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  • CLASSES

    Anthracyclines

    BOXED WARNING

    Cardiomyopathy, cardiotoxicity, heart failure, maximum cumulative lifetime dose, myocardial infarction, myocarditis, pericarditis

    Cardiotoxicity (e.g., cardiomyopathy, pericarditis, myocarditis, and left ventricular heart failure) has been reported with doxorubicin therapy. Doxorubicin use is contraindicated in patients with severe myocardial insufficiency or recent (occurring within the past 4 to 6 weeks) myocardial infarction. Assess left ventricular function (e.g., MUGA or echocardiogram) before starting doxorubicin therapy and then regularly during and after therapy; use the same method of assessment at all time points. If the cumulative doxorubicin dose exceeds 300 mg/m2 in a patient that will continue to receive therapy, increase the frequency of cardiac assessment and consider starting dexrazoxane to reduce the incidence and severity of cardiomyopathy. Increased cumulative anthracycline (or anthracenediones) doses, concomitant cardiotoxicity medication (e.g., cyclophosphamide, trastuzumab), and prior mediastinum radiotherapy increase the risk of cardiotoxicity. The incidence of cardiotoxicity is highest in patients who exceed the maximum cumulative lifetime dose of 550 mg/m2. Cardiomyopathy may develop during treatment or up to several years after the completion of treatment. The estimated risk of developing cardiomyopathy (when doxorubicin is given every 3 weeks) is 1% to 2% at a cumulative dose of 300 mg/m2, 3% to 5% at a cumulative dose of 400 mg/m2, and 6% to 20% at a cumulative dose of 500 mg/m2.

    Bone marrow suppression, infection, leukopenia, neutropenia, thrombocytopenia

    Severe myelosuppression/bone marrow suppression (leukopenia, neutropenia, thrombocytopenia) has been reported with doxorubicin therapy; serious infection, septic shock, blood or platelet transfusions, hospitalization, and death may occur due to severe myelosuppression. Doxorubicin use is contraindicated in patients with severe persistent drug-induced myelosuppression. Monitor complete blood counts (CBC) prior to starting doxorubicin; monitor CBC and for signs of clinical complications (e.g., infection, bleeding) during therapy. A reversible, dose-dependent neutropenia is the most common doxorubicin-induced hematologic toxicity. When doxorubicin is given every 3 weeks, the neutrophil count nadir is typically reached 10 to 14 days following the dose.

    Extravasation, tissue necrosis

    Extravasation and severe local tissue necrosis have been reported with doxorubicin therapy; wide excision of the affected area and skin grafting may be necessary if severe tissue injury occurs. Immediately stop the injection or infusion of doxorubicin if signs or symptoms of extravasation occur. If extravasation occurs or is suspected, apply ice at the site for 15 minutes 4 times daily for 3 days; administer dexrazoxane at the site as soon as possible and within the first 6 hours following extravasation. Extravasation may occur in the absence of typical symptoms (e.g., stinging or burning sensation) or when patients have adequate blood return on aspiration of the infusion needle. If doxorubicin is administered through a peripheral IV line, infuse doxorubicin over 10 minutes or less to minimize the risk of extravasation.

    New primary malignancy

    A new primary malignancy, including acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS), has been reported with doxorubicin therapy. In patients who received doxorubicin as adjuvant treatment for breast cancer, the cumulative incidence of secondary malignancy ranged from 0.2% at 5 years to 1.5% at 10 years in 2 separate trials; AML/MDS typically occurred within 1 to 3 years following treatment.

