General

High Alert Medication: This medication bears a heightened risk of causing significant patient harm when it is used in error.

Pronunciation:
dox-oh-roo-bi-sin

Trade Name(s)

• Adriamycin
• Caelyx 

Ther. Class.

antineoplastics

Pharm. Class.

anthracyclines

Indications

• Breast cancer.
• Acute lymphoblastic leukemia.
• Acute myeloblastic leukemia.
• Hodgkin lymphoma.
• Non-Hodgkin lymphoma.
• Metastatic Wilms tumor.
• Metastatic neuroblastoma.
• Metastatic soft tissue sarcoma.
• Metastatic bone sarcoma.
• Metastatic ovarian carcinoma.

Action

• Inhibits DNA and RNA synthesis by forming a complex with DNA; action is cell-cycle S-phase specific.
• Also has immunosuppressive properties.

Therapeutic Effect(s):

Death of rapidly replicating cells, particularly malignant ones.

Pharmacokinetics

Absorption: IV administration results in complete bioavailability.

Distribution: Widely distributed to tissues; does not cross the blood-brain barrier.

Metabolism and Excretion: Primarily metabolized by the liver via the CYP2D6 and CYP3A4 isoenzymes to an active metabolite. Excreted predominantly in the bile, 50% as unchanged drug. <5% eliminated unchanged in the urine.

Half-life: 16.7 hr.

TIME/ACTION PROFILE (effect on blood counts)

Contraindication/Precautions

Contraindicated in:

• Hypersensitivity;
• OB:   Pregnancy;
• Lactation:  Lactation.

Use Cautiously in:

• Black Box:  History of cardiac disease or high cumulative doses of anthracyclines;
• Black Box:  Depressed bone marrow reserve;
• Hepatic impairment (↓ dose if serum bilirubin >1.2 mg/dL);
• Rep:  Women of reproductive potential and men with female partners of reproductive potential;
• Pedi:   Geri:  Children, older adults, mediastinal radiation, or concurrent cyclophosphamide (↑ risk of cardiotoxicity).

Adverse Reactions/Side Effects

CV: cardiomyopathy, ECG changes

Derm: alopecia, photosensitivity

Endo: prepubertal growth failure with temporary gonadal impairment (children only)

GI: diarrhea, esophagitis, nausea, stomatitis, vomiting

GU: red urine, sterility

Hemat: anemia, LEUKOPENIA, thrombocytopenia

Local: Black Box:  phlebitis at iv site, Black Box:  tissue necrosis

Metabolic: hyperuricemia

Resp: recall pneumonitis

Misc: hypersensitivity reactions, second malignancy

* CAPITALS indicate life-threatening.
Underline indicate most frequent.

Interactions

Drug-Drug

•  CYP2D6 inhibitors,  CYP3A4 inhibitors, and  P-glycoprotein inhibitors  may ↑ levels and risk of toxicity; avoid concurrent use.
•  CYP2D6 inducers,  CYP3A4 inducers, and  P-glycoprotein inducers  may ↓ levels and effectiveness; avoid concurrent use.
• ↑ risk of bone marrow depression with other  antineoplastics  or  radiation therapy.
• Pediatric patients who have received concurrent doxorubicin and  dactinomycin  have an ↑ risk of recall pneumonitis at variable times following local radiation therapy.
• May ↑ skin reactions at previous  radiation therapy  sites.
• If  paclitaxel  is administered first, clearance of doxorubicin is ↓ and the incidence and severity of neutropenia and stomatitis are ↑ (problem is diminished if doxorubicin is administered 1st).
• Hematologic toxicity is ↑ and prolonged by concurrent use of  cyclosporine ; risk of coma and seizures is also ↑.
• Incidence and severity of neutropenia and thrombocytopenia are ↑ by concurrent  progesterone.
• May ↑ levels and risk of toxicity of  phenytoin.
•  Streptozocin  may ↑ levels and risk of toxicity; ↓ dose of doxorubicin recommended.
• May ↑ risk of hemorrhagic cystitis from  cyclophosphamide.
• May ↑ risk of hepatotoxicity from  mercaptopurine.
• Cardiac toxicity may be ↑ by  radiation therapy  or  cyclophosphamide.
• ↑ risk of cardiac toxicity with  trastuzumab ; avoid use of doxorubicin for up to 7 mo after discontinuing trastuzumab.
• If  dexrazoxane  is administered at initiation of doxorubicin-containing regimens, may ↑ risk of therapeutic failure and tumor progression.
• May ↓ antibody response to  live-virus vaccines  and ↑ risk of adverse reactions.

