Physicians' Cancer Chemotherapy Drug Manual 2004
A B C D E F G H I J K L M N O P Q R S T U V W X Y Z

 

D

Doxorubicin


Generic Drug Name
Doxorubicin

 

 



 

Trade Names
Adriamycin, Adria, Hydroxydaunorubicin, DOX, Rubex
 


 

Classification
Antitumor antibiotic


 

Category
Chemotherapy drug


 

Drug Manufacturer
Pharmacia


 

Mechanism of Action
 

  • Anthracycline antibiotic isolated from Streptomyces species.
  • Intercalates into DNA resulting in inhibition of DNA synthesis and function.
  • Inhibits transcription through inhibition of DNA-dependent RNA polymerase.
  • Inhibits topoisomerase II by forming a cleavable complex with DNA and topoisomerase II to create uncompensated DNA helix torsional tension, leading to eventual DNA breaks.
  • Formation of cytotoxic oxygen free radicals results in single- and double-stranded DNA breaks with subsequent inhibition of DNA synthesis and function.

 


 

Mechanism of Resistance
 

  • Increased expression of the multidrug-resistant gene with elevated P170 levels. This leads to increased drug efflux and decreased intracellular drug accumulation.
  • Decreased expression of topoisomerase II.
  • Mutation in topoisomerase II with decreased binding affinity to doxorubicin.
  • Increased expression of sulfhydryl proteins, including glutathione and glutathione-dependent proteins.

 


 

Absorption
Not absorbed orally.


 

Distribution
Widely distributed to tissues. Does not cross the blood-brain barrier. About 75% of doxorubicin and its metabolites are bound to plasma proteins.


 

Metabolism
Metabolized extensively in the liver to the active hydroxylated metabolite, doxorubicinol. About 40%–50% of drug is eliminated via biliary excretion in feces. Less than 10% of drug is cleared by the kidneys. Prolonged terminal half-life of 20–48 hours.


 

Indications
 

  1. Breast cancer.
  2. Hodgkin's and non-Hodgkin's lymphoma.
  3. Soft tissue sarcoma.
  4. Ovarian cancer.
  5. Non–small cell and small cell lung cancer.
  6. Bladder cancer.
  7. Thyroid cancer.
  8. Hepatoma.
  9. Gastric cancer.
  10. Wilms' tumor.
  11. Neuroblastoma.
  12. Acute lymphoblastic leukemia.

 


 

Dosage Range
 

  1. Single agent: 60–75 mg/m2 IV every 3 weeks.
  2. Single agent: 15–20 mg/m2 IV weekly.
  3. Combination therapy: 45–60 mg/m2 every 3 weeks.
  4. Continuous infusion: 60–90 mg/m2 IV over 96 hours.

 


 

Drug Preparation
 

  • Available in 10, 20, 50, 100, and 150 mg vials for IV use. Also available in 200 mg multidose vial.
  • Dilute with 0.9% sodium chloride (preservative-free) to yield a final concentration of 2 mg/mL. May be further diluted in 0.9% sodium chloride for prolonged infusions.
  • Reconstituted solution is stable for 7 days at room temperature and for 15 days under refrigeration.
  • Doxorubicin is compatible in solution with vincristine in prolonged infusions.

 


 

Drug Interaction 1
Dexamethasone, 5-FU, heparin―Doxorubicin is incompatible with dexamethasone, 5-FU, and heparin, as concurrent use will lead to precipitate formation.


 

Drug Interaction 2
Dexrazoxane―The cardiotoxic effects of doxorubicin are inhibited by the iron-chelating agent dexrazoxane (ICRF-187, Zinecard).


 

Drug Interaction 3
Cyclophosphamide―Increased risk of hemorrhagic cystitis and cardiotoxicity when doxorubicin is given with cyclophosphamide. Important to be able to distinguish between hemorrhagic cystitis and the normal red-orange urine observed with doxorubicin therapy.


 

Drug Interaction 4
Phenobarbital, phenytoin―Increased plasma clearance of doxorubicin when given concurrently with barbiturates and phenytoin.


 

Drug Interaction 5
Herceptin, mitomycin-C―Increased risk of cardiotoxicity when doxorubicin is given with herceptin or mitomycin-C.


 

Drug Interaction 6
Digoxin―Doxorubicin decreases the oral bioavailability of digoxin.


 

Drug Interaction 7
6-Mercaptopurine―Increased risk of hepatotoxicity when doxorubicin is given with 6-mercaptopurine.



 

Special Considerations
 

  1. Use with caution in patients with abnormal liver function. Dose reduction is required in the setting of liver dysfunction.
  2. Because doxorubicin is a strong vesicant, administer slowly with a rapidly flowing IV. Avoid using veins over joints or in extremities with compromised venous and/or lymphatic drainage. Use of a central venous catheter is recommended for patients with difficult venous access and mandatory for prolonged infusions. Careful monitoring is necessary to avoid extravasation. If extravasation is suspected, immediately stop infusion, withdraw fluid, elevate extremity, and apply ice to involved site. May administer local steroids. In severe cases, consult a plastic surgeon.
  3. Monitor cardiac function before (baseline) and periodically during therapy with either MUGA radionuclide scan or echocardiogram to assess LVEF. Risk of cardiotoxicity is higher in patients > 70 years of age, in patients with prior history of hypertension or pre-existing heart disease, in patients previously treated with anthracyclines, or in patients with prior radiation therapy to the chest. Cumulative doses of > 550 mg/m2 are associated with increased risk for cardiotoxicity.
  4. Risk of cardiotoxicity is decreased with weekly or continuous infusion schedules. Use of the iron-chelating agent dexrazoxane (ICRF-187) also is effective at reducing the development of cardiotoxicity.
  5. Use with caution in patients previously treated with radiation therapy as doxorubicin can cause radiation recall skin reaction. Increased risk of skin toxicity when doxorubicin is given concurrently with radiation therapy.
  6. Patients should be cautioned to avoid sun exposure and to wear sun protection when outside.
  7. Patients should be warned about the potential for red-orange discoloration of urine for 1–2 days after drug administration.
  8. Pregnancy category D. Breast-feeding should be avoided.

 


 

Toxicity 1
Myelosuppression. Dose-limiting toxicity with leukopenia more common than thrombocytopenia or anemia. Nadir usually occurs at days 10–14 with full recovery by day 21.
 


 

Toxicity 2
Nausea and vomiting. Usually mild, occurring in 50% of patients within the first 1–2 hours of treatment.
 


 

Toxicity 3
Mucositis and diarrhea. Common but not dose-limiting.
 


 

Toxicity 4
Cardiotoxicity. Acute form presents within the first 2–3 days as arrhythmias and/or conduction abnormalities, EKG changes, pericarditis, and/or myocarditis. Usually transient and mostly asymptomatic. Not dose-related.
Chronic form results in a dose-dependent, dilated cardiomyopathy associated with congestive heart failure. Risk increases when cumulative doses are greater than 550 mg/m2.
 


 

Toxicity 5
Strong vesicant. Extravasation can lead to tissue necrosis and chemical thrombophlebitis at the site of injection.
 


 

Toxicity 6
Hyperpigmentation of nails, rarely skin rash, and urticaria. Radiation recall skin reaction can occur at prior sites of irradiation. Increased hypersensitivity to sunlight.
 


 

Toxicity 7
Alopecia. Universal but usually reversible within 3 months after termination of treatment.
 


 

Toxicity 8
Red-orange discoloration of urine. Usually occurs within 1–2 days after drug administration.
 


 

Toxicity 9
Allergic, hypersensitivity reactions are rare.