Adult: As conventional formulation: As a single agent: 60-75 mg/m2 once every 3-4 weeks or 1.2-2.4 mg/kg once every 3 weeks. Alternatively, 20-25 mg/m2 may be given daily for 3 successive days every 3 or 4 weeks (although may increase the incidence of mucositis) or 20 mg/m2 once weekly. In combination with other antineoplastic agents: 30-60 mg/m2 every 3 weeks, or 40-75 mg/m2 every 21-28 days. Doses are administered via slow inj into a freely running IV infusion of 0.9% NaCl or 5% dextrose over 3-10 minutes. Alternatively, may also be given via continuous infusion through a central catheter. Total cumulative dose: 450-550 mg/m2. Dose modification or discontinuation may be required according to individual safety and tolerability (refer to detailed product guideline). Elderly: As conventional formulation: Dose reduction or longer intervals between cycles may be needed. ≥70 years Total cumulative dose: 450 mg/m2. Child: As conventional formulation: Dose reduction may be needed.
Intravenous Advanced ovarian carcinoma
Adult: As pegylated liposomal formulation: In patients who failed 1st-line platinum-based chemotherapy regimen: 50 mg/m2 via infusion over 60 minutes once every 4 weeks. Initial dose may be infused up to 1 mg/minute, if tolerated, may increase rate to complete the infusion over 60 minutes. Continue until disease progression or unacceptable toxicity. Dose reduction, dosing interruption or discontinuation may be required according to individual safety and tolerability (refer to detailed product guideline).
Intravenous Breast cancer
Adult: As conventional formulation: As a component of adjuvant therapy (multi-agent) in women with axillary lymph node involvement following resection of primary breast cancer: In combination with cyclophosphamide: 60 mg/m2 on day 1 of each 21-day treatment cycle, for a total of 4 cycles. Standard dosing regimen: As a single agent: 60-75 mg/m2 once every 3-4 weeks or 1.2-2.4 mg/kg once every 3 weeks. Alternatively, 20-25 mg/m2 may be given daily for 3 successive days every 3 or 4 weeks (although may increase the incidence of mucositis) or 20 mg/m2 once weekly. In combination with other antineoplastic agents: 30-60 mg/m2 every 3 weeks, or 40-75 mg/m2 every 21-28 days. Doses are administered via slow inj into a freely running IV infusion of 0.9% NaCl or 5% dextrose over 3-10 minutes. Alternatively, doses may be given via continuous infusion through a central catheter. Total cumulative dose: 450-550 mg/m2. Dose modification or discontinuation may be required according to individual safety and tolerability (refer to detailed product guideline). Elderly: As conventional formulation: Dose reduction or longer intervals between cycles may be needed. ≥70 years Total cumulative dose: 450 mg/m2.
Intravenous AIDS-related Kaposi's sarcoma
Adult: As pegylated liposomal formulation: In patients with low CD4 counts and extensive visceral or mucocutaneous disease, or after failure of or intolerance to previous systemic chemotherapy: 20 mg/m2 via infusion over 30 or 60 minutes once every 2-3 weeks. Initial dose may be infused up to 1 mg/minute, if tolerated, may increase rate to complete the infusion of over 60 minutes. Continue until disease progression or unacceptable toxicity. Dose reduction, dosing interruption or discontinuation may be required according to individual safety and tolerability (refer to detailed product guideline).
Intravenous Multiple myeloma
Adult: As pegylated liposomal formulation: In combination with bortezomib for the treatment of progressive cases in patients who have undergone or are unsuitable for a bone marrow transplant and who have received at least 1 prior therapy: 30 mg/m2 on day 4 of the bortezomib 3 week regimen given via infusion over 60 minutes immediately after bortezomib infusion. Initial dose may be infused up to 1 mg/minute, if tolerated, may increase rate to complete the infusion over 60 minutes. Continue until disease progression or unacceptable toxicity. Dose reduction or dosing interruption may be required according to individual safety and tolerability (refer to detailed product guideline).
Intravenous Metastatic breast cancer
Adult: As pegylated liposomal formulation: Monotherapy in patients with increased cardiac risk: 50 mg/m2 via infusion over 60 minutes once every 4 weeks. Initial dose may be infused up to 1 mg/minute, if tolerated, may increase rate to complete the infusion over 60 minutes. Continue until disease progression or according to patient tolerability. As non-pegylated liposomal formulation containing doxorubicin-citrate complex: In combination with cyclophosphamide: 60-75 mg/m2 every 3 weeks via infusion over 60 minutes. Dose reduction, dosing interruption or discontinuation may be required according to individual safety and tolerability (refer to detailed product guideline).
Intravesical Local malignant neoplasms in the bladder
Adult: As conventional formulation: Treatment of non-metastatic transitional cell carcinoma, carcinoma in situ, and papillary tumours of the bladder: Dissolve 50 mg of doxorubicin in 50 mL of normal saline, then instil via catheter into the bladder. Remove the catheter and instruct patient to be on one side and to make a quarter turn at 15-minute intervals over a period of 1 hour. May repeat procedure at weekly or monthly intervals.
