Usage
- Doxorubicin is primarily used in the treatment of various types of cancers, including breast cancer, ovarian cancer, bladder cancer, Kaposi’s sarcoma, leukemia, lymphoma, and certain solid tumors such as lung, stomach, thyroid, and soft tissue sarcomas. It can be utilized as a single agent or in combination with other chemotherapy drugs.
- Pharmacological classification: Antineoplastic agent, anthracycline antibiotic.
- Doxorubicin exerts its anticancer effects via multiple mechanisms, primarily by intercalating into DNA, inhibiting topoisomerase II, and generating free radicals, ultimately disrupting DNA synthesis and cell division, leading to apoptosis (programmed cell death) of cancer cells.
Alternate Names
- Adriamycin
- Hydroxydaunorubicin
- Doxorubicin hydrochloride
How It Works
- Pharmacodynamics: Doxorubicin’s main effect is cytotoxic, targeting rapidly dividing cells, especially cancer cells. It disrupts DNA replication and RNA synthesis, triggering apoptosis. The cardiotoxic effect is attributed to the generation of reactive oxygen species (ROS) damaging cardiac myocytes.
- Pharmacokinetics: Administered intravenously, Doxorubicin exhibits rapid distribution to tissues, with the highest concentrations found in the liver, kidneys, lungs, and heart. It is metabolized in the liver to doxorubicinol, an active metabolite. Excretion is primarily biliary (through the liver into bile and feces), with a small portion excreted renally (through the kidneys).
- Mode of action: Doxorubicin intercalates between DNA base pairs, interfering with DNA replication and transcription. It also inhibits topoisomerase II, an enzyme crucial for DNA unwinding, further impeding DNA processes. Additionally, it generates free radicals leading to oxidative stress and cell damage.
- Elimination pathways: Primarily hepatic excretion through bile into feces, with some renal excretion. Metabolism involves conversion to doxorubicinol in the liver.
Dosage
Standard Dosage
Adults:
- As a single agent: 60-75 mg/m² intravenously every 21 days.
- In combination chemotherapy: 30-60 mg/m² every 3 weeks or 40-75 mg/m² every 21-28 days.
- Administer as an intravenous bolus or slow infusion over 3-10 minutes into a freely running IV line of 0.9% NaCl or 5% dextrose. Alternatively, administer via continuous infusion through a central venous catheter.
Children:
- Pediatric dosing follows similar guidelines to adults, utilizing body surface area (BSA) calculations to determine dosage.
- Children are at higher risk of cardiotoxicity. Careful monitoring of cardiac function is essential.
Special Cases:
- Elderly Patients: Dose reduction or longer intervals between cycles may be necessary due to decreased organ function and bone marrow reserve. A maximum cumulative lifetime dose of 450 mg/m² is recommended for patients 70 years and older.
- Patients with Renal Impairment: Dose adjustments may not be strictly necessary, but close monitoring of renal function is recommended.
- Patients with Hepatic Dysfunction: Dose reduction is essential. If serum bilirubin is 1.2-3 mg/dL, administer 50% of the standard dose. If serum bilirubin is 3.1-5 mg/dL, administer 25% of the standard dose. Doxorubicin is contraindicated in severe hepatic impairment (bilirubin > 5 mg/dL or Child-Pugh class C).
- Patients with Comorbid Conditions: Careful evaluation of cardiac function is crucial for patients with pre-existing heart disease. Adjust dosage as needed for other comorbidities like diabetes or pre-existing myelosuppression.
Clinical Use Cases
Doxorubicin’s use in specific medical settings like intubation, surgical procedures, mechanical ventilation, and emergency situations is typically not indicated as the primary treatment modality. It can be used in ICU if its use is indicated for cancer treatment.
Dosage Adjustments
Dose adjustments are necessary based on patient-specific factors like age, organ function (renal and hepatic), and prior treatments. Close monitoring of blood counts, cardiac function, and liver function tests is vital throughout the treatment. Genetic polymorphisms affecting drug metabolism may also influence dosing strategies.
