DOXOrubicin (Conventional)

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Solution, Intravenous, as hydrochloride:

Generic: 2 mg/mL (5 mL, 10 mL, 25 mL, 100 mL)

Solution, Intravenous, as hydrochloride [preservative free]:

Adriamycin: 2 mg/mL (5 mL, 10 mL, 25 mL, 100 mL)

Generic: 2 mg/mL (5 mL, 10 mL, 25 mL, 75 mL, 100 mL)

Solution Reconstituted, Intravenous, as hydrochloride:

Generic: 50 mg (1 ea [DSC])

Solution Reconstituted, Intravenous, as hydrochloride [preservative free]:

Adriamycin: 10 mg (1 ea); 50 mg (1 ea) [contains lactose monohydrate]

Generic: 10 mg (1 ea [DSC])

Pharmacology

Mechanism of Action

Doxorubicin inhibits DNA and RNA synthesis by intercalation between DNA base pairs by inhibition of topoisomerase II and by steric obstruction. Doxorubicin intercalates at points of local uncoiling of the double helix. Although the exact mechanism is unclear, it appears that direct binding to DNA (intercalation) and inhibition of DNA repair (topoisomerase II inhibition) result in blockade of DNA and RNA synthesis and fragmentation of DNA. Doxorubicin is also a powerful iron chelator; the iron-doxorubicin complex can bind DNA and cell membranes and produce free radicals that immediately cleave the DNA and cell membranes.

Pharmacokinetics/Pharmacodynamics

Distribution

V_d: 809 to 1,214 L/m²; does not cross the blood-brain barrier

Metabolism

Primarily hepatic to doxorubicinol (active), then to inactive aglycones, conjugated sulfates, and glucuronides

Excretion

Feces (~40% as unchanged drug); urine (~5% to 12% as unchanged drug and metabolites)

Clearance:

Infants and Children <2 years: 813 mL/minute/m²

Children and Adolescents >2 years: 1,540 mL/minute/m²

Adults: 324 to 809 mL/minutes/m² (appears to be higher in men than women)

Half-Life Elimination

Distribution: ~5 minutes

Terminal: 20 to 48 hours

Male: 54 hours; Female: 35 hours

Protein Binding

Plasma: ~75%

Use in Specific Populations

Special Populations: Hepatic Function Impairment

Clearance is reduced.

Special Populations Note

Obesity: Systemic clearance is significantly reduced in obese women with ideal body weight greater than 130%. There was a significant reduction in clearance without any change in volume of distribution in obese patients when compared with healthy patients with less than 115% ideal body weight.

Use: Labeled Indications

Breast cancer: Treatment component of adjuvant therapy (multi-agent) in women with evidence of axillary lymph node involvement following resection of primary breast cancer

Metastatic cancers or disseminated neoplastic conditions: Treatment of acute lymphoblastic leukemia, acute myeloid leukemia, Wilms tumor, neuroblastoma, soft tissue and bone sarcomas, breast cancer, ovarian cancer, transitional cell bladder carcinoma, thyroid carcinoma, gastric carcinoma, Hodgkin lymphoma, non-Hodgkin lymphoma, and bronchogenic carcinoma in which the small cell histologic type is the most responsive compared with other cell types

Use: Off Label

Endometrial carcinomaa

Data from a large, randomized phase III trial supports the use of doxorubicin (in combination with cisplatin) in the management of advanced endometrial carcinoma Randall 2006.

Hepatocellular carcinoma (intermediate stage; chemoembolization)b

Data from a phase II study support the use of doxorubicin either as a component of conventional transcatheter arterial chemoembolization (TACE) or as drug-eluting beads in TACE for the treatment of cirrhotic patients (Child-Pugh class A or B) with previously untreated large and/or multinodular hepatocellular carcinoma that is unsuitable for resection Lammer 2010. A retrospective review performed across two institutions (with 2 years of follow-up data) also suggests the utility of doxorubicin as a component of TACE Morse 2012.

Hepatocellular carcinoma (metastatic)c

Data from 2 small phase II studies support the use of doxorubicin (in combination with cisplatin with or without capecitabine) in the treatment of metastatic hepatocellular carcinoma, in patients fit enough to tolerate therapy Lee 2004, Park 2006.

Multiple myelomaa

Data from large randomized phase III trials supports the use of doxorubicin (in combination with bortezomib, dexamethasone, thalidomide, cisplatin, cyclophosphamide, and etoposide) as induction therapy for the management of multiple myeloma Lee 2003, Pineda-Roman 2008. Another large open-label randomized phase II trial also supports the use of doxorubicin (in combination with bortezomib and dexamethasone) as induction therapy for multiple myeloma Sonneveld 2012.

Renal carcinoma (advanced)b

Data from a small phase II study supports the use of doxorubicin (in combination with gemcitabine) for the treatment of unresectable recurrent or metastatic renal carcinoma which has sarcomatoid features Haas 2012. Data from another small study also supports the use of doxorubicin (in combination with gemcitabine) for the treatment of advanced sarcomatoid renal cancer Dutcher 2009.

Salivary gland cancers (advanced)b

Data from 2 small studies support the use of doxorubicin (in combination with cisplatin and cyclophosphamide) in the palliative management of advanced salivary gland cancers Debaere 2011, Lictra 1996. Clinical experience also suggests the utility of doxorubicin (in combination with cisplatin and cyclophosphamide) for palliative management of advanced salivary gland cancers Laurie 2006.

Thymomas and thymic malignanciesb

Data from phase II trials supports the use of doxorubicin in combination with vincristine, cyclophosphamide, and cisplatin Fornasiero 1991 or in combination with cisplatin and cyclophosphamide Loehrer 1994 for the treatment of advanced thymomas.

Uterine sarcomaa

Data from a randomized phase III trial suggests that doxorubicin may be beneficial in the management of advanced uterine sarcoma Omura 1983. Additional data from a phase II trial also supports the use of doxorubicin (in combination with ifosfamide) for the treatment of advanced uterine sarcomas Sutton 1996.

Waldenström macroglobulinemiaa

Data from a randomized open-label phase III trial supports the use of doxorubicin (in combination with rituximab, cyclophosphamide, vincristine, and prednisone [R-CHOP]) for the management of Waldenström macroglobulinemia Buske 2009. Data from a small single institutional trial also supports the use of R-CHOP for treatment of this condition Treon 2005.

Contraindications

Hypersensitivity (including anaphylaxis) to doxorubicin, any component of the formulation, or to other anthracyclines or anthracenediones; recent MI (within past 4 to 6 weeks), severe myocardial insufficiency, severe arrhythmia; previous therapy with maximum cumulative doses of doxorubicin, daunorubicin, idarubicin, or other anthracycline and anthracenediones; severe persistent drug-induced myelosuppression or baseline neutrophil count <1,500/mm³; severe hepatic impairment (Child-Pugh class C or bilirubin >5 mg/dL).

