L-DOX

FDA-Approved Indications:

• AIDS-Related Kaposi’s Sarcoma (KS): For advanced disease in patients with HIV when other systemic chemotherapies have failed or are contraindicated.
• Ovarian Cancer: For metastatic ovarian cancer that is refractory to both platinum- and taxane-based chemotherapy.
• Multiple Myeloma: In combination with bortezomib for patients who have not previously received bortezomib and have received at least one prior therapy.
• Breast Cancer (off-label in some regions): Particularly for metastatic cases when conventional anthracyclines are contraindicated.

Clinically Accepted Off-Label Uses:

• Soft Tissue Sarcomas: When cardiotoxicity risk precludes conventional doxorubicin use.
• Endometrial Carcinoma: As second-line therapy in recurrent or metastatic cases.
• Hepatocellular Carcinoma (HCC): In select palliative settings.
• Gliomas and CNS Tumors: Investigational use due to enhanced tissue penetration.
• Liposomal delivery in anthracycline-pretreated patients: Where cardiac reserve is low.

Adults:

• Kaposi’s Sarcoma (AIDS-related):
  20 mg/m² IV every 3 weeks, administered over 30–60 minutes.
• Ovarian Cancer:
  50 mg/m² IV every 28 days as a single agent over 60–90 minutes.
• Multiple Myeloma (with bortezomib):
  30 mg/m² IV on day 4 of each 21-day cycle following bortezomib administration.

Pediatrics:

• Not FDA-approved for pediatric use; off-label use under clinical protocols may occur with careful cardiac monitoring and reduced dosing.

Elderly:

• No specific dosage adjustment, but consider baseline cardiac function and comorbidities. Closer monitoring for cardiotoxicity is recommended.

Hepatic Impairment:

• Mild to moderate impairment (bilirubin up to 3 mg/dL): Use with caution, consider dose reduction.
• Severe impairment (bilirubin >3 mg/dL): Not recommended.

Renal Impairment:

• No dose adjustment typically required; use with caution in severe impairment.

Administration Instructions:

• IV infusion only; do not administer via bolus or IM route.
• Infuse over 30–90 minutes depending on indication and formulation.
• Do not substitute with conventional doxorubicin—they are not bioequivalent.

Doxorubicin liposome contains the same active anthracycline as conventional doxorubicin, which intercalates DNA strands, inhibits topoisomerase II, and induces free radical formation, leading to DNA damage and apoptosis in rapidly dividing cells. The liposomal encapsulation alters its pharmacokinetics, allowing preferential tumor tissue uptake and extended circulation time, thereby enhancing efficacy while reducing systemic and cardiac toxicity.

• Absorption: Not applicable (IV only).
• Distribution: Confined within liposomes; limited immediate tissue distribution. Preferentially accumulates in tumors and inflamed tissue (e.g., Kaposi’s lesions).
• Protein Binding: ~70% (largely to plasma proteins).
• Metabolism: Slowly released from liposomes, then metabolized in the liver to doxorubicinol.
• Half-life: Terminal half-life ~55 hours (significantly longer than conventional form).
• Elimination: Primarily hepatic via biliary excretion; minimal renal clearance (<10%).
• Onset of Action: Variable; typically within days depending on tumor type.

• Pregnancy:
  FDA Pregnancy Category D. Known to be embryotoxic and teratogenic based on animal studies. Should not be used during pregnancy unless benefits outweigh risks.
• Lactation:
  Excretion into breast milk is expected. Breastfeeding is contraindicated during therapy and for at least 10 days after the final dose due to risk of serious adverse effects in infants.

• Primary Class: Antineoplastic Agent
• Subclass: Anthracycline Antibiotic (Liposomal Formulation)

• Known hypersensitivity to doxorubicin, other anthracyclines, or any component of the liposomal formulation
• Severe hepatic impairment (bilirubin >3 mg/dL)
• Persistent severe myelosuppression
• Pregnancy and lactation (unless benefit outweighs risk)
• History of cardiac failure or recent myocardial infarction (relative contraindication depending on cumulative anthracycline exposure)

• Cardiotoxicity: Reduced compared to conventional doxorubicin, but still possible, especially with cumulative exposure. Monitor LVEF before and during treatment.
• Infusion Reactions: May occur within minutes; includes flushing, back pain, chest tightness. Typically managed with infusion rate adjustments or premedication.
• Hand-Foot Syndrome (Palmar-Plantar Erythrodysesthesia): Common, dose-limiting toxicity. Dose delay or reduction may be necessary.
• Myelosuppression: Monitor blood counts regularly; dose modification may be needed.
• Secondary Malignancies: Increased risk with long-term use, especially therapy-related leukemia.
• Mucositis and Stomatitis: Especially at higher doses; oral care recommended.
• Hepatic impairment: May increase risk of toxicity; monitor liver function tests.

Common:

• Hematologic: Neutropenia, anemia, thrombocytopenia
• Dermatologic: Palmar-plantar erythrodysesthesia (hand-foot syndrome), rash, alopecia
• Gastrointestinal: Stomatitis, mucositis, nausea, vomiting, diarrhea
• General: Fatigue, fever, weakness, weight loss

Serious/Rare:

• Cardiac: Congestive heart failure, arrhythmias, cardiomyopathy
• Hypersensitivity: Anaphylactic reactions, chest tightness, back pain during infusion
• Secondary malignancy: AML, MDS
• Sepsis or febrile neutropenia: Due to immunosuppression
• Liver toxicity: Elevated liver enzymes, bilirubin

• Trastuzumab, Cyclophosphamide, Paclitaxel: Additive cardiotoxicity risk.
• CYP3A4 and CYP2D6 substrates/inhibitors: Metabolism of free doxorubicin may be affected.
• Live vaccines: Avoid due to immunosuppressive effect.
• Phenytoin: Reduced absorption or plasma concentration when co-administered.
• Verapamil or P-glycoprotein inhibitors: May alter distribution and clearance of doxorubicin.

• FDA Black Box Warning Reinforcement: Emphasis that liposomal and conventional forms are not interchangeable.
• Updated Safety Guidance (ASCO/EMA): Reinforces LVEF monitoring every 3 months during therapy, particularly in cumulative exposures approaching 550 mg/m².
• Revised Product Label: Infusion reaction management updated; more detailed guidance on managing hand-foot syndrome and mucositis.
• Combination Use in Myeloma: Continued endorsement of use with bortezomib based on clinical outcomes with reduced cardiotoxicity.

• Vials (unopened): Store at 2°C to 8°C (refrigerated); do not freeze.
• After dilution: Store at 2°C to 8°C; use within 24 hours.
• Protect from light at all times.
• Handling precautions:
• Cytotoxic: Use protective gloves and gown during preparation.
• Dispose of using cytotoxic drug waste procedures.
• Avoid shaking the vial vigorously to prevent liposomal disruption.