowed within the range of 15 to 30 degrees Celsius (59 to 86 degrees Fahrenheit). This means that short periods of exposure to temperatures outside the controlled room temperature range are permissible.

• Refrigeration: Dexrazoxane can be stored by refrigeration within the temperature range of two to eight degrees Celsius (36 to 46 degrees Fahrenheit).

For Doctors:

Indication:

Dexrazoxane has several indications, including:

1. Cardioprotection During Anthracycline Chemotherapy: Dexrazoxane is used as a cardioprotective agent to reduce the risk of cardiotoxicity associated with anthracycline chemotherapy, such as Doxorubicin. It helps protect the heart muscle from damage caused by these chemotherapy drugs.

2. Extravasation Treatment: Dexrazoxane is indicated for the treatment of extravasation, which occurs when chemotherapy drugs leak from the intended vein into surrounding tissues during intravenous administration. It can help minimize tissue damage and potential complications resulting from extravasation.

3. Reduction of Cardiomyopathy in Metastatic Breast Cancer: Dexrazoxane is suggested for diminishing the occurrence and intensity of cardiomyopathy in women with metastatic breast cancer who have been administered a cumulative dosage of Doxorubicin, reaching 300 mg/m2. It is used in conjunction with continued Doxorubicin therapy to maintain tumor control.

Dose:

• Dexrazoxane is indicated for the reduction of cardiomyopathy occurrence and severity in women with metastatic breast cancer who have already received a cumulative Doxorubicin dose of 300 mg/m2. This treatment is recommended for patients who will continue receiving Doxorubicin therapy to maintain tumor control.

Dosing Considerations:

• In individuals presenting with moderate to severe renal impairment (creatinine clearance less than 40 mL/min), it is recommended to reduce the Dexrazoxane dosage by 50 percent. This adjustment results in a Dexrazoxane to Doxorubicin ratio of 5:1, for example, 250 mg/m² Dexrazoxane to 50 mg/m² Doxorubicin.

What Are the Pharmacological Aspects of Dexrazoxane?

Pharmacodynamics: Dexrazoxane is a cardioprotective agent used in combination with Doxorubicin to reduce the occurrence and severity of cardiomyopathy in women with metastatic breast cancer who have received cumulative Doxorubicin doses. Anthracycline-based chemotherapy can lead to different types of cardiotoxicity, including acute transient, chronic subacute, and late-onset cardiotoxicity. While the exact mechanism remains incompletely understood, anthracyclines have been shown to affect cardiac muscle gene expression and cause myocyte damage through calcium overload, altered adrenergic function, the release of vasoactive amines, and proinflammatory cytokines. Anthracyclines can also induce free-radical damage to DNA through intercalation, metal chelation, and the generation of superoxide radicals. The presence of anthracycline-metal complexes catalyzes the production of reactive oxygen free radicals, leading to lipid peroxidation. Cardiac cells have limited enzyme activity involved in detoxifying free radicals, which may contribute to the increased toxicity in these cells.

Mechanism:

Dexrazoxane, a cyclic derivative of EDTA (ethylenediaminetetraacetic acid), has the ability to penetrate cell membranes. Laboratory studies have suggested that Dexrazoxane undergoes intracellular conversion to a ring-opened chelating agent. This chelating agent interferes with the iron-mediated generation of free radicals, which is believed to play a role in the development of anthracycline-induced cardiomyopathy. By disrupting the formation of these harmful free radicals, Dexrazoxane may help protect cardiac cells from oxidative damage and mitigate the cardiotoxic effects associated with anthracycline chemotherapy. While further research is needed to fully comprehend the intricacies of Dexrazoxane's mechanism of action, these preliminary findings offer valuable insights into its potential as a cytoprotective agent.

Pharmacokinetics:

• Absorption: Complete bioavailability is achieved with intravenous (IV) administration.

• The Volume of Distribution: The range of the volume of distribution spans from 9.0 to 22.6 L/m2.

• Protein Binding: Dexrazoxane has very low protein binding (less than two percent).

• Metabolism: Dexrazoxane is metabolized by the enzyme dihydropyrimidine amidohydrolase in the liver and kidney. This metabolism results in the formation of active metabolites capable of binding to metal ions.

• Route of Elimination: Urinary excretion plays a significant role in the elimination of Dexrazoxane. Approximately 42 percent of a 500 mg/m2 dose of Dexrazoxane is excreted in the urine.

• Half-life: The half-life of Dexrazoxane is approximately 2.5 hours.

• Clearance: The clearance of Dexrazoxane is 7.88 L/h/m2 when administered with a dose of 50 mg/m2 Doxorubicin and 500 mg/m2 Dexrazoxane. The clearance is 6.25 L/h/m2 when administered with a dose of 60 mg/m2 Doxorubicin and 600 mg/m2 Dexrazoxane.

Toxicity:

Toxicity data for Dexrazoxane are not available from clinical trials, and there is no known antidote described in the literature for its reversal. In the event of a suspected overdose, it is recommended to provide appropriate supportive care. This includes implementing measures such as infection treatment and control, fluid management, and ensuring adequate nutrition to support the patient's needs. These supportive interventions aim to address and manage potential complications resulting from an overdose of Dexrazoxane.