Canadian labeling: Additional contraindications (not in US labeling): History of severe cardiac disease.

Dosage and Administration

Dosing: Adult

Doxorubicin is associated with a moderate to high emetic potential (depending on dose or regimen); antiemetics are recommended to prevent nausea and vomiting (Hesketh 2017; Roila 2016). Monitor cumulative dose (doxorubicin and other anthracyclines) received; the risk for cardiomyopathy increases as the cumulative dose increases and is also dependent on other/additional risk factors.

Acute lymphoblastic leukemia (off-label dosing): IV:

Hyper-CVAD regimen: 50 mg/m² on day 4 of Courses 1, 3, 5, and 7 (in combination with cyclophosphamide, vincristine, and dexamethasone); alternating cycles with high-dose methotrexate and cytarabine (Kantarjian 2004)

CALGB 8811 regimen: 30 mg/m² on days 1, 8 and 15 of late intensification (Course IV; 8-week cycle); in combination with vincristine, dexamethasone, cyclophosphamide, thioguanine, and cytarabine (Larson 1995)

Bladder cancer, transitional cell (off-label dosing): IV: Dose-dense MVAC regimen: 30 mg/m² on day 2 every 14 days (in combination with methotrexate, vinblastine, and cisplatin) (Sternberg 2001)

Breast cancer: IV:

AC regimen: 60 mg/m² on day 1 every 21 days for 4 cycles (in combination with cyclophosphamide) (Fisher 1990)

Dose dense AC (ddAC) followed by T regimen: 60 mg/m² on day 1 every 14 days for 4 cycles (in combination with cyclophosphamide [and filgrastim], then followed by paclitaxel) (Citron 2003)

CAF regimen (off-label dosing): 30 mg/m² on days 1 and 8 every 28 days for 6 cycles (in combination with cyclophosphamide and fluorouracil) (Bull 1978)

FAC regimen: 50 mg/m² on day 1 (or administered as a 72-hour continuous infusion) every 21 days for 6 cycles (in combination with fluorouracil and cyclophosphamide) (Assikis 2003)

TAC regimen: 50 mg/m² on day 1 every 21 days for 6 cycles (in combination with docetaxel and cyclophosphamide) (Martin 2005)

Endometrial carcinoma, advanced (off-label use): IV: 60 mg/m² on day 1 every 21 days for 8 cycles; maximum cumulative dose: 420 mg/m² (in combination with cisplatin) (Randall 2006)

Ewing sarcoma (off-label dosing): IV:

VDC/IE regimen: Adults ≤30 years: 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: Adults <35 years: 30 mg/m²/day on days 1 and 2 every 21 days (doxorubicin alternates with dactinomycin; in combination with vincristine and ifosfamide) for14 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)

Hepatocellular cancer, intermediate stage, chemoembolization (off-label use): Note: Refer to protocol and institutional policies for additional dosing/administration details. Intra-arterial:

Conventional transcatheter arterial chemoembolization (cTACE): 50 to 75 mg/m² (maximum: 150 mg) as a single dose via intra-arterial injection every 2 months for a maximum of 3 doses; dose may require adjustment based on bilirubin level (Lammer 2010)

Drug-eluting bead-transcatheter arterial chemoembolization (DEB-TACE): 150 mg administered via loaded drug-eluting bead every 2 months for a maximum of 3 doses (Lammer 2010); drug-eluting beads loaded with doses ranging from 25 to 150 mg have been shown to be safe and effective.

Hepatocellular cancer, metastatic (off-label use): IV: 60 mg/m² on day 1 every 28 days (in combination with cisplatin) for up to 6 cycles (Lee 2004) or 60 mg/m² on day 1 every 21 days (in combination with cisplatin and capecitabine) for up to 6 cycles (Park 2006).

Hodgkin lymphoma (off-label dosing): IV:

ABVD regimen: 25 mg/m² on days 1 and 15 every 28 days (in combination with bleomycin, vinblastine, and dacarbazine) for 2 to 4 cycles (Bonadonna 2004; Engert 2010)

A-AVD regimen: 25 mg/m² on days 1 and 15 every 4 weeks (in combination with brentuximab vedotin, vinblastine, and dacarbazine) for up to 6 cycles (Connors 2018). Administer primary prophylaxis with G-CSF (filgrastim) beginning with cycle 1.

BEACOPP and escalated BEACOPP regimens: 25 mg/m² (BEACOPP) or 35 mg/m² (escalated BEACOPP) on day 1 every 21 days (in combination with bleomycin, etoposide, cyclophosphamide, vincristine, procarbazine, and prednisone) (Engert 2009)

Stanford V regimen: 25 mg/m² on weeks 1, 3, 5, 7, 9, and 11 of a 12-week cycle (in combination with mechlorethamine, vinblastine, vincristine, bleomycin, etoposide, and prednisone) (Horning 2002)

Multiple myeloma (off-label use): IV:

PAD regimen: Induction: 9 mg/m²/day on days 1 to 4 for 3 cycles (in combination with bortezomib and dexamethasone) (Sonneveld 2012)

VDT-PACE regimen: 10 mg/m²/day administered as a continuous infusion on days 1 to 4 of each cycle (in combination with bortezomib, dexamethasone, thalidomide, cisplatin, cyclophosphamide, and etoposide) (Lee 2003; Pineda-Roman 2008)

Non-Hodgkin lymphoma (off-label dosing): IV:

CHOP or RCHOP regimen (diffuse large B cell lymphoma [DLBCL]): 50 mg/m² on day 1 every 21 days (in combination with cyclophosphamide, vincristine, and prednisone +/- rituximab) (Coiffier 2010; McKelvey 1976)

Hyper-CVAD + rituximab regimen (Burkitt lymphoma): 50 mg/m² administered as a continuous infusion over 24 hours on day 4 of Courses 1, 3, 5, and 7 (21-day treatment cycles; in combination with cyclophosphamide, vincristine, dexamethasone, and rituximab); alternating cycles with high-dose methotrexate and cytarabine (Thomas 2006)

Dose-adjusted EPOCH or REPOCH regimen (DLBCL): 10 mg/m²/day administered as a continuous infusion on days 1 to 4 every 21 days (in combination with etoposide, vincristine, cyclophosphamide, and prednisone +/- rituximab) (Garcia-Suarez 2007; Wilson 2002)

Nordic regimen (Maxi-CHOP) (mantle cell lymphoma): 75 mg/m² on day 1 every 21 days (in combination with cyclophosphamide, vincristine, prednisone, and rituximab), alternating cycles with high-dose cytarabine (Geisler 2008)

RCHOP/RDHAP (mantle cell lymphoma): 50 mg/m² on day 1 of a 21-day treatment cycle (in combination with rituximab, cyclophosphamide, vincristine, and prednisone), alternating or sequentially with RDHAP (rituximab, dexamethasone, cytarabine, and cisplatin) for a total of 6 cycles (3 cycles of each) followed by autologous stem cell transplant (Delarue 2013; Hermine 2016)