Special Patient Group
IV:
Obese patients, heavily pre-treated patients, or those with neoplastic bone marrow infiltration: As conventional formulation: Lower initial dose or longer intervals between cycles may be needed.
Patients who received mediastinal radiotherapy or other cardiotoxic agents: As conventional formulation: May further limit the total cumulative dose.
Renal Impairment
Hepatic Impairment
Acute leukaemia; Advanced soft tissue sarcoma; Hodgkin’s lymphoma; Non-Hodgkin’s lymphoma; Neuroblastoma; Solid tumours; Lung cancer; Ovarian cancer; Wilm's tumour; Osteosarcoma; Breast cancer:
As conventional formulation: Serum bilirubin levels of 1.2-3 mg/dL: Give 50% of usual dose; Serum bilirubin levels of 3.1-5 mg/dL: Give 25% of usual dose. Severe (Child-Pugh class C or bilirubin levels of >5 mg/dL): Contraindicated.
AIDS-related Kaposi's sarcoma; Advanced ovarian carcinoma; Multiple myeloma:
As pegylated liposomal formulation: Serum bilirubin ≥1.2 mg/dL: Dose reduction may be required (refer to detailed product guideline).
Metastatic breast cancer:
As pegylated liposomal formulation: Serum bilirubin ≥1.2 mg/dL: Dose reduction may be required (refer to detailed product guideline). As non-pegylated formulation: Dose reduction may be required (refer to detailed product guideline).
Reconstitution
IV: Powder for inj (conventional formulation): Reconstitute vial labelled as 10 mg, 20 mg, or 50 mg with 5 mL, 10 mL, or 25 mL of 0.9% NaCl inj, respectively, to make a final concentration of 2 mg/mL. Pegylated liposomal formulation: Prior to administration, doses <90 mg must be diluted in 250 mL of 5% dextrose solution for infusion and doses ≥90 mg must be diluted in 500 mL of 5% dextrose solution for infusion. Non-pegylated liposomal formulation: Refer to detailed product guideline for the preparation and reconstitution procedures; after reconstitution, further dilute the solution in 0.9% NaCl inj or 5% dextrose solution for inj to obtain a final concentration of 0.4-1.2 mg/mL.
Incompatibility
Conventional formulation: Incompatible with any solution of alkaline pH, heparin Na; fluorouracil (in the same IV infusion bag or Y-site of infusion line). Pegylated liposomal formulation: May cause precipitation with other diluents or bacteriostatic agents (e.g. benzyl alcohol).
Contraindications
Conventional formulation: IV: Recent MI (within past 4-6 weeks), severe myocardial insufficiency, severe persistent drug-induced myelosuppression or stomatitis, severe arrhythmias, generalised infection. Severe hepatic impairment (Child-Pugh class C or bilirubin >5 mg/dL). Prior treatment with Max cumulative doses of doxorubicin, epirubicin, daunorubicin, idarubicin, or other anthracyclines and anthracenediones. Intravesical: Invasive tumours that penetrated the bladder wall, bladder inflammation, catheterisation problems (e.g. due to massive intravesical tumours), haematuria, urinary infections. Pegylated liposomal formulation: AIDS-related Kaposi’s sarcoma that may be effectively treated by local therapy or systemic alfa-interferon. Lactation.
Special Precautions
Patient with active, dormant or history of CV disease; previous or concurrently receiving radiotherapy to the mediastinal or pericardial area. Obese or heavily pre-treated patients; patient with neoplastic bone marrow infiltration. Concomitant administration with cardiotoxic agents (e.g. cyclophosphamide, trastuzumab). Not recommended for use in splenectomised patients with AIDS-related Kaposi’s sarcoma (pegylated liposomal formulation). Different liposomal and conventional formulations must not be used interchangeably (refer to detailed product guideline). Avoid concurrent vaccination with live vaccines. Avoid extravasation. Hepatic impairment (particularly elevated bilirubin levels). Children and elderly. Pregnancy (avoid use of pegylated liposomal formulation during the 1st trimester).
