Daunorubicin

Approved Indications:

• Acute Myeloid Leukemia (AML):
• Used in combination with other antileukemic agents for remission induction in adults and pediatric patients with AML.
• Acute Lymphoblastic Leukemia (ALL):
• Approved for induction therapy in combination regimens in pediatric and adult patients with ALL, including Philadelphia chromosome-negative ALL.
• HIV-related Kaposi’s Sarcoma (Liposomal Daunorubicin only):
• Indicated in patients with advanced, progressive, or relapsed HIV-associated Kaposi’s sarcoma when systemic chemotherapy is required.

Clinically Accepted Off-label Uses:

• Maintenance chemotherapy in specific leukemias (in institutional protocols)
• Other pediatric leukemias as part of multi-agent regimens

Route:

• Intravenous (IV) only. Never administer intramuscularly or subcutaneously.

Adult Dosing (conventional):

• AML Induction (with Cytarabine):
• Daunorubicin 45–90 mg/m² IV once daily on Days 1–3 (varies by protocol)
• ALL (in combination regimens):
• 25–50 mg/m² IV once weekly or as part of multi-agent regimens.

Pediatric Dosing:

• AML and ALL:
• Typically 25–45 mg/m² IV on Day 1 or Days 1–3, per protocol.

Liposomal Formulation (for Kaposi’s Sarcoma):

• 40 mg/m² IV over 60 minutes every 2 weeks.

Renal Impairment:

• Use with caution; no specific adjustment, but monitor renal function.

Hepatic Impairment:

• Moderate to Severe Impairment (e.g., bilirubin >3 mg/dL):
• Dose reduction required or consider alternative.

Elderly:

• Use with caution due to age-related organ function decline; adjust based on tolerability and comorbidities.

Important Notes:

• Administer via a free-flowing IV infusion; avoid extravasation.
• In case of suspected extravasation, stop infusion immediately and manage per protocol.

Daunorubicin is an anthracycline antibiotic that exhibits antitumor activity by intercalating between DNA base pairs, thereby inhibiting DNA and RNA synthesis. It also inhibits the enzyme topoisomerase II, preventing the re-ligation of DNA strands during replication. Additionally, daunorubicin generates free radicals that contribute to cytotoxicity by damaging cellular membranes, DNA, and proteins. These combined actions induce apoptosis in rapidly dividing leukemic cells.

Absorption:

• Not orally bioavailable; administered IV.

Distribution:

• Rapidly distributes into tissues, especially in the liver, heart, and kidneys.
• Volume of distribution: 809–2340 L/m²
• Plasma protein binding: 60–70%

Metabolism:

• Primarily metabolized in the liver to daunorubicinol (active metabolite).

Elimination:

• Half-life:
• Daunorubicin: ~18–50 hours
• Daunorubicinol: ~26 hours
• Excretion:
• 40–60% via biliary/fecal route
• ~14% via urine

• Pregnancy:
• FDA Category D. Known teratogenic and embryotoxic effects in humans. Use only if potential benefits justify the risks.
• Lactation:
• Likely excreted in breast milk; breastfeeding is not recommended during treatment and for several days after last dose.

• Primary Class: Antineoplastic agent
• Subclass: Anthracycline antitumor antibiotic (cell cycle–nonspecific)

• Hypersensitivity to daunorubicin or other anthracyclines
• Severe hepatic or renal impairment
• Severe myocardial insufficiency or recent myocardial infarction
• Uncontrolled infection
• Preexisting bone marrow suppression not due to malignancy

• Cardiotoxicity:
• Dose-dependent and potentially irreversible. Cumulative dose should generally not exceed 550 mg/m². Monitor LVEF regularly.
• Risk increases with prior anthracycline use, chest irradiation, or preexisting cardiac disease.
• Myelosuppression:
• Severe neutropenia, thrombocytopenia, and anemia are common. Monitor CBC frequently.
• Extravasation Risk:
• Can cause severe tissue necrosis. Administer through a central line when possible.
• Secondary Malignancies:
• Increased risk of therapy-related acute myeloid leukemia (t-AML) and myelodysplastic syndrome (MDS).
• Hepatic/Renal Dysfunction:
• Adjust dose or avoid in significant impairment. Monitor liver and kidney function.

Hematologic:

• Neutropenia
• Thrombocytopenia
• Anemia
• Febrile neutropenia

Cardiovascular:

• Arrhythmias
• Congestive heart failure
• QT prolongation (rare)

GI:

• Nausea, vomiting
• Mucositis
• Diarrhea
• Anorexia

Dermatologic:

• Alopecia
• Skin discoloration along the vein
• Injection site reactions (phlebitis, necrosis)

Others:

• Fatigue
• Fever
• Infections
• Elevated liver enzymes

Serious/Rare:

• Cardiomyopathy
• Secondary malignancies
• Severe extravasation injury
• Anaphylaxis (rare)

• Cardiotoxic Agents (e.g., trastuzumab, cyclophosphamide):
• Additive cardiotoxicity risk. Avoid or monitor cardiac function.
• CYP450 Interactions:
• Daunorubicin is metabolized by hepatic enzymes; inhibitors or inducers may affect levels.
• Live Vaccines:
• Immunosuppression increases risk of serious infection; avoid live vaccines during and after treatment.
• Radiation Therapy:
• Increases risk of cardiac toxicity and mucosal damage when combined with radiation to chest or GI tract.

• Combination Formulations:
• Liposomal formulations (e.g., DaunoXome) offer altered pharmacokinetics and reduced cardiotoxicity for Kaposi’s sarcoma.
• Pediatric Oncology Guidelines:
• Recent protocols (e.g., Children’s Oncology Group) continue to incorporate daunorubicin in induction therapy for AML and ALL.
• Cardiac Monitoring Updates:
• Newer guidelines emphasize echocardiography or MUGA scanning before, during, and after therapy to monitor for subclinical cardiac dysfunction.

Conventional Daunorubicin (vial):

• Store refrigerated at 2°C to 8°C (36°F to 46°F)
• Protect from light
• Do not freeze
• Use immediately after dilution

Liposomal Daunorubicin:

• Store at 2°C to 8°C
• Once diluted, infuse within 6 hours if stored at 2°C–8°C
• Do not shake or freeze

Handling Precautions:

• Cytotoxic agent; handle using appropriate PPE
• Dispose of per institutional cytotoxic waste protocols