Doxorubicin Hydrochloride: Uses, Dosage, Precautions, Side Effects, and Pharmacological Aspects

Overview

Doxorubicin hydrochloride, classified as an anthracycline medication, manages diverse cancer types. Administered intravenously or into the vein (IV), it operates by impeding cancer cell proliferation and is frequently employed alongside complementary chemotherapy agents. It is prescribed for breast cancer and other malignancies. Doxorubicin hydrochloride, also referred to as Doxorubicin, attained United States Food and Drug Administration (US FDA) approval in 1974 for treating multiple cancer types.

Drug Group

Doxorubicin hydrochloride is classified within the drug group of anthracyclines, which are potent chemotherapy medications widely used in cancer treatment. Anthracyclines work by inhibiting DNA or deoxyribonucleic acid replication in cancer cells, thereby preventing their growth and proliferation.

Indications

Doxorubicin hydrochloride injection serves as a vital component within multi-agent adjuvant chemotherapy, prescribed for treating women with axillary lymph node involvement after the resection (removal) of primary breast cancer.

Other Cancers

Doxorubicin hydrochloride injection is also recommended for treating:

• Acute Lymphoblastic Leukemia (ALL): It is a cancer impacting white blood cells, characterized by the rapid production of immature lymphocytes, a type of white blood cell.

• Acute Myeloblastic Leukemia (AML): Blood cancer where abnormal myeloid cells disrupt healthy blood cell production.

• Hodgkin Lymphoma: Lymphatic system cancer with Reed-Sternberg cells causing swollen lymph nodes and other symptoms.

• Non-Hodgkin Lymphoma (NHL): Lymphatic cancer without Reed-Sternberg cells, potentially spreading to other organs.

• Metastatic Breast Cancer: Breast cancer spreads to distant sites like bones, liver, lungs, or brain.

• Metastatic Wilms’ Tumor: Kidney cancer metastasizes to other body parts.

• Metastatic Neuroblastoma: Childhood nerve tissue cancer spreading to bones, marrow, liver, and skin.

• Metastatic Soft Tissue Sarcoma: Soft tissue cancer spreading to distant sites.

• Metastatic Bone Sarcoma: Bone cancer spreads to other bones or organs.

• Metastatic Ovarian Carcinoma: Ovarian cancer spreads to the peritoneum, liver, and lungs.

• Metastatic Transitional Cell Bladder Carcinoma: Bladder cancer spreads beyond the bladder.

• Metastatic Thyroid Carcinoma: Thyroid cancer spreads to lymph nodes, lungs, bones, or organs.

• Metastatic Gastric Carcinoma: Stomach cancer spreads from the stomach to other areas.

• Metastatic Bronchogenic Carcinoma: It is a lung cancer spreading to the brain, bones, or liver.

Dosage Forms and Available Strengths

Doxorubicin hydrochloride is available in injection of 60 mg/m2 (milligrams per square meter)

• Dosage for Doxorubicin or Cyclophosphamide Combination Therapy:

  • Administration: Intravenous (IV) bolus on day one of a 21-day treatment cycle.

  • Dosage: 60 mg/m2 (milligrams per square meter).

  • Duration: Typically for four cycles, combined with Cyclophosphamide.

• Recommended Dosage for Other Cancers:

  • When Used Alone: 60 mg/m2 to 75 mg/m2 IV every 21 days.

  • When Administered With Other Chemotherapy Drugs: 40 mg/m2 to 75 mg/m2 IV every 21 to 28 days.

Note: Cumulative doses exceeding 550 mg/m2 are associated with a heightened risk of cardiomyopathy (heart muscle disease weakening pumping ability).

Warnings and Precautions

• Cardiomyopathy and Arrhythmias: Doxorubicin hydrochloride can damage the heart muscle, leading to acute left ventricular failure (sudden inability of the heart's left ventricle to pump blood) and cardiomyopathy. Symptoms may include decreased left ventricular ejection fraction (LVEF), the percentage of blood pumped out of the left ventricle with each heartbeat, and signs of congestive heart failure (when the heart cannot efficiently pump blood). Risk increases with cumulative dosage, especially when combined with other cardiotoxic therapies or prior chest radiotherapy. Arrhythmias (irregular heart rhythm), including life-threatening ones, may also occur. Electrocardiographic changes may not always require dosage adjustment.

• Secondary Malignancies: An increased risk of secondary acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) is seen, conditions that can develop as a result of previous cancer treatment or exposure to certain environmental factors, following Doxorubicin treatment, typically within one to three years post-treatment.