R-CODOX-M/IVAC (high-grade B cell and Burkitt lymphoma): Cycles 1 and 3 (CODOX-M): 50 mg/m² on day 1 (Barnes 2011; Lacasce 2004) or 40 mg/m² on day 1 (Mead 2002), in combination with cyclophosphamide, vincristine, methotrexate, and CNS prophylaxis; CODOX-M alternates with IVAC (ifosfamide, mesna, etoposide, cytarabine, and CNS prophylaxis) ± rituximab for a total of 4 cycles

Osteosarcoma (off-label dosing): IV:

Cisplatin/doxorubicin regimen: Adults ≤40 years: 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: Adults <40 years:

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)

MAP regimen: Adults ≤40 years:

Preoperative: 37.5 mg/m²/day administered as a continuous infusion (over 48 hours) days 1 and 2 of weeks 1 and 6 (in combination with cisplatin, high-dose methotrexate, and leucovorin rescue) (Bielack 2015; Marina 2016; Whelan 2015)

Postoperative: 37.5 mg/m²/day administered as a continuous infusion (over 48 hours) days 1 and 2 of weeks 12, 17, 22, and 26 (in combination with cisplatin, high-dose methotrexate, and leucovorin rescue); refer to protocol for criteria, frequency, and other specific information (Bielack 2015; Marina 2016; Whelan 2015)

Renal carcinoma (advanced; with sarcomatoid features) (off-label use): IV: 50 mg/m² on day 1 every 14 days (in combination with gemcitabine and growth factor support) for 6 to 9 cycles (Haas 2012)

Salivary gland cancers, advanced (off-label use): IV: 50 mg/m² on day 1 every 21 days (in combination with cisplatin and cyclophosphamide); continue until disease progression or unacceptable toxicity (Lictra 1996) or 50 mg/m² on day 1 every 21 days (in combination with cisplatin and cyclophosphamide) for 6 to 8 cycles or until disease progression or unacceptable toxicity (Debaere 2011).

Small cell lung cancer, recurrent (off-label dosing): IV: CAV regimen: 45 mg/m² (maximum dose: 100 mg) on day 1 every 21 days (in combination with cyclophosphamide and vincristine) until disease progression or unacceptable toxicity or for at least 4 or 6 cycles past maximum response (von Pawel 1999)

Soft tissue sarcoma: IV:

Nonspecific histologies:

AD regimen: 60 mg/m² on day 1 every 21 days (either as a bolus infusion or administered continuously over 96 hours; in combination with dacarbazine) (Zalupski 1991)

AIM regimen (off-label dosing): 30 mg/m² on days 1 and 2 every 21 days (in combination with ifosfamide and mesna) (Edmonson 1993)

MAID regimen (off-label dosing): 20 mg/m²/day as a continuous infusion on days 1 to 3 every 21 days (in combination with ifosfamide, mesna, and dacarbazine) (Elias 1989)

Single-agent regimen: 75 mg/m² on day 1 every 21 days until disease progression or unacceptable toxicity (Santoro 1995)

Rhabdomyosarcoma (off-label dosing):

VAC/IE regimen: Adults <21 years: 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)

VAI regimen (based on a limited number of patients): Adults: 25 mg/m²/day on days 1 to 3 every 21 days (in combination with vincristine and ifosfamide) (Ogilvie 2010)

Thymomas and thymic malignancies (off-label use): IV:

CAP regimen: 50 mg/m² on day 1 every 21 days for up to 8 cycles (in combination with cisplatin and cyclophosphamide) (Loehrer 1994)

ADOC regimen: 40 mg/m² on day 1 every 21 days (in combination with cisplatin, vincristine, and cyclophosphamide) (Fornasiero 1991)

Uterine sarcoma (off-label use): IV: 60 mg/m² on day 1 every 21 days; maximum cumulative dose: 480 mg/m² (Omura 1983) or 50 mg/m² (over 15 minutes) on day 1 every 21 days; maximum cumulative dose: 450 mg/m² (in combination with ifosfamide/mesna) (Sutton 1996)

Waldenstrom macroglobulinemia (off-label use): IV: R-CHOP regimen: 50 mg/m² on day 1 every 21 days for 4 to 8 cycles (in combination with cyclophosphamide, vincristine, prednisone, and rituximab) (Buske 2009)

Metastatic solid tumors, leukemia, or lymphoma: Manufacturer's labeling: Dosing in the prescribing information may not reflect current clinical practice. Note: Consider lower dosages in patients with inadequate marrow reserve (due to advanced age, prior treatment, or neoplastic marrow infiltration). IV:

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

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

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Note: Dose, frequency, number of doses, and start date may vary by protocol and treatment phase; refer to individual protocols. In pediatric patients, dosing may be based on either BSA (mg/m²) or weight (mg/kg); use extra precaution to verify dosing parameters during calculations.

Monitor cumulative anthracycline dose (combined); the risk for cardiomyopathy increases as the cumulative dose increases (>250 mg/m² in pediatric patients <18 years and 550 mg/m² in patients >18 years); also dependent on other/additional risk factors; interpatient variability exists (eg, some patients may experience left ventricular dysfunction at lower doses) (ESC [Zamorano 2016]; Long-Term Follow-Up Guidelines [COG 2018]).

Doxorubicin is associated with a moderate to high emetic potential (depending on dose or regimen); antiemetics are recommended to prevent nausea and vomiting (Dupuis 2013; Paw Cho Sing 2019).

Acute lymphoblastic leukemia (ALL): Limited data available: Children and Adolescents: IV:

DFCI Consortium Protocol 00-01 (Vrooman 2013):

Induction: 30 mg/m²/day on days 0 and 1 of a 4-week cycle (in combination with dexrazoxane [high-risk patients], vincristine, methotrexate, Escherichia coli asparaginase, prednisone, intrathecal cytarabine, and intrathecal methotrexate/cytarabine/hydrocortisone).

CNS therapy: High-risk patients: 30 mg/m²/day on day 1 of a 3-week cycle (in combination with dexrazoxane, vincristine, mercaptopurine, intrathecal methotrexate/cytarabine, and cranial radiation).

Intensification: High-risk patients: 30 mg/m²/day on day 1 of every 3-week cycle (in combination with dexrazoxane, vincristine, mercaptopurine, E. coli asparaginase, prednisone or dexamethasone, and intrathecal methotrexate/cytarabine/hydrocortisone); cumulative doxorubicin dose: 300 mg/m².

AALL0232 (High risk, newly diagnosed) (Larsen 2016): Delayed Intensification I: 25 mg/m²/day on days 1, 8, and 15 of an 8-week cycle (in combination with vincristine, pegaspargase, dexamethasone, cytarabine, cyclophosphamide, thioguanine, and intrathecal methotrexate).

