Doxorubicine

Uses

Doxorubicine is an anthracycline topoisomerase II inhibitor used for:

• Ovarian cancer: After failure of platinum-based chemotherapy.
• AIDS-related Kaposi’s Sarcoma: After failure of prior systemic chemotherapy or intolerance to such therapy.
• Multiple Myeloma: In combination with bortezomib in patients who have not previously received bortezomib and have received at least one prior therapy.

Doxorubicine is also used to associated treatment for these conditions: Acute Lymphoblastic Leukaemias (ALL), Acute Myeloblastic Leukemia, Advanced Endometrial Cancer, Advanced Soft Tissue Sarcoma, Bladder transitional cell carcinoma, Carcinoma, Bronchogenic, Gastric Carcinoma, Kaposi's Sarcoma AIDS Related, Lymphoma, Hodgkins, Malignant Lymphomas, Metastatic Breast Cancer, Multiple Myeloma (MM), Mycosis Fungoides (MF), Neuroblastomas, Ovarian Cancer Metastatic, Ovarian Carcinoma, Sarcoma, Bone, Sezary Syndrome, Soft Tissue Sarcoma (STS), Thyroid Carcinoma, Waldenström's Macroglobulinemia (WM), Wilms' tumor, Advanced Thymoma, Advanced uterine sarcoma

How Doxorubicine works

Doxorubicine has antimitotic and cytotoxic activity through a number of proposed mechanisms of action: Doxorubicine forms complexes with DNA by intercalation between base pairs, and it inhibits topoisomerase II activity by stabilizing the DNA-topoisomerase II complex, preventing the religation portion of the ligation-religation reaction that topoisomerase II catalyzes.

Dosage

Doxorubicine dosage

Administer Doxorubicine at an initial rate of 1 mg/min to minimize the risk of infusion reactions. If no infusion related reactions occur, increase rate of infusion to complete administration over 1 hour. Do not administer as bolus injection or undiluted solution.

• Ovarian cancer: 50 mg/m2 IV every 4 weeks
• AIDS-related Kaposi’s Sarcoma: 20 mg/m2 IV every 3 weeks
• Multiple Myeloma: 30 mg/m2 IV on day 4 following bortezomib

Side Effects

Leucopenia, thrombocytopenia, nausea, vomiting, diarrhoea. Rarely facial flushing, rash, alopecia. Blurred vision, headache, seizures, paraesthesia, confusion, malaise, lethargy, skin pigmentation.

Toxicity

LD₅₀=21800 ug/kg (rat, subcutaneous)

Precaution

Elderly, children, hepatic impairment. Monitor blood counts and ECG.

Interaction

Doxorubicine interacts with a number of other drugs e.g. antibiotics (aminoglycosides), steroids, aminophylline and propranolol.

Food Interaction

• Avoid St. John's Wort. This herb induces CYP3A4 metabolism, which may reduce the serum concentration of doxorubicin.
• Exercise caution with grapefruit products. Grapefruit inhibits CYP3A4 metabolism, which may increase the serum concentration of doxorubicin.

Doxorubicine Drug Interaction

Moderate: aprepitant, aprepitant, pegfilgrastim, pegfilgrastim, ondansetron, ondansetronMinor: sulfamethoxazole / trimethoprim, sulfamethoxazole / trimethoprim, cyclophosphamide, cyclophosphamideUnknown: lorazepam, lorazepam, diphenhydramine, diphenhydramine, loratadine, loratadine, cyanocobalamin, cyanocobalamin, cholecalciferol, cholecalciferol

Doxorubicine Disease Interaction

Major: infections, cardiomyopathy, hepatic dysfunction, myelosuppression

Volume of Distribution

The distributive half-life is 5 minutes, which suggests that doxorubicin is rapidly taken up by tissue. Steady state volume of distribution = 809 to 1214 L/m2

Half Life

Terminal half life = 20 - 48 hours.

Clearance

• 324-809 mL/min/m2 [by metabolism and biliary excretion]
• 1088 mL/min/m2 [Men]
• 433 mL/min/m2 [Women]
• 1540 mL/min/m2 [children greater than 2 years of age receiving administration of 10 to 75 mg/m2 doses]
• 813 mL/min/m2 [infants younger than 2 years of age receiving administration of 10 to 75 mg/m2 doses]

Elimination Route

40% of the dose appears in bile in 5 days. 5-12% of the drug and its metabolites appears in urine during the same time period. <3% of the dose recovered in urine was doxorubicinol.

Pregnancy & Breastfeeding use

Category D: There is positive evidence of human foetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).

Contraindication

Cardiac disease, neonates, pregnancy and lactation, prior irradiation to mediastinum. IM/SC admin. Severe myelosuppression due to previous treatment with antitumour agents or radiotherapy.

Special Warning

Hepatic Impairment-

serum-bilirubin: 12-30 mcg/ml: Half the normal dose;

serum-bilirubin: >30 mcg/ml: Quarter of the usual dose.

Acute Overdose

Acute overdosage may increase the toxic effects of mucositis, leukopenia and thrombocytopenia. Treatment includes hospitalisation of the severely myelosuppressed patient, antimicrobials, platelet transfusions and symptomatic treatment of mucositis. Use of haemopoietic growth factor (G-CSF, GM-CSF) may be considered. Cumulative dosage increases risk of cardiomyopathy and resultant congestive heart failure which may be managed with digitalis preparations, diuretics, and after load reducers such as ACE inhibitors.

Storage Condition

Powder for injection: Store at 15-30°C.

Solution for injection & liposomal formulations: Refrigerate at 2-8°C. Do not freeze.

Innovators Monograph

You find simplified version here Doxorubicine