• Extravasation and Tissue Necrosis: Extravasation of Doxorubicin can cause severe local tissue damage, requiring prompt action if suspected.

• Severe Myelosuppression: Doxorubicin can cause severe myelosuppression (reduced blood cell production from the bone marrow), necessitating regular monitoring and possible dosage adjustments.

• Use in Patients with Hepatic Impairment: Doxorubicin clearance is reduced in patients with elevated serum bilirubin, increasing the risk of toxicity. Dosage adjustments are recommended in such cases.

• Tumor Lysis Syndrome: Evaluate patients with rapidly growing tumors for tumor lysis syndrome (a severe complication of cancer treatment where rapid breakdown of cancer cells releases toxins into the bloodstream) and implement preventive measures as necessary.

• Potentiation of Radiation Toxicity and Radiation Recall: Doxorubicin can heighten radiation-induced toxicity and may trigger radiation recall reactions, especially following prior radiation therapy.

• Embryo-Fetal Toxicity: Doxorubicin carries a risk of fetal harm when administered to pregnant women, with potential teratogenic (birth defects) and embryotoxic (harmful to embryo development) effects. Effective contraception is advised during and after treatment for both males and females of reproductive potential.

For Patients

What Is Cancer?

Cancer is a disease where abnormal cells grow uncontrollably, forming tumors or invading nearby tissues. It can occur anywhere in the body and requires various treatments depending on the type and stage. Early detection is key for effective management.

How Does the Doxorubicin Hydrochloride Work?

Doxorubicin hydrochloride works by disrupting the growth and spread of cancer cells. It inhibits DNA and RNA or ribonucleic acid synthesis, causing breaks in DNA strands, ultimately leading to cancer cell death.

What Are the Clinical Uses of Doxorubicin Hydrochloride?

Doxorubicin is employed alongside other medications to combat various cancers such as bladder, breast, lung, stomach, and ovarian cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, and certain types of leukemia, including acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). It is also used as a standalone or in combination for thyroid cancer, certain soft tissue or bone sarcomas, neuroblastoma, and Wilms' tumor. Doxorubicin operates by impeding the growth of cancer cells in the body.

What Is the Dosage of Doxorubicin Hydrochloride?

Doxorubicin is available as a solution or powder for intravenous injection by a healthcare professional. Typically administered every 21 to 28 days, the duration of treatment varies based on the medication regimen, individual response, and cancer type.

How Are Doxorubicin Hydrochloride Administered?

Administering Doxorubicin hydrochloride injection requires careful handling and disposal due to its cytotoxic nature. It is administered in a hospital setting. Here is a simplified guide:

• Preparation:

  • Mix Doxorubicin hydrochloride for injection with 0.9 percent sodium chloride injection per instructions.

  • Gently shake until fully dissolved and shield from light.

• Dilution:

  • Dilute the solution in 0.9 percent sodium chloride or five percent dextrose Injection.

  • Protect from light and use within one hour of preparation.

• Administration:

  • Inspect for any abnormalities before administering.

  • Inject intravenously over three to 10 minutes.

  • Monitor for reactions like erythematous streaking (red lines) or flushing on the skin.

  • Consider continuous intravenous infusion if needed.

• Extravasation Management:

  • If leakage occurs, stop administration immediately.

  • Apply ice intermittently and elevate the affected area.

  • In adults, consider Dexrazoxane administration.

• Skin or Eye Contact:

  • Rinse with water immediately; avoid scrubbing.

  • Seek medical attention if needed.

• Incompatibility:

  • Do not mix Doxorubicin hydrochloride with other drugs to prevent precipitation.

  • Avoid contact with alkaline solutions to prevent degradation.

What Are the Side Effects of Doxorubicin Hydrochloride?

Doxorubicin may induce side effects. Notify the doctor if any of the following symptoms are persistent or severe:

• Nausea.

• Vomiting.

• Mouth and throat sores.

• Loss of appetite (along with weight loss).

• Increased body weight.

• Pain in stomach.

• Diarrhea.

• Heightened thirst.

• Unusual fatigue or weakness.

• Dizziness.

• Loss of hair.

• Nail detachment from the nail bed.

• Itchy, red, watery, or irritated eyes.

• Eye pain.

• Pain, burning, or tingling in the hands or feet.

• Red discoloration of urine (lasting one to two days after dose).

Certain Side Effects Can Be Severe:

• Hives.

• Skin rash.

• Itching.

