Doxorubicin (Conventional)

Name: Doxorubicin (Conventional)

What are some things I need to know or do while I take Doxorubicin?

  • Tell all of your health care providers that you take this medicine. This includes your doctors, nurses, pharmacists, and dentists.
  • You may have more chance of getting an infection. Wash hands often. Stay away from people with infections, colds, or flu.
  • You may bleed more easily. Be careful and avoid injury. Use a soft toothbrush and an electric razor.
  • If you have upset stomach, throwing up, loose stools (diarrhea), or are not hungry, talk with your doctor. There may be ways to lower these side effects.
  • To help with mouth sores, use a soft toothbrush or cotton swabs and rinse the mouth. Do not use mouth rinses that have alcohol in them.
  • Use care to keep body fluids from coming in contact with family members or caregivers. Wash soiled clothing right away and use gloves when touching body fluids for at least 5 days after each treatment.
  • Talk with your doctor before getting any vaccines. Use with doxorubicin may either raise the chance of an infection or make the vaccine not work as well.
  • You will need to have heart function tests while taking this medicine. Talk with the doctor.
  • Have blood work checked as you have been told by the doctor. Talk with the doctor.
  • If you have had or will be having radiation treatment, talk with your doctor. Worse side effects from radiation treatment have happened with doxorubicin.
  • Use with care in children. Talk with the doctor.
  • This medicine may affect sperm in men. This may affect being able to father a child. Talk with the doctor.
  • If you are a man and have sex with a female who could get pregnant, protect her from pregnancy during care and for 6 months after care ends. Use birth control that you can trust.
  • This medicine may cause menstrual periods to stop in females who can get pregnant. This may affect being able to have children. It is not known if this will go back to normal. Talk with the doctor.
  • This medicine may cause harm to the unborn baby if you take it while you are pregnant. If you are pregnant or you get pregnant while taking this medicine, call your doctor right away.
  • Use birth control that you can trust to prevent pregnancy while taking doxorubicin and for 6 months after stopping this medicine.
  • If you or your sex partner gets pregnant while taking doxorubicin (conventional) or within 6 months after stopping this medicine, call your doctor right away.
  • Tell your doctor if you are breast-feeding. You will need to talk about any risks to your baby.

Pharmacologic Category

  • Antineoplastic Agent, Anthracycline
  • Antineoplastic Agent, Topoisomerase II Inhibitor

Special Populations Hepatic Function Impairment

Clearance is reduced.

Dosing Geriatric

Refer to adult dosing.

Dosing Pediatric

Doxorubicin is associated with a moderate to high emetic potential (depending on dose or regimen); antiemetics are recommended to prevent nausea and vomiting (Dupuis 2011).

Manufacturer's labeling: Note: Lower dosages should be considered for patients with inadequate marrow reserve (due to advanced age, prior treatment, or neoplastic marrow infiltration). Cumulative doses above 550 mg/m2 are associated with an increased risk of cardiomyopathy.

Metastatic solid tumors, leukemia, or lymphoma: Children and Adolescents: IV:

Single-agent therapy: 60 to 75 mg/m2 every 21 days

Combination therapy: 40 to 75 mg/m2 every 21 to 28 days

Indication-specific dosing (off-label dosing):

Acute lymphoblastic leukemia: IV:

DFCI Consortium Protocol 00-01: Children ≥1 year and Adolescents:

Induction: 30 mg/m2/dose on days 0 and 1 of a 4-week cycle (Vrooman 2013)

CNS therapy: High-risk patients: 30 mg/m2 on day 1 of a 3-week cycle (with dexrazoxane) (Vrooman 2013)

Intensification: High-risk patients: 30 mg/m2 on day 1 of every 3-week cycle (with dexrazoxane; cumulative doxorubicin dose: 300 mg/m2) (Vrooman 2013)

Ewing sarcoma: Children and Adolescents: IV:

VAC/IE regimen: 75 mg/m2 on day 1 every 21 days for 5 cycles (in combination with vincristine and cyclophosphamide; after 5 cycles, dactinomycin replaced doxorubicin), alternating cycles with ifosfamide and etoposide for a total of 17 cycles (Grier 2003)

VAIA regimen: 30 mg/m2/day on days 1 and 2 every 21 days (doxorubicin alternates with dactinomycin; in combination with vincristine and ifosfamide) for 14 cycles (Paulussen 2008)

VIDE regimen: 20 mg/m2/day over 4 hours on days 1 to 3 every 21 days for 6 cycles (in combination with vincristine, ifosfamide, and etoposide) (Juergens 2006)

Osteosarcoma: Children and Adolescents: IV:

Cisplatin/doxorubicin regimen: 25 mg/m2 (bolus infusion) on days 1 to 3 every 21 days (in combination with cisplatin) (Bramwell, 1992)

High-dose methotrexate/cisplatin/doxorubicin/ifosfamide regimen:

Preoperative: 75 mg/m2 administered as a continuous infusion over 24 hours on day 3 of weeks 1 and 7 (in combination with methotrexate, cisplatin, and ifosfamide) (Bacci 2003)

Postoperative: 90 mg/m2 administered as a continuous infusion over 24 hours on weeks 13, 22, and 31 (in combination with methotrexate, cisplatin, and ifosfamide) (Bacci 2003)

High-dose methotrexate/cisplatin/doxorubicin regimen:

Preoperative: 60 mg/m2 over 8 hours on days 9 and 36 (in combination with methotrexate and cisplatin) (Bacci 2000)

Postoperative: 45 mg/m2/day over 4 hours for 2 consecutive days (in combination with methotrexate, cisplatin +/- ifosfamide, +/- etoposide; refer to protocol for criteria, frequency, and other specific information) (Bacci 2000)

Rhabdomyosarcoma: Children and Adolescents: IV:

VAC/IE regimen: 37.5 mg/m2 on days 1 and 2 (administered over 18 hours each day) every 6 weeks (in combination with vincristine and cyclophosphamide), alternating cycles with ifosfamide and etoposide (Arndt, 1998)

Dosing Hepatic Impairment

The manufacturers' labeling recommends the following adjustments:

Serum bilirubin 1.2 to 3 mg/dL: Administer 50% of dose.

Serum bilirubin 3.1 to 5 mg/dL: Administer 25% of dose.

Severe hepatic impairment (Child-Pugh class C or bilirubin >5 mg/dL): Use is contraindicated.

The following adjustments have also been recommended (Floyd 2006):

Transaminases 2 to 3 times ULN: Administer 75% of dose.

Transaminases >3 times ULN: Administer 50% of dose.

Dosing Obesity

ASCO Guidelines for appropriate chemotherapy dosing in obese adults with cancer: Utilize patient’s actual body weight (full weight) for calculation of body surface area- or weight-based dosing, particularly when the intent of therapy is curative; manage regimen-related toxicities in the same manner as for nonobese patients; if a dose reduction is utilized due to toxicity, consider resumption of full weight-based dosing with subsequent cycles, especially if cause of toxicity (eg, hepatic or renal impairment) is resolved (Griggs 2012).

ALERT U.S. Boxed Warning

Experienced physician:

Doxorubicin should be administered only under the supervision of a health care provider who is experienced in the use of cancer chemotherapeutic agents.

Extravasation:

Extravasation of doxorubicin can result in severe local tissue injury and necrosis requiring wide excision of the affected area and skin grafting. Immediately terminate the drug and apply ice to the affected area. Doxorubicin must not be given by the intramuscular (IM) or subcutaneous route.

Cardiotoxicity:

Myocardial toxicity manifested in its most severe form by potentially fatal congestive heart failure (CHF) may occur during therapy or months to years after termination of therapy. The probability of developing impaired myocardial function based on a combined index of signs, symptoms, and decline in left ventricular ejection fraction (LVEF) is estimated to be 1% to 2% at a total cumulative dose of 300 mg/m2, 3% to 5% at 400 mg/m2, 5% to 8% at 450 mg/m2, and 6% to 20% at 500 mg/m2. The risk of developing CHF increases rapidly with increasing total cumulative doses of doxorubicin in excess of 400 mg/m2. Risk factors (active or dormant cardiovascular disease, prior or concomitant radiotherapy to the mediastinal/pericardial area, previous therapy with other anthracyclines or anthracenediones, concomitant use of other cardiotoxic drugs) may increase the risk of cardiac toxicity. Cardiac toxicity with doxorubicin may occur at lower cumulative doses whether or not cardiac risk factors are present. Pediatric patients are at an increased risk for developing delayed cardiotoxicity.

Secondary malignancy:

Secondary acute myelogenous leukemia (AML) or myelodysplastic syndrome have been reported in patients treated with doxorubicin. The occurrence of refractory secondary AML or myelodysplastic syndrome is more common when anthracyclines are given in combination with DNA-damaging antineoplastic agents or radiotherapy, when patients have been heavily pretreated with cytotoxic drugs, or when doses of anthracyclines have been escalated. Pediatric patients are also at risk of developing secondary AML.

Hepatic function impairment:

The dosage should be reduced in patients with impaired hepatic function.

Myelosuppression:

Severe myelosuppression, resulting in serious infection, septic shock, requirement for transfusions, hospitalization, and death, may occur.

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: [US Boxed Warning]: May cause severe myelosuppression, which may result in serious infection, septic shock, transfusion requirements, hospitalization, and death. Myelosuppression may be dose-limiting and primarily manifests as leukopenia and neutropenia; anemia and thrombocytopenia may also occur. The nadir typically occurs 10 to 14 days after administration with cell count recovery around day 21. Monitor blood counts at baseline and regularly during therapy.