    DEA CLASS

    Rx

    DESCRIPTION

    A cytotoxic anthracycline antibiotic that inhibits nucleotide replication and repair
    Approved for use in certain types of leukemias, lymphomas, and solid tumors
    Cardiotoxicity including congestive heart failure has been reported; use is contraindicated in patients with severe myocardial insufficiency or recent myocardial infarction

    COMMON BRAND NAMES

    Adriamycin, Adriamycin PFS

    HOW SUPPLIED

    Adriamycin/Adriamycin PFS/Doxorubicin/Doxorubicin Hydrochloride Intravenous Inj Sol: 1mL, 2mg
    Adriamycin/Doxorubicin/Doxorubicin Hydrochloride Intravenous Inj Pwd F/Sol: 10mg, 50mg

    DOSAGE & INDICATIONS

    For the treatment of acute lymphocytic leukemia (ALL).
    Intravenous dosage
    Adults, Adolescents, Children, and Infants

    60 to 75 mg/m2 IV repeated every 21 days as a single agent; 40 to 75 mg/m2 IV repeated every 21 to 28 days in combination with other chemotherapy agents. Cumulative doses above 550 mg/m2 are associated with an increased risk of cardiomyopathy. Avoid concomitant use with CYP3A4, CYP2D6, and P-glycoprotein inhibitors and inducers.

    For the treatment of acute myelogenous leukemia (AML).
    Intravenous dosage
    Adults, Adolescents, Children, and Infants

    60 to 75 mg/m2 IV repeated every 21 days as a single agent; 40 to 75 mg/m2 IV repeated every 21 to 28 days in combination with other chemotherapy agents. Cumulative doses above 550 mg/m2 are associated with an increased risk of cardiomyopathy. Avoid concomitant use with CYP3A4, CYP2D6, and P-glycoprotein inhibitors and inducers.

    For the treatment of bladder cancer.
    For the treatment of rapidly recurrent (stage Ta or T1) or in situ transitional cell bladder cancer.
    Intravesical dosage†
    Adults

    50 to 150 mg in 150 mL of normal saline instilled into the bladder. The solution is then retained for at least 30 minutes. Responses of up to 90% have been seen with doses of 50 to 150 mg; however, the duration of response is short. In a comparison trial of intravesical doxorubicin and BCG, the disease-free survival of BCG was significantly longer at 5 years than that of doxorubicin. FDA approved labeling for doxorubicin states to avoid concomitant use with CYP3A4, CYP2D6, and P-glycoprotein inhibitors and inducers and that cumulative doses above 550 mg/m2 are associated with an increased risk of cardiomyopathy.

    For the neoadjuvant treatment of bladder cancer.
    Intravenous dosage
    Adults

    30 mg/m2 slow IV push on day 2 in combination with vinblastine (3 mg/m2 IV on days 2, 15, and 22), methotrexate (30 mg/m2 slow IV push on days 1, 15, and 22), and cisplatin (70 mg/m2 IV on day 2); give every 28 days for 3 cycles (MVAC regimen). FDA approved labeling for doxorubicin states to avoid concomitant use with CYP3A4, CYP2D6, and P-glycoprotein inhibitors and inducers and that cumulative doses above 550 mg/m2 are associated with an increased risk of cardiomyopathy.

    For the treatment of metastatic transitional cell bladder cancer.
    Intravenous dosage
    Adults

    60 to 75 mg/m2 IV repeated every 21 days as a single agent; 40 to 75 mg/m2 IV repeated every 21 to 28 days in combination with other chemotherapy agents. Cumulative doses above 550 mg/m2 are associated with an increased risk of cardiomyopathy. Avoid concomitant use with CYP3A4, CYP2D6, and P-glycoprotein inhibitors and inducers. Doxorubicin 30 mg/m2 slow IV push on day 2 in combination with vinblastine (3 mg/m2 IV on days 2, 15, and 22), methotrexate (30 mg/m2 slow IV push on days 1, 15, and 22), and cisplatin (70 mg/m2 IV on day 2) repeated every 28 days for up to a maximum of 6 cycles (MVAC regimen) has been evaluated in clinical trials.