• Difficulty breathing or swallowing.

• Seizures (uncontrolled brain activity).

What Are the Things to Inform the Doctor Before Taking Doxorubicin Hydrochloride?

Before receiving a Doxorubicin injection:

• Notify the doctor and pharmacist about any allergies to Doxorubicin or related medications.

• Disclose all current medications, especially those listed, and any medical conditions one has.

  • Certain chemotherapy medications include Cytarabine, Dexrazoxane, Mercaptopurine, and Streptozocin.

  • Phenobarbital.

  • Phenytoin.

• Understand that Doxorubicin can affect menstrual cycles in women and sperm production in men, necessitating reliable birth control during treatment.

• Avoid vaccinations without consulting the doctor.

Dietary Considerations:

If the doctor does not instruct otherwise, stick to the usual diet.

Missed Dose

Doxorubicin hydrochloride is typically administered in a clinical setting, minimizing the risk of missing a dose.

Overdose

• Acute overdose of Doxorubicin exacerbates the toxic effects of mucositis (inflammation and ulceration of the mucous membranes), leukopenia (low white blood cell count), and thrombocytopenia (characterized by a low platelet count in the blood). Management involves hospitalization and treatment of severely myelosuppressed patients with antimicrobials, platelet transfusions, and symptomatic relief for mucositis. Hemopoietic growth factors like G-CSF (granulocyte colony-stimulating factor) and GM-CSF (granulocyte-macrophage colony-stimulating factor) may be considered. Caution should be exercised with multiple dose vials to prevent an inadvertent overdose. Cumulative Doxorubicin dosage increases the risk of cardiomyopathy and congestive heart failure, necessitating aggressive management with digitalis preparations, diuretics, and ACE (angiotensin-converting enzyme) inhibitors.

Storage and Handling

• Doxorubicin hydrochloride injection is a sterile, isotonic solution in polypropylene Cyto-safe vials.

• Available as single-dose vials as 10 mg or milligram /5 mL or milliliters, 20 mg/10 mL, 50 mg/25 mL.

• Multiple-dose vials are 150 mg/75 mL, 200 mg/100 mL.

• Store at 35.6 to 46.4 degrees Fahrenheit to protect from light.

• Refrigeration may cause gel formation; return to room temperature for two to four hours.

Disposal

Doxorubicin hydrochloride injection is a cytotoxic drug, meaning it is toxic to cells. Special handling and disposal procedures must be followed to ensure safety. These procedures typically involve using protective gear and specific waste disposal methods to prevent exposure to the drug and minimize environmental contamination. It is necessary to adhere to FDA-disposal guidelines.

For Doctors

Chemical Taxonomy

Doxorubicin hydrochloride is a topoisomerase inhibitor derived from Streptomyces peucetius var. caesius. Its chemical name is 5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-α-L-lyxo-hexopyranosyl)oxy]-7,8,9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxylacetyl)-1-methoxy-, hydrochloride (8S-cis).

What Are the Pharmacological Actions of Doxorubicin Hydrochloride?

• Pharmacodynamics: Doxorubicin hydrochloride's pharmacodynamics involve inhibiting DNA and RNA in cancer cells, disrupting synthesis, and resulting in cell death and tumor regression.

• Mechanism of Action: Doxorubicin hydrochloride kills cancer cells by intercalating with nucleotide bases, disrupting DNA and RNA function, and forming DNA-cleavable complexes with topoisomerase II.

• Pharmacokinetics: Pharmacokinetic studies in tumor patients indicate a multiphasic disposition of Doxorubicin following intravenous injection. Across doses ranging from 30 mg/m2 to 70 mg/m2, its pharmacokinetics appear to be dose-independent.

  • Distribution: The distribution half-life of Doxorubicin is about five minutes, with a steady-state distribution volume of 809-1214 L/m2 or liters per square meter. Roughly 75 percent binds to plasma proteins, independent of concentration up to 1.1 μg/mL or micrograms per milliliter. It does not cross the blood-brain barrier.

  • Elimination: Plasma clearance ranges from 324 mL/min/m2 or milliliters per minute per square meter to 809 mL/min/m2, with a terminal half-life of 20 to 48 hours. Metabolism of Doxorubicin primarily occurs through CYP3A4, CYP2D6, and P-gp enzymes. Its cardiotoxic activity may involve enzymatic reduction and free radical formation.

  • Metabolism: Doxorubicin undergoes enzymatic reduction at the seven position and cleavage of the daunosamine sugar, resulting in aglycones accompanied by free radical formation, potentially contributing to its cardiotoxic activity.