Desmoplastic small round cell tumor (DSRCT): Limited data available: Children and Adolescents: IV: HD-CAV regimen: 25 mg/m²/day administered as a continuous infusion on days 1, 2, and 3 (total course dose: 75 mg/m²) (in combination with vincristine and cyclophosphamide for courses 1, 2, 4, and 6) alternating cycles with ifosfamide and etoposide for courses 4, 5, and 7 (Kushner 1996).

Ewing sarcoma: Limited data available: Children and Adolescents: IV:

VAC/IE regimen: 75 mg/m²/day 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).

Hepatoblastoma: Limited data available:

INT-0098 protocol (Ortega 2000): Children and Adolescents: IV:

Regimen B (Stage I-Unfavorable Histology, II, III, IV): 20 mg/m²/day administered as a continuous infusion for 4 days (total dose per course: 80 mg/m²) (in combination with cisplatin).

Regimen C (Stage I-Favorable Histology): 20 mg/m²/day on days 1, 2, and 3 every 3 weeks for 4 cycles.

PLADO regimen: Children and Adolescents: IV: 30 mg/m²/day administered as a continuous infusion on days 2 and 3 (total dose per course: 60 mg/m²) every 21 days for up to 6 courses (in combination with cisplatin) administered preoperatively (Czauderna 2002).

Siopel-3HR regimen: High risk: Infants, Children, and Adolescents <16 years: IV: 30 mg/m²/day administered as a continuous infusion over 48 hours (total dose per course: 60 mg/m² in combination with carboplatin and alternating with cisplatin) beginning on day 15 every 28 days (days 15, 43, and 71) for up to 3 preoperative cycles of doxorubicin/carboplatin. If the tumor is not resectable after 3 preoperative cycles another 2 cycles of doxorubicin/carboplatin may be given. Regardless of when surgery takes place a maximum of 5 cycles of each doxorubicin/carboplatin and cisplatin were administered (Zsíros 2010).

Hodgkin lymphoma: Limited data available: Children and Adolescents: IV:

Low risk, lymphocyte-predominant Hodgkin lymphoma: AV-PC regimen: 50 mg/m²/day on day 1 of a 21-day cycle (in combination with vincristine, prednisone, cyclophosphamide) (Appel 2016).

Low risk, classical Hodgkin lymphoma: AVPC regimen: 25 mg/m²/day on days 1 and 2 of a 21-day cycle (in combination with vincristine, prednisone, cyclophosphamide) (Keller 2018).

Intermediate or high risk: ABVE-PC regimen: 30 mg/m²/day on days 0 and 1 of a 21-day cycle (in combination with bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide) (Schwartz 2009).

Advanced stage or high risk:

AVBD regimen: 25 mg/m²/day on days 0 and 14 of a 28-day cycle (in combination with bleomycin, vinblastine, and dacarbazine) (Kelly 2011).

BEACOPP regimen: 35 mg/m²/day administered on day 0 of a 21-day treatment cycle (in combination with bleomycin, etoposide, cyclophosphamide, vincristine, procarbazine, and prednisone) (Kelly 2011).

Neuroblastoma: Limited data available:

High risk (Stage IV disease):

CAV-P/VP regimen: Infants and Children: IV:

≤12 kg: 0.83 mg/kg/day as a continuous infusion on days 1, 2, and 3 (total dose: 2.49 mg/kg) of courses 1, 2, 4, and 6 (in combination with cyclophosphamide, and vincristine [CAV] with etoposide and cisplatin [P/VP] during courses 3, 5, and 7) (Park 2016).

>12 kg: 25 mg/m²/day as a continuous infusion on days 1, 2, and 3 (total dose: 75 mg/m²) of courses 1, 2, 4, and 6 (in combination with cyclophosphamide, and vincristine [CAV] with etoposide and cisplatin [P/VP] during courses 3, 5, and 7) (Kreissman 2013; Kushner 1994; Park 2016).

Cisplatin-Doxorubicin-Etoposide-Cyclophosphamide regimen: Infants, Children, and Adolescents: IV:

<10 kg: 1 mg/kg/day on day 2 of a 28-day cycle (in combination with cisplatin, etoposide, and cyclophosphamide) for a total of 5 cycles (Parikh 2015).

≥10 kg: 30 mg/m²/day on day 2 of a 28-day cycle (in combination with cisplatin, etoposide, and cyclophosphamide) for a total of 5 cycles (Matthay 1999; Parikh 2015).

Unresectable disease: CE-CAdO regimen:

Infants: IV: 2 mg/kg/day on day 5 of cycles 3 and 4 (CAdO; 21-day cycles) (in combination with cyclophosphamide, vincristine [CAdO], and carboplatin and etoposide [CE]) (Rubie 2001).

Children: IV: 60 mg/m²/day on day 5 of cycles 3 and 4 (CAdO; 21-day cycles) (in combination with cyclophosphamide, vincristine [CAdO], and carboplatin and etoposide [CE]) (Rubie 1998).

Non-Hodgkin lymphoma: Limited data available: Children and Adolescents: IV:

Anaplastic large cell lymphoma (ALCL):

NHL-BFM 90 Regimen, Course B and BB: 25 mg/m²/day infused over 1 hour on days 4 and 5 of a 21- to 28-day cycle (depending on neutrophil recovery) (in combination with dexamethasone, cyclophosphamide, methotrexate, and intrathecal prophylaxis therapy) (Seidemann 2001).

ALCL-99 Regimen, Course BM and BV: 25 mg/m²/day on days 4 and 5 of a 21-day cycle (in combination with cyclophosphamide, methotrexate, vinblastine, and intrathecal prophylaxis therapy) (Wrobel 2011).

Mature B-cell Lymphomas (Burkitt lymphoma, Burkitt-like lymphoma, etc):

High risk (Group C):

COPADM 1 and 2 regimen: Induction: 60 mg/m²/day on day 2 of a 16- to 21-day cycle (depending on neutrophil recovery) (in combination with cyclophosphamide, vincristine, prednisone, methotrexate, and intrathecal chemotherapy [refer to protocol and institution guidelines]) (Cairo 2007; Goldman 2014).

COPA regimen: Maintenance 1 (M1) and 3 (M3): 60 mg/m²/day over 30 to 60 minutes on Day 2 (M1) or Day 1 (M3) (in combination with cyclophosphamide, vincristine, prednisone, with/without methotrexate) (Cairo 2007; Goldman 2014).

Intermediate risk (Group B): COPADM 1 and 2: Induction: 60 mg/m²/day over ≤1 hour on day 1 (in combination with cyclophosphamide, vincristine, prednisone, methotrexate with/without rituximab) (Goldman 2013).