Route/Dosage

IV (Adults): 60–75 mg/m²  daily, repeat every 21 days; or 25–30 mg/m²  daily for 2–3 days, repeat every 3–4 wk or 20 mg/m² /wk. Total cumulative dose should not exceed 550 mg/m²  without monitoring of cardiac function or 400 mg/m²  in patients with previous chest radiation or other cardiotoxic chemotherapy.

IV (Children): 30 mg/m² /day for 3 days every 4 wk.

Hepatic Impairment 
IV (Adults): Serum bilirubin 1.2–3 mg/dL:  ↓ dose by 50%;  Serum bilirubin 3.1–5 mg/dL:  ↓ dose by 75%.

Availability (generic available)

Powder for injection: 10 mg/vial, 50 mg/vial, 150 mg/vial 

Solution for injection: 2 mg/mL

Assessment

• Monitor BP, HR, respiratory rate, and temperature frequently during administration.
• Black Box:  Monitor for bone marrow depression. Assess for bleeding (bleeding gums; bruising; petechiae; guaiac stools, urine, and emesis) and avoid IM injections and taking rectal temperatures if platelet count is low. Apply pressure to venipuncture sites for 10 min. Assess for signs of infection during neutropenia. Anemia may occur. Monitor for ↑ fatigue, dyspnea, and orthostatic hypotension.
• Monitor intake and output. Encourage fluid intake of 2000–3000 mL/day. Allopurinol and alkalinization of the urine may be used to ↓ serum uric acid levels and to help prevent urate stone formation.
• Severe and protracted nausea and vomiting may occur as early as 1 hr after therapy and may last 24 hr. Administer parenteral antiemetics 30–45 min before therapy and routinely around the clock for the next 24 hr as indicated. Monitor amount of emesis and notify health care provider if emesis exceeds guidelines to prevent dehydration.
• Monitor for development of signs of cardiac toxicity, which may be either acute and transient (ST segment depression, flattened T wave, sinus tachycardia, extrasystoles) or late onset (usually occurs 1–6 mo after initiation of therapy) and characterized by intractable HF (peripheral edema, dyspnea, rales/crackles, weight gain). Chest x-ray, echocardiography, ECG, and radionuclide angiography may be ordered before and periodically during therapy. Cardiotoxicity is more prevalent in children <2 yr and older adults and when cumulative dose >300 mg/m² . Dexrazoxane may be used to prevent cardiotoxicity in patients receiving cumulative doses of >300 mg/m² .
• Black Box:  Assess injection site frequently for redness, irritation, or inflammation during and for up to 2 hr after completion of infusion. Doxorubicin is a vesicant but may infiltrate painlessly even if blood returns on aspiration of infusion needle. Severe tissue damage may occur if doxorubicin extravasates. If extravasation occurs, stop infusion immediately, restart, and complete dose in another vein. Local infiltration of antidote is not recommended. If extravasation is suspected, intermittent application of ice to site for 15 min 4 times daily for 3 days may be useful. Because of the progressive nature of extravasation reactions, close observation and plastic surgery consultation are recommended. Blistering, ulceration, and/or persistent pain are indications for wide excision surgery, followed by split-thickness skin grafting. May use dexrazoxane to treat extravasation. Administer 1st infusion of dexrazoxane as soon as possible within 6 hr of extravasation. Remove ice packs for >15 min before and during dexrazoxane administration. Recommended dose of dexrazoxane for day 1 is 1000 mg/m²  (up to 2000 mg); the dose for day 2 is 1000 mg/m²  (up to 2000 mg); the dose for day 3 is 500 mg/m²  (up to 1000 mg). Dexrazoxane is administered as an IV infusion over 1–2 hr. If swelling, redness, and/or pain persists beyond 48 hr, immediate consultation for possible debridement is indicated.
• Assess oral mucosa frequently for development of stomatitis. ↑ dosing interval and/or ↓ dose is recommended if lesions are painful or interfere with nutrition.

Lab Test Considerations:

Verify negative pregnancy test before starting therapy.