    For the first-line treatment of advanced or metastatic bladder cancer in combination with vinblastine, cisplatin, and methotrexate.
    Intravenous dosage
    Adults

    30 mg/m2 IV on day 2 in combination with methotrexate (30 mg/m2 IV on days 1, 15, and 22), cisplatin 70 mg/m2 IV on day 2, and vinblastine (3 mg/m2 IV on days 2, 15, and 22) repeated every 28 days (MVAC regimen) for up to 6 cycles has been evaluated in patients with advanced or metastatic transitional cell carcinoma of the bladder in a long-term analysis of a multicenter, randomized, phase III trial. Doxorubicin 30 mg/m2 IV on day 1 plus methotrexate (30 mg/m2 IV on days 1, 15, and 22), cisplatin (70 mg/m2 IV on day 1), and vinblastine (3 mg/m2 IV on days 1, 15, and 22) repeated every 4 weeks was studied in another randomized, phase III trial. All patients in this study received granulocyte colony-stimulating factor (G-CSF) following chemotherapy. FDA approved labeling for doxorubicin states to avoid concomitant use with CYP3A4, CYP2D6, and P-glycoprotein inhibitors and inducers and that cumulative doses above 550 mg/m2 are associated with an increased risk of cardiomyopathy.

    For the treatment of breast cancer.
    As adjuvant therapy in women with axillary lymph node involvement following resection of primary breast cancer in combination with cyclophosphamide.
    Intravenous dosage
    Adults

    60 mg/m2 as an IV bolus on day 1 repeated every 21 days for 4 cycles of therapy, in combination with cyclophosphamide. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Disease-free survival and overall survival were not significantly different in women with axillary lymph node-positive early breast cancer who received adjuvant doxorubicin hydrochloride-containing regimens (n = 2,157) compared with cyclophosphamide, methotrexate, and fluorouracil (CMF) (n = 1,353) in a meta-analysis of 6 trials conducted by the Early Breast Cancer Trialists Collaborative Group (EBCTCG). Additionally, a dose-dense regimen of doxorubicin 60 mg/m2 IV plus cyclophosphamide 600 mg/m2 IV on day 1 repeated every 14 days with growth-factor support has been studied.

    For the treatment of metastatic breast cancer.
    Intravenous dosage
    Adults

    60 mg/m2 to 75 mg/m2 IV repeated every 21 days as a single agent; 40 mg/m2 to 75 mg/m2 IV repeated every 21 to 28 days in combination with other chemotherapy agents. Cumulative doses above 550 mg/m2 are associated with an increased risk of cardiomyopathy. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

    For the neoadjuvant treatment of hormone receptor (HR)-negative, HER2-negative (triple-negative) breast cancer, in combination with cyclophosphamide (dose-dense AC) and atezolizumab, after completion of neoadjuvant nab-paclitaxel and atezolizumab.
    Intravenous dosage
    Adults

    60 mg/m2 IV in combination with cyclophosphamide (600 mg/m2 IV) every 2 weeks (dose-dense AC) and atezolizumab (840 mg IV every 2 weeks) for 8 weeks, followed by surgery. Begin dose-dense AC plus atezolizumab after completion of neoadjuvant nab-paclitaxel (125 mg/m2 once weekly) plus atezolizumab (840 mg IV every 2 weeks) for 12 weeks. After surgery, continue atezolizumab 1,200 mg IV every 3 weeks for 11 cycles to complete approximately 12 months of atezolizumab therapy. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In a randomized, phase 3 clinical trial (IMpassion031), neoadjuvant treatment with atezolizumab plus sequential nab-paclitaxel and AC chemotherapy significantly improved pCR compared with neoadjuvant placebo plus sequential nab-paclitaxel and AC chemotherapy in patients with early TNBC, regardless of PD-L1 status.

    For the neoadjuvant treatment of hormone receptor (HR)-negative, HER2-negative (triple-negative) breast cancer, in combination with cyclophosphamide and pembrolizumab, after completion of neoadjuvant paclitaxel/carboplatin/pembrolizumab.
    Intravenous dosage
    Adults

    60 mg/m2 IV plus cyclophosphamide (600 mg/m2 IV) (AC) and pembrolizumab (200 mg IV) on day 1, every 3 weeks for 4 cycles, followed by surgery. Begin AC plus pembrolizumab after completion of 4 cycles of neoadjuvant carboplatin (AUC 5 IV on day 1 every 3 weeks), paclitaxel (80 mg/m2 IV once weekly) and pembrolizumab (200 mg IV every 3 weeks); alternatively, carboplatin may be dosed once weekly at an AUC of 1.5 IV for 12 weeks. After surgery, patients received adjuvant pembrolizumab every 3 weeks for up to 9 cycles. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Neoadjuvant treatment with pembrolizumab in combination with carboplatin and paclitaxel, followed by neoadjuvant pembrolizumab plus anthracycline and cyclophosphamide significantly improved pCR in patients with PD-L1 positive TNBC compared with placebo plus chemotherapy in another phase 3 trial (KEYNOTE-522); patients with PD-L1 negative TNBC numerically benefited from pembrolizumab but the results were not statistically significant.