Primary mediastinal large B-cell lymphoma (PMBCL): Very limited data available: Children ≥9 years and Adolescents: DA-EPOCH-R regimen: IV: 10 mg/m²/day as a continuous infusion on days 1 to 4 (96 hours) (total dose: 40 mg/m² per course); dose-adjusted for subsequent cycles based on neutrophil and platelet counts during nadir (in combination with etoposide, vincristine, cyclophosphamide, prednisone, and rituximab) (Dunleavy 2013; Giulino-Roth 2017; Wilson 2013).

Osteosarcoma: Limited data available: Children and Adolescents: IV: High-dose methotrexate/cisplatin/doxorubicin (MAP) regimen:

Preoperative: 37.5 mg/m²/day on days 1 and 2 of week 1 and 6 (in combination with cisplatin and alternating with cycles of methotrexate) (Marina 2016).

Postoperative: 37.5 mg/m²/day on days 1 and 2 of weeks 12, 17, 22, and 26 (weeks 12 and 17 are in combination with cisplatin and alternating with methotrexate); refer to protocol for criteria, frequency, and other specific information (Marina 2016).

Rhabdomyosarcoma: Limited data available: Children and Adolescents: IV: VAC/IE regimen: 37.5 mg/m²/day 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).

Wilms tumor:

DD-4A regimen: Note: Begin regimen when ANC ≥750 mm³ and platelet count ≥75,000 mm³.

Infants: IV: 1.5 mg/kg/day on day 1 of weeks 4 and 10 and then 1 mg/kg/day on day 1 of week 16 and 22 (in combination with dactinomycin and vincristine). Reduce dose by 50% (ie, 0.75 mg/kg/day) for the first dose given within 6 weeks following whole lung or whole abdominal radiation (but not after flank radiation) unless administered concurrently with the start of radiation therapy (Ehrlich 2017).

Children and Adolescents: IV: 45 mg/m²/day on day 1 of weeks 4 and 10 and then 30 mg/m²/day on day 1 of weeks 16 and 22 (in combination with dactinomycin and vincristine). Reduce dose by 50% (ie, 22.5 mg/m²/day) for the first dose given within 6 weeks following whole lung or whole abdominal radiation (but not after flank radiation) unless administered concurrently with the start of radiation therapy (Ehrlich 2017).

NWTS-5 Regimen I (unresectable tumors or stage II to IV tumors with blastemal predominance at time of definitive surgical procedure at either week 6 or 12 or relapsed disease):

Infants: IV: 1.5 mg/kg/day administered as an IV push on day 1 of weeks 7, 13, 19, and 25 (in combination with vincristine, cyclophosphamide, mesna, etoposide, and filgrastim); reduce dose by 50% (ie, 0.75 mg/kg) at week 6 if patient undergoes radiation; omit week 25 if patient received 6 or 12 weeks of preoperative therapy with Regimen VAD (Ehrlich 2017).

Children and Adolescents: IV: 45 mg/m²/day administered as IV push on day 1 of weeks 7, 13, 19, and 25 (in combination with vincristine, cyclophosphamide, mesna, etoposide, and filgrastim); reduce dose by 50% (ie, 22.5 mg/m²) at week 6 if patient undergoes radiation; omit week 25 if patient received 6 or 12 weeks of preoperative therapy with Regimen VAD (Ehrlich 2017).

Revised UH-1 Regimen:

Infants: IV: 1.5 mg/kg/day administered as an IV push on day 1 of weeks 1, 10, 13, 22, and 28 (in combination with vincristine, cyclophosphamide, mesna, carboplatin, and filgrastim); reduce dose by 50% (0.75 mg/kg) if administered during or within 6 weeks of completing radiation; omit week 28 if patient received 6 weeks of Regimen VAD; omit weeks 13, 22, and 28 if patient received 12 weeks of Regimen VAD (Ehrlich 2017).

Children and Adolescents: IV: 45 mg/m²/day administered as IV push on day 1 of weeks 1, 10, 13, 22, and 28 (in combination with vincristine, cyclophosphamide, mesna, carboplatin, and filgrastim); reduce dose by 50% (22.5 mg/m²) if administered during or within 6 weeks of completing radiation; omit week 28 if patient received 6 weeks of Regimen VAD; omit weeks 13, 22, and 28 if patient received 12 weeks of Regimen VAD (Ehrlich 2017).

VAD regimen:

Infants: IV: 1.2 mg/kg/day on day 1 of weeks 1, 4, 7, and 10 (in combination with vincristine and dactinomycin) (Ehrlich 2017).

Children and Adolescents: IV: 35 mg/m²/day on day 1 of weeks 1, 4, 7, 10 (in combination with vincristine and dactinomycin) (Ehrlich 2017).

Dosing: Adjustment for Toxicity

Cardiotoxicity: Discontinue in patients who develop signs/symptoms of cardiomyopathy.

Metastatic disease, leukemia, or lymphoma: Consider lower dosages in patients with inadequate marrow reserve (due to advanced age, prior treatment, or neoplastic marrow infiltration).

Dosing: Obesity

ASCO Guidelines for appropriate chemotherapy dosing in obese adults with cancer (excludes leukemias): 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).

Reconstitution

Reconstitute lyophilized powder with NS (using 5 mL for the 10 mg vial; 10 mL for the 20 mg vial; or 25 mL for the 50 mg vial) to a final concentration of 2 mg/mL; gently shake until contents are dissolved. May further dilute doxorubicin solution or reconstituted doxorubicin solution in 50 to 1000 mL D₅W or NS for infusion. Unstable in solutions with a pH <3 or >7.

Administration

Doxorubicin is associated with a moderate to high emetic potential (depending on dose or regimen); antiemetics are recommended to prevent nausea and vomiting (Hesketh 2017; Roila 2016).

IV: Administer IV push over at least 3 to 10 minutes or by continuous infusion (infusion via central venous line recommended). Do not administer IM or SubQ. Rate of administration varies by protocol, refer to individual protocol for details. Protect from light until completion of infusion. Avoid contact with alkaline solutions. Monitor for local erythematous streaking along vein and/or facial flushing (may indicate rapid infusion rate); decrease the rate if occurs.

Vesicant; ensure proper needle or catheter placement prior to and during infusion; avoid extravasation.

Extravasation management: If extravasation occurs, stop infusion immediately and disconnect (leave cannula/needle in place); gently aspirate extravasated solution (do NOT flush the line); remove needle/cannula; elevate extremity. Initiate antidote (dexrazoxane or dimethyl sulfate [DMSO]). Apply dry cold compresses for 20 minutes 4 times daily for 1 to 2 days (Perez Fidalgo 2012); withhold cooling beginning 15 minutes before dexrazoxane infusion; continue withholding cooling until 15 minutes after infusion is completed. Topical DMSO should not be administered in combination with dexrazoxane; may lessen dexrazoxane efficacy.