Side Effects
Common Side Effects
- Myelosuppression (low blood cell counts): neutropenia, thrombocytopenia, anemia
- Nausea and vomiting
- Mucositis (mouth sores)
- Alopecia (hair loss)
- Red discoloration of urine, sweat, and tears
- Fatigue
Rare but Serious Side Effects
- Cardiomyopathy (weakening of the heart muscle)
- Congestive heart failure
- Secondary malignancies (leukemia)
- Extravasation injury (tissue damage at the injection site)
- Anaphylaxis (severe allergic reaction)
Long-Term Effects
- Persistent cardiomyopathy
- Increased risk of secondary cancers
Adverse Drug Reactions (ADR)
- Severe myelosuppression leading to infections
- Cardiotoxicity: arrhythmias, heart failure
- Anaphylaxis
- Extravasation necrosis
Contraindications
- Hypersensitivity to doxorubicin or other anthracyclines
- Severe heart failure
- Recent myocardial infarction
- Severe hepatic impairment
- Severe myelosuppression
- Pregnancy (especially first trimester)
- Breastfeeding
Drug Interactions
- Other cardiotoxic drugs (e.g., trastuzumab)
- Hepatotoxic drugs
- CYP450 enzyme inhibitors (e.g., ketoconazole) and inducers
- Live vaccines
- Anticoagulants (increased bleeding risk)
Pregnancy and Breastfeeding
- Pregnancy Safety Category: D (contraindicated, especially in the first trimester)
- Doxorubicin is teratogenic and embryotoxic. Avoid use during pregnancy.
- Breastfeeding: Doxorubicin is excreted in breast milk and is contraindicated during breastfeeding.
Drug Profile Summary
- Mechanism of Action: DNA intercalation, topoisomerase II inhibition, free radical generation.
- Side Effects: Myelosuppression, nausea, vomiting, alopecia, cardiotoxicity.
- Contraindications: Heart failure, hepatic impairment, pregnancy, breastfeeding.
- Drug Interactions: Cardiotoxic drugs, hepatotoxic drugs, CYP450 modulators.
- Pregnancy & Breastfeeding: Contraindicated.
- Dosage: Variable, depending on indication and patient factors. See dosage section.
- Monitoring Parameters: ECG, LVEF, CBC, liver function tests.
Popular Combinations
Doxorubicin is frequently used in combination regimens, often with cyclophosphamide, fluorouracil, paclitaxel, docetaxel and other chemotherapeutic agents, tailored to specific cancer types.
Precautions
- Monitor cardiac function regularly.
- Administer through a freely running IV line to avoid extravasation.
- Monitor blood counts regularly.
- Avoid live vaccines.
- Counsel patients on contraceptive use.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Doxorubicin?
A: Dosage depends on the indication, patient factors, and whether it is used as a single agent or part of combination chemotherapy. Standard adult doses range from 60-75 mg/m² every 21 days as monotherapy, and 30-75 mg/m² every 21-28 days as part of combination therapy. Pediatric, elderly, and patients with hepatic impairment require dose adjustments.
Q2: What are the primary side effects to watch out for?
A: Myelosuppression (low blood cell counts), cardiotoxicity (manifesting as weakening of heart muscles, irregular heartbeat, or heart failure), nausea and vomiting, mucositis, and alopecia are the key side effects to monitor.
Q3: Is Doxorubicin safe during pregnancy or breastfeeding?
A: No, Doxorubicin is contraindicated during pregnancy, particularly in the first trimester, due to its teratogenic effects. It is also contraindicated during breastfeeding.
Q4: What are the major drug interactions with Doxorubicin?
A: Interactions occur with other cardiotoxic drugs (like trastuzumab), drugs that affect liver function, CYP450 inhibitors and inducers, certain antibiotics and antifungals. These can lead to increased toxicity or decreased efficacy.
Q5: How is Doxorubicin administered?
A: Intravenously, either as a bolus injection over a few minutes or a slow infusion over several hours.
Q6: How is cardiotoxicity managed in patients receiving Doxorubicin?
A: Careful monitoring of cardiac function (ECG and LVEF) is essential. Limiting the cumulative lifetime dose and using cardioprotectants like dexrazoxane can help reduce cardiotoxicity risk.
Q7: What are the signs and symptoms of Doxorubicin extravasation?
A: Pain, redness, swelling, blistering, and ulceration at the injection site indicate extravasation, potentially leading to severe tissue damage. Immediate discontinuation of the infusion and application of cold compresses are recommended.
Q8: What is the role of Doxorubicin in adjuvant therapy for breast cancer?
A: Doxorubicin is a key component of adjuvant chemotherapy regimens for breast cancer, especially in patients with lymph node involvement, to reduce the risk of recurrence after surgery.
Q9: What is the maximum cumulative lifetime dose of Doxorubicin usually recommended?
A: 450-550 mg/m² to minimize the risk of cardiotoxicity.
Q10: What are the signs and symptoms of Doxorubicin-induced cardiomyopathy?
A: Shortness of breath, swelling in the legs and feet, fatigue, irregular heartbeat, and chest pain might be signs of cardiotoxicity which needs to be diagnosed and managed.