    For the treatment of metastatic gastric cancer.
    Intravenous dosage
    Adults

    60 to 75 mg/m2 IV repeated every 21 days as a single agent; 40 to 75 mg/m2 IV repeated every 21 to 28 days in combination with other chemotherapy agents. Cumulative doses above 550 mg/m2 are associated with an increased risk of cardiomyopathy. Avoid concomitant use with CYP3A4, CYP2D6, and P-glycoprotein inhibitors and inducers.

    For the treatment of Hodgkin lymphoma.
    For the treatment of Hodgkin lymphoma as part of the Stanford V regimen.
    Intravenous dosage
    Adults and Adolescents 15 years and older

    25 mg/m2 IV on weeks 1, 3, 5, 7, 9, and 11 in combination with mechlorethamine (6 mg/m2 IV on weeks 1, 5, and 9), vinblastine (6 mg/m2 IV on weeks 1, 3, 5, 7, 9, and 11), vincristine (1.4 mg/m2 [Max of 2 mg] IV on weeks 2, 4, 6, 8, 10, and 12), bleomycin (5 units/m2 IV on weeks 2, 4, 6, 8, 10, and 12), etoposide (60 mg/m2 per day IV on 2 consecutive days in weeks 3, 7, and 11), and prednisone (40 mg/m2 PO every other day for 10 weeks then tapered by 10 mg PO every other day between weeks 10 and 12). Total duration of Stanford V regimen is 12 weeks (three 4-week cycles). Doses of mechlorethamine, doxorubicin, vinblastine, and etoposide have been reduced to 65% if the absolute neutrophil count (ANC) is less than 1,000 cells/mm3 (treatment delayed if ANC is less than 500 cells/mm3). Prophylactic sulfamethoxazole-trimethoprim, acyclovir, and a H2-blocker were given throughout the treatment period. G-CSF has also been used to maintain dose intensity as needed after the first dose reduction. Alternative prophylactic medications have also been used. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Interruption of therapy and/or a dosage reduction may be necessary in patients who develop toxicity or intolerable side effects. Cumulative doxorubicin doses above 550 mg/m2 are associated with an increased risk of cardiomyopathy.

    For the treatment of Hodgkin lymphoma as part of the BEACOPP regimen.
    Intravenous dosage
    Adults and Adolescents 15 years and older

    25 mg/m2 IV on day 1 in combination with bleomycin (10 units/m2 IV on day 8), etoposide (100 mg/m2/day IV on days 1, 2, and 3), cyclophosphamide (650 mg/m2 IV on day 1), vincristine (1.4 mg/m2 [Max of 2 mg] IV on day 8), procarbazine (100 mg/m2 per day PO on days 1 to 7), and prednisone (40 mg/m2 PO on days 1 to 14). Cycles are repeated every 21 days for up to 8 cycles. Filgrastim was administered beginning on day 8 of each cycle and continued until the leukocyte count returned to normal in some clinical trials. The escalated dose BEACOPP regimen includes doxorubicin 35 mg/m2 IV on day 1 in combination with bleomycin (10 units/m2 IV on day 8), etoposide (200 mg/m2 per day IV on days 1, 2, and 3), cyclophosphamide (1,200 mg/m2 IV on day 1), vincristine (1.4 mg/m2 [Max of 2 mg] IV on day 8), procarbazine (100 mg/m2 per day PO on days 1 to 7), and prednisone (40 mg/m2 PO on days 1 to 14). Cycles are repeated every 21 days for up to 8 cycles. Filgrastim was administered beginning on day 8 of each cycle and continued until the leukocyte count returned to normal in some clinical trials. The standard dose BEACOPP and escalated dose BEACOPP regimens have shown benefit for the treatment of advanced Hodgkin lymphoma in clinical trials. Escalated dose BEACOPP has shown a significantly better freedom from treatment failure at 10 years (82% vs. 70%, p < 0.0001) and overall survival at 10 years (86% vs. 80%, p = 0.0053) compared to standard dose BEACOPP. A regimen of 4 cycles of escalated dose BEACOPP followed by 4 cycles of standard dose BEACOPP has also been used in patients who achieve a complete response after the initial 4 cycles of escalated dose BEACOPP. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Interruption of therapy and/or a dosage reduction may be necessary in patients who develop toxicity or intolerable side effects. Cumulative doxorubicin doses above 550 mg/m2 are associated with an increased risk of cardiomyopathy.