Dexrazoxane: 1000 mg/m² (maximum dose: 2000 mg) IV (administer in a large vein remote from site of extravasation) over 1 to 2 hours days 1 and 2, then 500 mg/m² (maximum dose: 1000 mg) IV over 1 to 2 hours day 3; begin within 6 hours of extravasation. Day 2 and day 3 doses should be administered at approximately the same time (± 3 hours) as the dose on day 1 (Mouridsen 2007; Perez Fidalgo 2012). Note: Reduce dexrazoxane dose by 50% in patients with moderate to severe renal impairment (CrCl <40 mL/minute).

DMSO: Apply topically to a region covering twice the affected area every 8 hours for 7 days; begin within 10 minutes of extravasation; do not cover with a dressing (Perez Fidalgo 2012).

Transcatheter arterial chemoembolization (TACE): For conventional TACE, doxorubicin was administered with lipiodol followed by particle embolization with an embolic agent (Lammer 2010). IV antibiotics were administered prior to the procedure and embolic material was injected through the catheter until hemostasis was achieved (Morse 2012). For drug-eluting bead TACE, patients received a 4 mL bead loaded with doxorubicin mixed with non-ionic contrast media (Lammer 2010). Refer to protocol and institutional policies for additional administration details.

Storage

Lyophilized powder: Store powder at 20°C to 25°C (68°F to 77°F). Protect from light. Retain in carton until time of use. Discard unused portion from single-dose vials. Reconstituted doxorubicin is stable for 7 days at room temperature under normal room lighting and for 15 days when refrigerated at 2°C to 8°C (36°F to 46°F). Follow USP 797 recommendations for beyond use dates based on the level of risk for preparation. Protect reconstituted solution from light.

Solution: Store refrigerated at 2°C to 8°C (36°F to 46°F). Protect from light. Retain in carton until time of use. Discard unused portion. Storage of vials of solution under refrigeration may result in formation of a gelled product; if gelling occurs, place vials at room temperature for 2 to 4 hours to return the product to a slightly viscous, mobile solution.

Drug Interactions

Abiraterone Acetate: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Management: Avoid concurrent use of abiraterone with CYP2D6 substrates that have a narrow therapeutic index whenever possible. When concurrent use is not avoidable, monitor patients closely for signs/symptoms of toxicity. Consider therapy modification

Ado-Trastuzumab Emtansine: May enhance the cardiotoxic effect of Anthracyclines. Management: When possible, patients treated with ado-trastuzumab emtansine should avoid anthracycline-based therapy for up to 7 months after stopping ado-trastuzumab emtansine. Monitor closely for cardiac dysfunction in patients receiving this combination. Consider therapy modification

Ajmaline: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Monitor therapy

Asunaprevir: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Consider therapy modification

Baricitinib: Immunosuppressants may enhance the immunosuppressive effect of Baricitinib. Management: Use of baricitinib in combination with potent immunosuppressants such as azathioprine or cyclosporine is not recommended. Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted. Consider therapy modification

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Bevacizumab: May enhance the cardiotoxic effect of Anthracyclines. Avoid combination

Bosentan: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Cardiac Glycosides: May diminish the cardiotoxic effect of Anthracyclines. Anthracyclines may decrease the serum concentration of Cardiac Glycosides. The effects of liposomal formulations may be unique from those of the free drug, as liposomal formulation have unique drug disposition and toxicity profiles, and liposomes themselves may alter digoxin absorption/distribution. Monitor therapy

Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Monitor therapy

Cladribine: May enhance the immunosuppressive effect of Immunosuppressants. Avoid combination

Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Avoid combination

CloBAZam: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Monitor therapy

Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Cyclophosphamide: May enhance the cardiotoxic effect of Anthracyclines. Monitor therapy

CycloSPORINE (Systemic): May increase the serum concentration of DOXOrubicin (Conventional). Management: Consider a doxorubicin dose reduction, as clinically appropriate, when used with cyclosporine. Use this combination with caution; increase monitoring for toxic effects of doxorubicin. Consider therapy modification

CYP2D6 Inhibitors (Moderate): May increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to moderate CYP2D6 inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. Consider therapy modification

CYP2D6 Inhibitors (Strong): May increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to strong CYP2D6 inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. Consider therapy modification

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to strong CYP3A4 inducers in patients treated with doxorubicin. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. Consider therapy modification

CYP3A4 Inhibitors (Moderate): May increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to moderate CYP3A4 inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. Exceptions: Grapefruit Juice. Consider therapy modification

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to strong CYP3A4 inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dacomitinib: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Management: Avoid concurrent use of dacomitinib with CYP2D6 subtrates that have a narrow therapeutic index. Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Consider therapy modification

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Dexrazoxane: May diminish the therapeutic effect of DOXOrubicin (Conventional). Management: Do not administer dexrazoxane for cardioprotection at the time of doxorubicin initiation. This recommendation does not apply to the use of dexrazoxane for other indications (e.g., extravasation), or to the use of dexrazoxane later in treatment. Consider therapy modification

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Erdafitinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Erdafitinib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

Fam-Trastuzumab Deruxtecan: May enhance the cardiotoxic effect of Anthracyclines. Management: When possible, patients treated with fam-trastuzumab deruxtecan should avoid anthracycline-based therapy for up to 7 months after stopping fam-trastuzumab deruxtecan. Monitor closely for cardiac dysfunction in patients receiving this combination. Consider therapy modification

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Idelalisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Larotrectinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Lasmiditan: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Avoid combination

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Lenograstim: Antineoplastic Agents may diminish the therapeutic effect of Lenograstim. Management: Avoid the use of lenograstim 24 hours before until 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Consider therapy modification

Lipegfilgrastim: Antineoplastic Agents may diminish the therapeutic effect of Lipegfilgrastim. Management: Avoid concomitant use of lipegfilgrastim and myelosuppressive cytotoxic chemotherapy. Lipegfilgrastim should be administered at least 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Consider therapy modification

Lorlatinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Avoid concurrent use of lorlatinib with any CYP3A4 substrates for which a minimal decrease in serum concentrations of the CYP3A4 substrate could lead to therapeutic failure and serious clinical consequences. Consider therapy modification

Lumefantrine: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Monitor therapy

Mercaptopurine: DOXOrubicin (Conventional) may enhance the hepatotoxic effect of Mercaptopurine. Monitor therapy

Mesalamine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

MiFEPRIStone: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Consider therapy modification

Mitotane: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy

Palbociclib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Palifermin: May enhance the adverse/toxic effect of Antineoplastic Agents. Specifically, the duration and severity of oral mucositis may be increased. Management: Do not administer palifermin within 24 hours before, during infusion of, or within 24 hours after administration of myelotoxic chemotherapy. Consider therapy modification

Panobinostat: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Monitor therapy

Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Peginterferon Alfa-2b may increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Monitor therapy

P-glycoprotein/ABCB1 Inducers: May decrease the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to P-glycoprotein inducers in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. Consider therapy modification

P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to P-glycoprotein inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. Consider therapy modification

Pidotimod: Immunosuppressants may diminish the therapeutic effect of Pidotimod. Monitor therapy