Adverse Reactions
Significant: Cardiomyopathy (e.g. acute left ventricular failure), secondary malignancy (e.g. acute myelogenous leukaemia, acute myelodysplastic syndromes, oral cancers primarily squamous cell carcinoma), tumour lysis syndrome resulting in hyperuricaemia; nausea, vomiting, mucositis, radiation recall (in patients who received prior radiation therapy); impaired fertility, amenorrhoea, oligospermia or azoospermia; palmar-plantar erythrodysaesthesia (or hand-foot syndrome). Blood and lymphatic system disorders: Lymphophenia, pancytopenia. Cardiac disorders: CV disorder, sinus tachycardia, chest pain. Eye disorders: Conjunctivitis, retinitis, lacrimation, blurred vision. Gastrointestinal disorders: Diarrhoea, stomatitis, constipation, dyspepsia, abdominal pain, dysgeusia, oesophagitis, oral moniliasis, glossitis. General disorders and administration site conditions: Fatigue, asthenia, fever, chills, malaise, peripheral oedema, pain. Immune system disorders: Hypersensitivity reactions. Infections and infestations: Herpes simplex or zoster infection, sepsis. Investigations: Decreased or increased weight, increased AST/ALT and blood creatinine, ECG changes. Metabolism and nutrition disorders: Anorexia, decreased appetite, dehydration, hypocalcaemia, hypokalaemia, hyponatraemia. Musculoskeletal and connective tissue disorders: Back pain, musculoskeletal pain. Nervous system disorders: Dizziness, headache, paraesthesia, peripheral neuropathy, neuralgia. Psychiatric disorders: Somnolence, anxiety, insomnia, depression. Renal and urinary disorders: UTI, dysuria, red discolouration of urine; chemical cystitis, bladder contraction (intravesical use). Reproductive system and breast disorders: Breast pain, vaginitis. Respiratory, thoracic and mediastinal disorders: Pharyngitis, increased cough, dyspnoea, epistaxis, pneumonia. Skin and subcutaneous tissue disorders: Rash, alopecia, pruritus, dry skin, erythema, urticaria; skin or nail discolouration or hyperpigmentation; acne, skin ulcer, cellulitis. Vascular disorders: Hypotension, flushing, vasodilatation, syncope, thrombophlebitis. Potentially Fatal: Severe myelosuppression (e.g. neutropenia, leucopenia, thrombocytopenia, anaemia), arrhythmias, CHF, pulmonary embolism; infusion-related reactions (liposomal formulations).
Confirm pregnancy status before treatment initiation in females of reproductive potential. Monitor CBC with differential and platelet count, LFTs (AST/ALT, alkaline phosphatase, bilirubin) at baseline and periodically during treatment; cardiac function (ECG, LVEF by echocardiography or multi-gated radionuclide angiography [MUGA]) at baseline, periodically during and after therapy; serum electrolytes (e.g. Ca, K, phosphate), serum creatinine and uric acid; hydration status. Closely monitor the infusion site for extravasation; for infusion-related reactions, oral ulceration suggestive of secondary oral malignancy, hand-foot syndrome (liposomal formulation). Perform cystoscopic examination and monitor urine cytology at regular intervals (intravesical use).
Overdosage
Symptoms: Increased risk of severe mucositis, acute myocardial degeneration, severe myelosuppression (leucopenia and thrombocytopenia). Management: Symptomatic and supportive treatment. Administer antibiotics, platelet and granulocyte transfusions for severe myelosuppression. Monitoring of cardiac function is recommended.
Drug Interactions
May cause profound and prolonged haematologic toxicity, seizures and coma with ciclosporin. Increased risk of cardiotoxic effect with trastuzumab. May potentiate the toxic effects of other anticancer therapies (e.g. exacerbated cyclophosphamide-induced haemorrhagic cystitis, enhanced hepatotoxicity of mercaptopurine). Increased plasma concentrations and clinical effects with inhibitors of CYP3A4, CYP2D6, and P-glycoprotein (P-gp) such as verapamil. May decrease plasma levels with CYP3A4 (e.g. phenobarbital, phenytoin) and P-gp inducers. Plasma levels of doxorubicin may be increased when paclitaxel is given initially. Potentially Fatal: May lead to serious infections when given with live vaccines in immunocompromised patients.
Food Interaction
Conventional formulation: May decrease plasma concentration with St. John’s wort.
Action
Description: Mechanism of Action: Doxorubicin is an anthracycline, cell-cycle non-specific antineoplastic agent. Its exact mechanism is not yet clearly determined; however, it appears to inhibit deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) synthesis by intercalation between DNA base pairs and inhibition of topoisomerase II. It is also a powerful Fe chelator forming free radicals that cleave the DNA and cell membranes. Pharmacokinetics: Absorption: Rapidly cleared from the blood after IV administration. Distribution: IV: Distributed into tissues including lungs, liver, heart, spleen and kidneys (conventional formulation). Largely confined into the vascular fluid (pegylated liposomal formulation). Crosses the placenta and enters breast milk. Volume of distribution: 809-1,214 L/m2 (conventional formulation); approx 2.7-2.8 L/m2. Plasma protein binding: Approx 75% (conventional formulation). Metabolism: Rapidly metabolised mainly in the liver by aldo-keto reductases into active doxorubicinol (adriamycinol), and inactive aglycones, conjugated sulfates and glucuronides. Excretion: Conventional formulation: Via faeces (approx 40% as unchanged drug); urine (5-12% as unchanged drug and metabolites; <3% as doxorubicinol). Terminal elimination half-life: 20-48 hours (conventional formulation); approx 52-55 hours (pegylated liposomal formulation).
Chemical Structure
Doxorubicin Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 31703, Doxorubicin. https://pubchem.ncbi.nlm.nih.gov/compound/Doxorubicin. Accessed Feb. 22, 2021.
Storage
Powder for inj (conventional formulation): Store between 20-25°C. Protect from light. Solution for inj (conventional formulation): Store between 2-8°C. Do not freeze. Protect from light. Liposomal formulations: Store between 2-8°C. Do not freeze. Storage recommendations may vary among individual products. Refer to detailed product guideline. This is a cytotoxic drug. Follow applicable procedures for receiving, handling, administration, and disposal.
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