• Cardiotoxicity: [US Boxed Warning]: May cause cumulative, dose-related, myocardial toxicity (early or delayed, including acute left ventricular failure and HF). The risk of cardiomyopathy increases with cumulative exposure and with concomitant cardiotoxic therapy; the incidence of irreversible myocardial toxicity increases as the total cumulative (lifetime) dosages approach 300 to 500 mg/m2 (with an every-3-week regimen). Assess left ventricular ejection fraction (LVEF) with either an echocardiogram or MUGA scan before, during, and after therapy; increase the frequency of assessments as the cumulative dose exceeds 300 mg/m2. Cardiotoxicity is dose-limiting. Delayed cardiotoxicity may occur late in treatment or within months to years after completion of therapy, and is typically manifested by LVEF reduction and/or heart failure (may be life threatening). Subacute effects such as pericarditis and myocarditis may also occur. Early toxicity may consist of tachyarrhythmias, including sinus tachycardia, premature ventricular contractions, and ventricular tachycardia, as well as bradycardia. Electrocardiographic changes including ST-T wave changes, atrioventricular and bundle-branch block have also been reported. These effects are not necessarily predictive of subsequent delayed cardiotoxicity. Total cumulative dose should take into account prior treatment with other anthracyclines or anthracenediones, previous or concomitant treatment with other cardiotoxic agents or irradiation of chest. The risk for delayed cardiotoxicity is estimated to range from 1% to 2% at cumulative lifetime doses of 300 mg/m2 to 6% to 20% at cumulative lifetime doses of 500 mg/m2 administered every 3 weeks. Although the risk increases with cumulative dose, irreversible cardiotoxicity may occur at any dose level. Patients with active or dormant cardiovascular disease, concurrent administration of cardiotoxic drugs, prior therapy with other anthracyclines or anthracenediones, prior or concurrent chest irradiation, advanced age, and infants and children are at increased risk. Alternative administration schedules (weekly or continuous infusions) are associated with less cardiotoxicity. Children are at increased risk for developing delayed cardiotoxicity.

• Extravasation: [US Boxed Warning]: Vesicant; if extravasation occurs, severe local tissue damage leading to tissue injury, blistering, ulceration, and necrosis may occur. Discontinue infusion immediately and apply ice to the affected area. For IV administration only. Do not administer IM or SubQ. Ensure proper needle or catheter placement prior to and during infusion. Avoid extravasation.

• Fertility impairment: In men, doxorubicin may damage spermatozoa and testicular tissue, resulting in possible genetic fetal abnormalities; may also result in oligospermia, azoospermia, and permanent loss of fertility (sperm counts have been reported to return to normal levels in some men, occurring several years after the end of therapy). In females of reproductive potential, doxorubicin may cause infertility and result in amenorrhea; premature menopause can occur.

• Gastrointestinal toxicity: Doxorubicin is associated with a moderate or high emetic potential (depending on dose or regimen); antiemetics are recommended to prevent nausea and vomiting (Basch 2011; Dupuis 2011; Roila 2016).

• Secondary malignancy: [US Boxed Warnings]: Secondary acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) have been reported following treatment. AML and MDS typically occur within 1 to 3 years of treatment; risk factors for development of secondary AML or MDS include treatment with anthracyclines in combination with DNA-damaging antineoplastics (eg, alkylating agents) and/or radiation therapy, heavily pretreated patients, and escalated anthracycline doses.

• Tumor lysis syndrome: May cause tumor lysis syndrome and hyperuricemia (in patients with rapidly growing tumors). Urinary alkalinization and prophylaxis with an antihyperuricemic agent may be necessary. Monitor electrolytes, renal function, and hydration status.

Disease-related concerns:

• Hepatic impairment: [US Boxed Warning]: Dosage modification is recommended in patients with hepatic impairment; toxicities may be increased in patients with hepatic impairment. Use is contraindicated in patients with severe impairment (Child-Pugh class C or bilirubin >5 mg/dL). Monitor hepatic function tests (eg, transaminases, alkaline phosphatase, and bilirubin) closely.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Pediatric: Children are at increased risk for developing delayed cardiotoxicity; long-term periodic cardiac function monitoring is recommended. Doxorubicin may contribute to prepubertal growth failure in children; may also contribute to gonadal impairment (usually temporary). Radiation recall pneumonitis has been reported in children receiving concomitant dactinomycin and doxorubicin.

• Radiation recipients: Use with caution in patients who have received radiation therapy; radiation recall may occur. May increase radiation-induced toxicity to the myocardium, mucosa, skin, and liver.

Dosage form specific issues:

• Formulations (conventional vs liposomal): Use caution when selecting product for preparation and dispensing; indications, dosages and adverse event profiles differ between conventional doxorubicin hydrochloride solution and doxorubicin liposomal. Both formulations are the same concentration. As a result, serious errors have occurred.

Other warnings/precautions:

• Experienced physician: [US Boxed Warning]: Should be administered under the supervision of an experienced cancer chemotherapy physician.

• Vaccines: Administration of live vaccines to immunosuppressed patients may be hazardous.

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