  • Excretion: The primary route of excretion is through metabolism and biliary excretion, with about 40 percent of the dose excreted in bile over five days. Minimal amounts are excreted in urine, with less than three percent recovered as Doxorubicinol over seven days.

Non-Clinical Toxicity

Carcinogenesis, Mutagenesis, Impairment of Fertility: Doxorubicin hydrochloride treatment may heighten the risk of secondary malignancies. It has shown mutagenic and clastogenic properties in various assays. In female rats, it reduced fertility at certain doses. In animal studies, even a single intravenous dose adversely affected male reproductive organs, inducing testicular atrophy, degeneration of seminiferous tubules, and sperm abnormalities.

What Are the Contraindications of Doxorubicin Hydrochloride?

Doxorubicin hydrochloride injection should not be used in patients with:

• Severe myocardial insufficiency or recent myocardial infarction within the past four to six weeks.

• Severe, persistent drug-induced myelosuppression.

• Severe hepatic impairment (Child-Pugh Class C or serum bilirubin level of more than five mg/dL).

• Severe hypersensitivity reaction to Doxorubicin hydrochloride, including anaphylaxis.

What Are the Drug Interactions of Doxorubicin Hydrochloride?

Effect of other drugs on Doxorubicin Hydrochloride:

• Inhibitors of CYP3A4, CYP2D6, and P-gp: Avoid using these inhibitors with Doxorubicin hydrochloride, as they can increase Doxorubicin concentrations, potentially worsening adverse reactions.

• Inducers of CYP3A4, CYP2D6, or P-gp: Avoid using these inducers alongside Doxorubicin hydrochloride, as they may decrease Doxorubicin concentrations.

• Paclitaxel: If administered together, give Doxorubicin hydrochloride first to avoid increased Doxorubicin concentrations caused by Paclitaxel.

• Concomitant Use of Trastuzumab: Combining Trastuzumab with Doxorubicin hydrochloride heightens the risk of cardiac dysfunction. Avoid their simultaneous use and be cautious when administering Doxorubicin after stopping Trastuzumab.

• Concomitant Use of Dexrazoxane: Due to potential reduced efficacy, do not use Dexrazoxane as a cardioprotectant at the beginning of Doxorubicin hydrochloride-based chemotherapy regimens.

• Concomitant Use of 6-Mercaptopurine: Doxorubicin hydrochloride may increase the risk of hepatotoxicity when used with 6-Mercaptopurine. Caution is advised, as hepatic dysfunction has been observed in patients receiving both medications.

Clinical Studies

The effectiveness of Doxorubicin hydrochloride-containing regimens for post-operative, adjuvant treatment of surgically removed breast cancer was assessed in a meta-analysis by the Early Breast Cancer Trialists Collaborative Group (EBCTCG). This analysis compared these regimens with Cyclophosphamide, Methotrexate, and Fluorouracil (CMF) as an active control. The study included approximately 70 percent premenopausal and 30 percent postmenopausal women with early breast cancer involving axillary lymph nodes. Results showed that Doxorubicin hydrochloride-containing regimens maintained at least 75 percent of the historical CMF adjuvant effect on disease-free survival (DFS) and overall survival (OS).

Use in Specific Populations

• Pregnancy: Avoid using Doxorubicin hydrochloride injection during the first trimester due to potential fetal harm. Limited human data exists for the second and third trimesters. Animal studies indicate teratogenic and embryotoxic effects.

• Lactation: Doxorubicin can pass into breast milk, posing risks to the nursing infant. Avoid breastfeeding during treatment and for 10 days after the last dose.

• Reproductive Potential:

  • Females: Use reliable contraception throughout the treatment period and for an additional six months afterward.

  • Males: Utilize reliable contraception during the treatment phase and for three months thereafter; use condoms during treatment if one is pregnant.

• Infertility:

  • Females: Doxorubicin may cause infertility and premature menopause.

  • Males: Doxorubicin may result in sperm abnormalities and permanent infertility.

• Pediatric Use: Pediatric patients treated with Doxorubicin are at risk for late cardiovascular dysfunction; periodic cardiovascular monitoring is recommended.

• Geriatric Use: No significant differences in safety or efficacy were noted between elderly patients aged 65 and older and younger patients.

• Hepatic Impairment: Avoid Doxorubicin hydrochloride injection in severe hepatic impairment; dose adjustment is necessary in patients with elevated bilirubin levels.