    For the treatment of Hodgkin lymphoma as part of the ABVD or MOPP/ABV regimens.
    Intravenous dosage
    Adults, Adolescents, and Children

    25 mg/m2 IV on days 1 and 15 repeated every 28 days in combination with vinblastine, bleomycin, and dacarbazine (ABVD regimen). A variation of this regimen includes doxorubicin 35 mg/m2 IV on day 8 in combination with mechlorethamine, vincristine, procarbazine, prednisone, bleomycin, and vinblastine (MOPP/ABV hybrid regimen). Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Interruption of therapy and/or a dosage reduction may be necessary in patients who develop toxicity or intolerable side effects. Cumulative doxorubicin doses above 550 mg/m2 are associated with an increased risk of cardiomyopathy.

    For the treatment of previously untreated advanced classical Hodgkin lymphoma, in combination with brentuximab vedotin, vinblastine, and dacarbazine.
    NOTE: Brentuximab vedotin is FDA approved in combination with chemotherapy (e.g., doxorubicin, vinblastine, and dacarbazine) for the treatment of previously untreated stage III or IV classical Hodgkin lymphoma.
    Intravenous dosage
    Adults

    25 mg/m2 IV in combination with brentuximab vedotin 1.2 mg/kg IV (not to exceed 120 mg/dose), vinblastine 6 mg/m2 IV, and dacarbazine 375 mg/m2 IV each given on days 1 and 15 repeated every 28 days for up to 6 cycles was evaluated in a randomized, phase III trial. Patients should receive primary prophylaxis with a granulocyte colony-stimulating factor due to the high incidence of febrile neutropenia. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Interruption of therapy and/or a dosage reduction may be necessary in patients who develop toxicity or intolerable side effects. Cumulative doxorubicin doses above 550 mg/m2 are associated with an increased risk of cardiomyopathy.

    For the treatment of metastatic ovarian cancer.
    Intravenous dosage
    Adults

    60 to 75 mg/m2 IV repeated every 21 days as a single agent; 40 to 75 mg/m2 IV repeated every 21 to 28 days in combination with other chemotherapy agents. Cumulative doses above 550 mg/m2 are associated with an increased risk of cardiomyopathy. Avoid concomitant use with CYP3A4, CYP2D6, and P-glycoprotein inhibitors and inducers.

    For the treatment of small cell lung cancer (SCLC).
    For the treatment of newly-diagnosed SCLC in combination with cyclophosphamide and vincristine.
    Intravenous dosage
    Adults

    Multiple dosage regimens have been studied. Doxorubicin 40 mg/m2 IV on day 1 in combination with cyclophosphamide 750 mg/m2 IV on day 1 and vincristine 1.2 mg/m2 (Max of 2 mg) IV on day 1, every 4 weeks for 4 cycles. Doxorubicin 50 mg/m2 IV on day 1 in combination with cyclophosphamide 800 mg/m2 IV on day 1 and vincristine 1.4 mg/m2 (Max of 2 mg) IV on day 1, every 3 to 4 weeks for 4 cycles. Doxorubicin 40 mg/m2 IV on day 1 in combination with cyclophosphamide 1,000 mg/m2 IV on day 1 and vincristine 1 mg/m2 (Max of 2mg) IV on day 1, every 3 weeks for 6 cycles. FDA approved labeling for doxorubicin states to avoid concomitant use with CYP3A4, CYP2D6, and P-glycoprotein inhibitors and inducers and that cumulative doses above 550 mg/m2 are associated with an increased risk of cardiomyopathy.