• Black Box:  Monitor CBC with differential before and periodically during therapy. WBC nadir occurs 10–14 days after administration, and recovery usually occurs by the 21st day. Thrombocytopenia and anemia may also occur. ↑ dosing interval and/or ↓ dose is recommended if ANC is <1000 cells/mm³  and/or platelet count is <50,000 cells/mm³.
• Monitor renal (BUN and serum creatinine) and hepatic (AST, ALT, LDH, and serum bilirubin) function before and periodically during therapy. Dose ↓ is required for bilirubin >1.2 mg/dL or serum creatinine >3 mg/dL.
• May ↑ serum and urine uric acid concentrations.

Implementation

• High Alert: Fatalities have occurred with incorrect administration of chemotherapeutic agents. Before administering, clarify all ambiguous orders; double-check single, daily, and course-of-therapy dose limits; have 2nd practitioner independently double-check original order, calculations, and infusion pump settings.
• High Alert: Do not confuse doxorubicin hydrochloride with doxorubicin liposomal, daunorubicin hydrochloride, or idarubicin. Clarify orders that do not include both generic and brand names.
• High Alert: Black Box:  Administer under supervision of a physician experienced in use of cancer chemotherapeutic agents.
• Black Box:  Monitor cumulative dose of doxorubicin and other anthracyclines received; risk for cardiomyopathy ↑ as the cumulative dose ↑ (>250 mg/m²  in pediatric patients <18 yr and 550 mg/m²  in patients >18 yr).

• Wear gloves, gown, and mask while handling medication. Discard IV equipment in specially designated containers.

  • Aluminum needles may be used to administer doxorubicin but should not be used during storage, because prolonged contact results in discoloration of solution and formation of a dark precipitate. Solution is red.

Patient/Family Teaching

• Explain purpose and side effects of medication. Advise patient to read  Patient Information  before starting therapy.
• Instruct patient to notify health care provider of all Rx or OTC medications, vitamins, or herbal products being taken and to consult health care provider before taking other Rx, OTC, or herbal products.
• Black Box:  Instruct patient to notify health care provider promptly if fever; sore throat; signs of infection; bleeding gums; bruising; petechiae; blood in stools, urine, or emesis; ↑ fatigue; dyspnea; or orthostatic hypotension occurs. Caution patient to avoid crowds and persons with known infections. Instruct patient to use soft toothbrush and electric razor and to avoid falls. Caution patient not to drink alcoholic beverages or take medication containing aspirin or NSAIDs, because these may precipitate gastric bleeding.
• Black Box:  Instruct patient to report pain at injection site immediately.
• Instruct patient to inspect oral mucosa for erythema and ulceration. If ulceration occurs, advise patient to use sponge brush, rinse mouth with water after eating and drinking, and confer with health care provider if mouth pain interferes with eating. Pain may require treatment with opioid analgesics. The risk of developing stomatitis is greatest 5–10 days after a dose; usual duration is 3–7 days.
• Instruct patient to notify health care provider immediately if irregular heartbeat, shortness of breath, swelling of lower extremities, or skin irritation (swelling, pain, or redness of feet or hands) occurs.
• Discuss the possibility of hair loss with patient. Explore methods of coping. Regrowth usually occurs 2–3 mo after discontinuation of therapy.
• Instruct patient not to receive any vaccinations without advice of health care provider.
• Inform patient that medication may cause urine to appear red for 1–2 days.
• Instruct patient to notify health care provider if skin irritation occurs at site of previous radiation therapy.
• Advise family and/or caregivers to take precautions (i.e., latex gloves) in handling body fluids for >5 days post-treatment.
• Inform patient that doxorubicin may ↑ risk of developing secondary cancers.
• Emphasize the need for periodic lab tests to monitor for side effects.
• Rep:  May cause fetal harm. Advise women of reproductive potential to use effective contraception during therapy and for 6 mo after last dose and to avoid breastfeeding during therapy and for 10 days–6 wk after last dose. Advise men with female partners of reproductive potential to use effective contraception during therapy and for 3–6 mo after last dose of doxorubicin. A pregnancy registry is available for all cancers diagnosed during pregnancy at Cooper Health (877-635-4499). Inform patient before initiating therapy that this medication may cause irreversible gonadal suppression, irreversible amenorrhea, or early menopause.

Evaluation/Desired Outcomes

Death of rapidly replicating cells, particularly malignant ones.