Clinical Studies:

The effectiveness of Dexrazoxane in preventing or reducing Doxorubicin-induced cardiomyopathy was evaluated in three studies with a placebo control group. Patients received Dexrazoxane or a placebo along with doxorubicin-containing chemotherapy from the start. Dexrazoxane-treated patients had smaller reductions in cardiac function and lower rates of congestive heart failure. However, in a large study with advanced breast cancer patients receiving FAC (Fluorouracil, Doxorubicin, Cyclophosphamide) chemotherapy, those treated with Dexrazoxane had a lower response rate and shorter time to disease progression. Retrospective analysis showed that patients not receiving Dexrazoxane had a higher risk of cardiac events at a cumulative Doxorubicin dose exceeding 300 mg/m². Overall, three percent of Dexrazoxane-treated patients developed congestive heart failure compared to 22 percent of non-Dexrazoxane-treated patients.

What Are the Contraindications of Dexrazoxane?

Dexrazoxane should not be used in combination with non-anthracycline chemotherapy regimens.

Warnings and Precautions:

The warning and precautions associated with Dexrazoxane are as follows:

• Myelosuppression: Dexrazoxane can contribute to the myelosuppressive effects caused by chemotherapeutic agents. Prior to each treatment cycle, it is important to obtain a complete blood count and ensure adequate hematologic parameters before administering Dexrazoxane and chemotherapy.

• Concomitant Chemotherapy: Dexrazoxane is recommended only for patients who have already received a cumulative dose of 300 mg/m² of Doxorubicin and are continuing with Doxorubicin therapy. It should not be used at the beginning of chemotherapy as it may interfere with the effectiveness of the chemotherapy regimen. In a clinical trial with metastatic breast cancer patients receiving FAC chemotherapy with or without Dexrazoxane, those who received Dexrazoxane had a lower response rate and shorter time to disease progression compared to those who received a placebo.

• Cardiac Toxicity: Dexrazoxane can reduce the risk of anthracycline-induced cardiotoxicity, but it does not eliminate the possibility entirely. Cardiac function should be monitored before and periodically during therapy, assessing the left ventricular ejection fraction (LVEF). In case there is a decline in cardiac function related to Doxorubicin, it is crucial to thoroughly assess the potential advantages of continuing the therapy in comparison to the risk of enduring irreversible cardiac harm.

• Secondary Malignancies: Secondary malignancies like AML (acute myeloid leukemia) and MDS (myelodysplastic syndrome) have been observed in patients, both pediatric and adult, who were treated with Dexrazoxane in combination with carcinogenic anticancer drugs. Dexrazoxane is not indicated for use in pediatric patients.

• Embryo-Fetal Toxicity: Dexrazoxane can cause harm to the fetus when administered to pregnant women.

What Are the Drug Interactions of Dexrazoxane?

Here are some examples of drug interactions involving Dexrazoxane:

• Anthracycline Chemotherapy: Dexrazoxane is specifically used with Doxorubicin, an anthracycline chemotherapy drug. It is intended to reduce the risk of cardiomyopathy associated with Doxorubicin treatment.

• Abacavir: Dexrazoxane may affect the excretion rate of Abacavir, potentially leading to higher levels of Abacavir in the body.

• Abatacept: The combination of Dexrazoxane and Abatacept may increase the risk or severity of adverse effects.

• Anticoagulants (Such as Warfarin): Dexrazoxane may increase the risk of bleeding when used with anticoagulant medications.

• Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): NSAIDs like Ibuprofen or Aspirin may affect the excretion rate of Dexrazoxane, potentially leading to higher levels of Dexrazoxane in the body.

• Acetazolamide: Acetazolamide may affect the excretion rate of Dexrazoxane, potentially resulting in lower levels of Dexrazoxane in the body.

• Vaccines: Dexrazoxane may potentially decrease the effectiveness of certain vaccines. It is important to discuss vaccination schedules with the healthcare provider.

Specific Considerations:

1. Pregnancy:

Dexrazoxane is classified as pregnancy category D, indicating the potential for causing harm to the fetus when administered to pregnant women. Studies in rats and rabbits have shown maternal toxicity, embryotoxicity, and teratogenicity at doses lower than the recommended clinical dose. If this medication is administered during gestation or if the patient conceives while taking it, it is important to have a discussion about the potential risks to the fetus, taking into account the associated hazards.

2. Nursing Mothers:

It is unknown whether Dexrazoxane or its metabolites are excreted in human milk. Considering the possibility of serious adverse reactions in nursing infants, a decision should be made regarding the discontinuation of nursing or the discontinuation of the drug, taking into consideration the significance of the drug for the mother.

3. Pediatric Use:

The safety and efficacy of Dexrazoxane have not been established in pediatric patients. Further research is needed on this population.

4. Geriatric Use:

Clinical studies of Dexrazoxane did not include a sufficient number of subjects aged 65 and over to determine differences in response compared to younger subjects. Caution should be exercised when dosing elderly patients, taking into account their decreased hepatic, renal, or cardiac function and potential concomitant diseases or other drug therapies.

5. Females of Reproductive Potential:

Female patients of reproductive age should utilize highly effective contraception methods while undergoing treatment with Dexrazoxane to prevent pregnancy.

6. Renal Impairment:

Patients with compromised renal function may experience increased exposure to Dexrazoxane. In such cases, the Dexrazoxane dose should be reduced by 50 percent in patients with creatinine clearance values below 40 mL/min.