    For the treatment of newly-diagnosed SCLC in combination with cyclophosphamide and etoposide.
    Intravenous dosage
    Adults

    45 mg/m2 IV on day 1 in combination with cyclophosphamide 1,000 mg/m2 IV on day 1 and etoposide 100 mg/m2 per day IV on days 1, 2, and 3 repeated every 3 weeks for 5 cycles. FDA approved labeling for doxorubicin states to avoid concomitant use with CYP3A4, CYP2D6, and P-glycoprotein inhibitors and inducers and that cumulative doses above 550 mg/m2 are associated with an increased risk of cardiomyopathy.

    For the treatment of non-Hodgkin's lymphoma (NHL).
    For the treatment of geriatric patients with NHL in combination with cyclophosphamide, vincristine, and prednisone.
    Intravenous dosage
    Adults 65 years and older

    50 mg/m2 IV on day 1 in combination with cyclophosphamide 750 mg/m2 IV on day 1, vincristine 1.4 mg/m2 IV on day 1 (Max dose of 2 mg), and prednisone 50 mg/m2 PO once daily on days 1, 2, 3, 4, and 5, repeated every 21 days. After 3 cycles, patients with a complete response received 3 additional cycles, patients with a partial response received 5 additional cycles, and patients with progressive disease discontinued treatment. FDA approved labeling for doxorubicin states to avoid concomitant use with CYP3A4, CYP2D6, and P-glycoprotein inhibitors and inducers and that cumulative doses above 550 mg/m2 are associated with an increased risk of cardiomyopathy.

    For the treatment of follicular NHL, in combination with rituximab, cyclophosphamide, vincristine, and prednisone (R-CHOP).
    Intravenous dosage
    Adults

    50 mg/m2 IV on day 1 in combination with rituximab 375 mg/m2 IV given on day 1 (or day 0), cyclophosphamide 750 mg/m2 IV on day 1, vincristine 1.4 mg/m2 IV (Max dose of 2 mg) on day 1, and prednisone 100 mg/m2 PO on days 1, 2, 3, 4, and 5 (R-CHOP regimen) repeated every 3 weeks for 6 to 8 cycles has been studied in previously untreated and previously treated patients with follicular lymphoma (FL) in randomized, phase III trials. FDA approved labeling for doxorubicin states to avoid concomitant use with CYP3A4, CYP2D6, and P-glycoprotein inhibitors and inducers and that cumulative doses above 550 mg/m2 are associated with an increased risk of cardiomyopathy.

    For the first-line treatment of diffuse large B-cell, CD20-positive NHL, in combination with rituximab, cyclophosphamide, vincristine, and prednisone (R-CHOP).
    Intravenous dosage
    Adults 60 years and older

    50 mg/m2 IV on day 1 in combination with rituximab 375 mg/m2 IV on day 1, cyclophosphamide 750 mg/m2 IV on day 1, vincristine 1.4 mg/m2 (Max dose of 2 mg) IV on day 1, and prednisone 40 or 100 mg/m2 per day PO on days 1, 2, 3, 4, and 5 (R-CHOP) repeated every 21 days for up to 8 cycles has been evaluated in patients 60 years of age and older with previously untreated diffuse large B-cell lymphoma in randomized, clinical trials. In a randomized, phase III study in 632 patients aged 60 years or older (range, 60 to 92 years), the 3-year failure-free survival rate was significantly higher with R-CHOP compared with CHOP (53% vs. 46%; hazard ratio (HR) = 0.78; 95% CI, 0.61 to 0.99; p = 0.04) at a median follow-up of 3.5 years. However, overall survival (OS) was not significantly improved in the R-CHOP arm (HR = 0.83; 95% CI, 0.63 to 1.09). In another randomized trial, the median progression-free survival (PFS) (4.8 vs. 1.2 years; p < 0.0001) and OS (8.4 vs. 3.5 years; p < 0.0001) times were significantly improved with R-CHOP compared with CHOP in 399 patients aged 60 to 75 years. The 10-year PFS rates were 36.5% and 20.1% in the R-CHOP and CHOP arms, respectively, and the 10-year OS rates were 43.5% and 27.6%, respectively. FDA approved labeling for doxorubicin states to avoid concomitant use with CYP3A4, CYP2D6, and P-glycoprotein inhibitors and inducers and that cumulative doses above 550 mg/m2 are associated with an increased risk of cardiomyopathy.