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Siponimod: Immunosuppressants may enhance the immunosuppressive effect of Siponimod. Monitor therapy

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Management: Evaluate patients to see if it is medically appropriate to reduce or discontinue therapy with immunosuppressants prior to initiating sipuleucel-T therapy. Consider therapy modification

Smallpox and Monkeypox Vaccine (Live): Immunosuppressants may diminish the therapeutic effect of Smallpox and Monkeypox Vaccine (Live). Monitor therapy

SORAfenib: May increase the serum concentration of DOXOrubicin (Conventional). Monitor therapy

St John's Wort: May decrease the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to St. Johns Wort in patients treated with doxorubicin. One US manufacturer (Pfizer) recommends that this combination be avoided. Consider therapy modification

Stavudine: DOXOrubicin (Conventional) may diminish the therapeutic effect of Stavudine. Monitor therapy

Stiripentol: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Taxane Derivatives: May decrease the metabolism of DOXOrubicin (Conventional). Management: Consider using docetaxel instead of paclitaxel as a way to avoid this potential interaction, and monitor closely for toxic effects of doxorubicin. Administer doxorubicin prior to paclitaxel when used concomitantly. Exceptions: DOCEtaxel. Consider therapy modification

Taxane Derivatives: May enhance the adverse/toxic effect of Anthracyclines. Taxane Derivatives may increase the serum concentration of Anthracyclines. Taxane Derivatives may also increase the formation of toxic anthracycline metabolites in heart tissue. Consider therapy modification

Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Consider therapy modification

Trastuzumab: May enhance the cardiotoxic effect of Anthracyclines. Management: When possible, patients treated with trastuzumab should avoid anthracycline-based therapy for up to 7 months after stopping trastuzumab. Monitor closely for cardiac dysfunction in patients receiving anthracyclines with trastuzumab. Consider therapy modification

Upadacitinib: Immunosuppressants may enhance the immunosuppressive effect of Upadacitinib. Avoid combination

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Exceptions: Smallpox and Monkeypox Vaccine (Live). Avoid combination

Vinflunine: DOXOrubicin (Conventional) may enhance the adverse/toxic effect of Vinflunine. Specifically, the risk for hematologic toxicities may be increased. Monitor therapy

Zidovudine: DOXOrubicin (Conventional) may enhance the adverse/toxic effect of Zidovudine. DOXOrubicin (Conventional) may diminish the therapeutic effect of Zidovudine. Consider therapy modification

Adverse Reactions

Frequency not always defined.

Cardiovascular:

Acute cardiotoxicity: Atrioventricular block, bradycardia, bundle branch block, ECG abnormality, extrasystoles (atrial or ventricular), nonspecific ST or T wave changes on ECG, sinus tachycardia, supraventricular tachycardia, tachyarrhythmia, ventricular tachycardia

Delayed cardiotoxicity: Cardiac failure (manifestations include ascites, cardiomegaly, dyspnea, edema, gallop rhythm, hepatomegaly, oliguria, pleural effusion, pulmonary edema, tachycardia), decreased left ventricular ejection fraction, myocarditis, pericarditis

Central nervous system: Malaise

Dermatologic: Alopecia, discoloration of sweat, pruritus, skin photosensitivity, skin rash; urticaria

Endocrine & metabolic: Amenorrhea, dehydration, hyperuricemia

Gastrointestinal: Abdominal pain, anorexia, diarrhea, discoloration of saliva, gastrointestinal ulcer, mucositis, nausea, vomiting

Genitourinary: Urine discoloration, infertility (may be temporary)

Hematologic & oncologic: Leukopenia (≤75%; nadir: 10 to 14 days; recovery: by day 21), neutropenia (≤75%; nadir: 10 to 14 days; recovery: by day 21), anemia, thrombocytopenia

Local: Post-injection flare

Neuromuscular & skeletal: Weakness

Ophthalmic: Discoloration of tears

Miscellaneous: Necrosis (colon), radiation recall phenomenon

<1%, postmarketing, and/or case reports: Acute myelocytic leukemia (secondary), anaphylaxis, azoospermia, chills, coma (when in combination with cisplatin or vincristine), conjunctivitis, dysgeusia (Rehwaldt 2009), febrile neutropenia, fever, gonadal disease (gonadal impairment; children), growth suppression (prepubertal), hepatitis, hyperpigmentation (nail, oral mucosa, skin), hypersensitivity reaction (systemic; including angioedema, dysphagia, and dyspnea, pruritus, urticaria), increased serum bilirubin, increased serum transaminases, infection, keratitis, lacrimation, myelodysplastic syndrome, oligospermia, onycholysis, peripheral neurotoxicity (with intra-arterial doxorubicin), phlebosclerosis, pneumonitis (radiation recall; children), seizure (when in combination with cisplatin or vincristine), sepsis, shock, Stevens-Johnson syndrome, toxic epidermal necrolysis, typhlitis (neutropenic)

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: [US Boxed Warning]: Severe myelosuppression resulting in serious infection, septic shock, transfusion requirements, hospitalization, and death may occur. 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 by day 21. Monitor blood counts at baseline and regularly during therapy.
• Cardiomyopathy: [US Boxed Warning]: Myocardial damage can occur with doxorubicin with incidences from 1% to 20% for cumulative doses from 300 mg/m² to 500 mg/m² when doxorubicin is administered every 3 weeks. The risk of cardiomyopathy is further increased with concomitant cardiotoxic therapy. Assess left ventricular ejection fraction (LVEF) before and regularly during and after doxorubicin treatment. Assess LVEF by MUGA or echocardiogram; use the same assessment method at all time points; increase the frequency of assessments as the cumulative dose exceeds 300 mg/m². Discontinue doxorubicin in patients who develop signs/symptoms of cardiomyopathy during treatment. Delayed cardiotoxicity may occur late in treatment or within months to years after completion of therapy, and is typically manifested by decreased LVEF and/or signs/symptoms of heart failure. The total cumulative doxorubicin dose should take into account prior treatment with other anthracyclines or anthracenediones. The risk for developing 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. The risk of cardiomyopathy is increased in patients who have received radiotherapy to the mediastinum or concomitant therapy with other known cardiotoxic agents such as cyclophosphamide and trastuzumab. Pericarditis and myocarditis have also been reported during or following doxorubicin treatment. Doxorubicin can result in arrhythmias, including life-threatening arrhythmias, during or within a few hours after administration and at any time point during treatment. Tachyarrhythmias (including sinus tachycardia, premature ventricular contractions, and ventricular tachycardia), and bradycardia may occur; ECG changes including non-specific ST-T wave changes, atrioventricular and bundle-branch block may also occur; ECG changes may be transient and self-limiting and may not require doxorubicin dose modifications.