    For the treatment of metastatic osteogenic sarcoma.
    Intravenous dosage
    Adults

    Multiple regimens have been studied. Doxorubicin 30 to 45 mg/m2 per day IV for 2 to 3 days monthly as a single agent (may be given daily in divided doses over 2 to 3 days) or 30 to 75 mg/m2 IV in combination with cisplatin or bleomycin, cyclophosphamide, methotrexate, and dactinomycin. Doxorubicin 25 mg/m2 per day IV on days 1, 2, and 3 or 37.5 mg/m2 per day IV on days 1 and 2 in combination with cisplatin, has been incorporated into multiple treatment protocols for osteogenic sarcoma. In the POG-8651 protocol, 106 patients (aged less than 30 years old) with previously untreated nonmetastatic high-grade osteogenic sarcoma were randomized to receive doxorubicin (37.5 mg/m2 per day IV on days 1 and 2) and cisplatin each cycle as part of a multiagent chemotherapy regimen in sequence with BCD (bleomycin, cyclophosphamide, and dactinomycin) and high-dose methotrexate, either before or after surgical resection. Patients also received single-agent doxorubicin (30 mg/m2 per day IV for 3 days) in week 20 of this regimen. Event-free survival (EFS), the primary endpoint, was not significantly different between the treatment arms, and reached 69% at 5 years in the post-operative group. In a comparison of the Memorial Sloan-Kettering Cancer Center T-10 and T-12 protocols, 73 patients (aged 4.6 to 36.4 years) with previously untreated, high-grade osteogenic sarcoma received doxorubicin (25 mg/m2 per day IV on days 1, 2, and 3) and cisplatin each cycle as part of a multiagent chemotherapy regimen in sequence with BCD, high-dose methotrexate, and surgical resection. The 5-year EFS was 78% and 73% in the T-12 and T-10 protocols, respectively. FDA approved labeling for doxorubicin states to avoid concomitant use with CYP3A4, CYP2D6, and P-glycoprotein inhibitors and inducers and that cumulative doses above 550 mg/m2 are associated with an increased risk of cardiomyopathy.

    Adolescents and Children

    25 mg/m2 per day IV on days 1, 2, and 3 or 37.5 mg/m2 per day IV on days 1 and 2 in combination with cisplatin has been incorporated into multiple treatment protocols for osteogenic sarcoma. In the POG-8651 protocol, 106 patients (aged less than 30 years old) with previously untreated nonmetastatic high-grade osteogenic sarcoma were randomized to receive doxorubicin (37.5 mg/m2 per day IV on days 1 and 2) and cisplatin each cycle as part of a multiagent chemotherapy regimen in sequence with BCD (bleomycin, cyclophosphamide, and dactinomycin) and high-dose methotrexate, either before or after surgical resection. Patients also received single-agent doxorubicin (30 mg/m2 per day IV for 3 days) in week 20 of this regimen. Event-free survival (EFS), the primary endpoint, was not significantly different between the treatment arms, and reached 69% at 5 years in the post-operative group. In a comparison of the Memorial Sloan-Kettering Cancer Center T-10 and T-12 protocols, 73 patients (aged 4.6 to 36.4 years) with previously untreated, high-grade osteogenic sarcoma received doxorubicin (25 mg/m2 per day IV on days 1, 2, and 3) and cisplatin each cycle as part of a multiagent chemotherapy regimen in sequence with BCD, high-dose methotrexate, and surgical resection. The 5-year EFS was 78% and 73% in the T-12 and T-10 protocols, respectively. FDA approved labeling for doxorubicin states to avoid concomitant use with CYP3A4, CYP2D6, and P-glycoprotein inhibitors and inducers and that cumulative doses above 550 mg/m2 are associated with an increased risk of cardiomyopathy.