ASCO has developed guidelines for prevention and monitoring of cardiac dysfunction in adult survivors of cancer (ASCO [Armenian 2017]). According to the guidelines, the risk of cardiac dysfunction is increased with the following:

• High-dose anthracycline therapy (eg, doxorubicin ≥250 mg/m², epirubicin ≥600 mg/m²)
• High-dose radiotherapy (≥30 Gy) with the heart in the treatment field
• Lower-dose anthracycline (eg, doxorubicin <250 mg/m², epirubicin <600 mg/m²) in combination with lower-dose radiotherapy (<30 Gy) with the heart in the treatment field
• Lower-dose anthracycline (eg, doxorubicin <250 mg/m², epirubicin <600 mg/m²) or trastuzumab alone AND any of the following risk factors: Multiple cardiovascular risk factors (≥2 risk factors), including smoking, hypertension, diabetes, dyslipidemia, and obesity (during or after completion of therapy), or older age (≥60 years) at cancer treatment, or compromised cardiac function (eg, borderline low LVEF [50% to 55%], history of MI, moderate or higher valvular heart disease) before or during treatment.
• Treatment with lower-dose anthracycline (eg, doxorubicin <250 mg/m², epirubicin <600 mg/m²) followed by trastuzumab (sequential therapy)
• Other risk factors for anthracycline-induced cardiotoxicity include age 60 and older at time of treatment and 2 or more cardiovascular risk factors (smoking, hypertension, diabetes, dyslipidemia, or obesity) during or after treatment.

The ASCO guidelines recommend a comprehensive assessment in patients with cancer (prior to treatment) that includes a history and physical examination, screening for cardiovascular disease risk factors such as hypertension, diabetes, dyslipidemia, obesity, and smoking. An echocardiogram should be obtained prior to initiating potentially cardiotoxic therapies. Modifiable risk factors (smoking, hypertension, diabetes, dyslipidemia, obesity) should be actively managed before initiating potentially cardiotoxic therapies. Consider cardioprotectants (eg, dexrazoxane), continuous infusions or liposomal formulations (if appropriate) in patients who are likely to receive high-dose anthracycline therapy. In patients who develop signs/symptoms of cardiac dysfunction during therapy, an echocardiogram is recommended for diagnostic workup; if echocardiogram is not available or feasible, a cardiac MRI (preferred) or MUGA scan may be utilized. Serum cardiac biomarkers are recommended, along with referral to a cardiologist if indicated.

• Extravasation: [US Boxed Warning]: Vesicant; extravasation may result in severe local tissue injury and necrosis requiring wide excision of the affected area and skin grafting. Immediately terminate infusion and apply ice to the affected area. For IV administration only; do not administer by intramuscular (IM) or subcutaneous routes. 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.
• GI toxicity: Doxorubicin is associated with a moderate or high emetic potential (depending on dose or regimen); antiemetics may be recommended to prevent nausea and vomiting (Hesketh 2017; Paw Cho Sing 2019; Roila 2016).
• Secondary malignancy: [US Boxed Warnings]: Secondary acute myelogenous leukemia (AML) and myelodysplastic syndromes (MDS) occur at a higher incidence in patients treated with anthracyclines, including doxorubicin. AML and MDS typically occur within 1 to 3 years of treatment.
• 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, uric acid, and hydration status.

Disease-related concerns:

• Hepatic impairment: Dose reduction is recommended in patients with bilirubin levels of 1.2 to 5 mg/dL; 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 (ALT, AST, alkaline phosphatase, and bilirubin) at baseline and during treatment.

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. A panel from the American Society of Pediatric Hematology/Oncology (ASPHO) and International Society of Pediatric Oncology (SIOP) recommends in favor of an anthracycline infusion duration of at least 1 hour in pediatric patients to reduce the potential for cardiotoxicity (ASPHO/SIOP [Loeffen 2017]). However, extravasation risks should also be minimized and the protocol infusion duration specified in a protocol should be followed, particularly if the patient is receiving dexrazoxane as a cardioprotectant. 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:

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

Monitoring Parameters

CBC with differential and platelet count; liver function tests (bilirubin, ALT/AST, alkaline phosphatase); serum uric acid, calcium, potassium, phosphate and creatinine; hydration status; cardiac function (baseline, periodic, and followup): ECG, left ventricular ejection fraction (echocardiography [ECHO] or multigated radionuclide angiography [MUGA]); monitor infusion site.

Cardiovascular monitoring (ASCO [Armenian 2017]): Comprehensive assessment prior to treatment including a history and physical examination, screening for cardiovascular disease risk factors such as hypertension, diabetes, dyslipidemia, obesity, and smoking. Echocardiogram (prior to treatment). In patients who develop signs/symptoms of cardiac dysfunction during therapy, an echocardiogram is recommended for diagnostic workup; if echocardiogram is not available or feasible, a cardiac MRI (preferred) or MUGA scan may be utilized; obtain serum cardiac biomarkers.

Pregnancy

Pregnancy Risk Factor

D

Pregnancy Considerations

Based on information from animal reproduction studies, doxorubicin may cause fetal harm if administered during pregnancy. Limited information is available from a retrospective study of women who received doxorubicin (in combination with cyclophosphamide) during the second or third (prior to week 35) trimester for the treatment of pregnancy-associated breast cancer (Ring 2005). Some pharmacokinetic properties of doxorubicin may be altered in pregnant women (van Hasselt 2014). The European Society for Medical Oncology (ESMO) has published guidelines for diagnosis, treatment, and follow-up of cancer during pregnancy (Peccatori 2013); the guidelines recommend referral to a facility with expertise in cancer during pregnancy and encourage a multidisciplinary team (obstetrician, neonatologist, oncology team). If chemotherapy is indicated, it should not be administered in the first trimester, but may begin in the second trimester. There should be a 3-week time period between the last chemotherapy dose and anticipated delivery, and chemotherapy should not be administered beyond week 33 of gestation.

Advise females of reproductive potential and males with female partners of reproductive potential to use effective nonhormonal contraception during and for 6 months following therapy.

Doxorubicin may impair fertility in men and women. 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.

A pregnancy registry is available for all cancers diagnosed during pregnancy at Cooper Health (877-635-4499).

Patient Education

What is this drug used for?

• It is used to treat cancer.

Frequently reported side effects of this drug

• Hair loss
• Nausea
• Vomiting
• Diarrhea
• Mouth irritation
• Mouth sores
• Nail changes
• Urine discoloration

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Infection
• Heart problems like cough or shortness of breath that is new or worse, swelling of the ankles or legs, abnormal heartbeat, weight gain of more than five pounds in 24 hours, dizziness, or passing out.
• Bleeding like vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding.
• Severe injection site redness, pain, swelling, or skin irritation
• Severe loss of strength or energy
• Tumor lysis syndrome like fast heartbeat or abnormal heartbeat; any passing out; not able to pass urine; muscle weakness or cramps; nausea, vomiting, diarrhea or lack of appetite; or feeling sluggish.
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.