    For the treatment of metastatic Ewing's sarcoma.
    Intravenous dosage
    Adults, Adolescents, and Children

    60 to 75 mg/m2 IV repeated every 21 days as a single agent; 40 to 75 mg/m2 IV repeated every 21 to 28 days in combination with other chemotherapy agents. Cumulative doses above 550 mg/m2 are associated with an increased risk of cardiomyopathy. Avoid concomitant use with CYP3A4, CYP2D6, and P-glycoprotein inhibitors and inducers.

    For the treatment of soft-tissue sarcoma.
    For the treatment of metastatic soft-tissue sarcoma.
    Intravenous dosage
    Adults

    60 to 75 mg/m2 IV repeated every 21 days as a single agent; 40 to 75 mg/m2 IV repeated every 21 to 28 days in combination with other chemotherapy agents. Cumulative doses above 550 mg/m2 are associated with an increased risk of cardiomyopathy. Avoid concomitant use with CYP3A4, CYP2D6, and P-glycoprotein inhibitors and inducers. Single-agent doxorubicin (given as 75 mg/m2 IV over 20 minutes on day 1 OR 25 mg/m2 per day as a continuous 24-hour IV infusion on days 1, 2, and 3) was compared with doxorubicin (25 mg/m2 per day as a IV bolus on days 1, 2, and 3) plus ifosfamide (2.5 grams/m2 per day IV over 4 hour on days 1, 2, 3, and 4) as first-line treatment of locally advanced, unresectable, or metastatic intermediate- or high-grade soft-tissue sarcoma in adult patients (age range, 18 to 63 years) in a multinational, randomized, open-label, phase III trial (n = 445; the EORTC 62012 trial). Patients in the doxorubicin/ifosfamide arm also received mesna (0.5 gram/m2 IV bolus prior to each ifosfamide dose, 1.5 grams/m2 IV over 4 hours given concurrently with each ifosfamide dose, and 1 gram/m2 orally at 2 and 6 hours after each ifosfamide infusion) and pegfilgrastim (6 mg subcutaneously given 24 hours after combination chemotherapy on day 5 of each cycle). Treatment was repeated every 3 weeks until disease progression or unacceptable toxicity, up to a maximum of 6 cycles. The median overall survival time (primary endpoint) was not significantly different with single-agent doxorubicin compared with doxorubicin/ifosfamide therapy (12.8 months vs. 14.3 months; hazard ratio (HR) = 0.83; 95.5% CI, 0.67 to 1.03; p = 0.076) at median follow-up times of 56 and 59 months, respectively. However, the median progression-free survival was significantly higher with doxorubicin/ifosfamide therapy (4.6 months vs. 7.4 months; HR = 0.74; 95.5% CI, 0.6 to 0.9; p = 0.003).

    Adolescents and Children

    60 to 75 mg/m2 IV repeated every 21 days as a single agent; 40 to 75 mg/m2 IV repeated every 21 to 28 days in combination with other chemotherapy agents. Cumulative doses above 550 mg/m2 are associated with an increased risk of cardiomyopathy. Avoid concomitant use with CYP3A4, CYP2D6, and P-glycoprotein inhibitors and inducers.

    For the first-line treatment of unresectable or metastatic soft-tissue sarcoma in combination with dacarbazine, ifosfamide, and mesna.
    Intravenous dosage
    Adults

    15 mg/m2 per day as a continuous IV infusion over 24 hours (CIV) for 4 days in combination with dacarbazine 250 mg/m2 per day CIV for 4 days, ifosfamide 2,000 mg/m2 per day CIV for 3 days, and mesna 2,500 mg/m2 per day CIV for 4 days repeated every 21 days (median of 3 cycles) (MAID regimen) was evaluated in patients with soft-tissue and bone sarcomas in a randomized, phase III trial. Five cycles of an intensified MAID regimen was compared with 6 cycles of a more standard MAID regimen (dacarbazine 300 mg/m2 per day IV over 1 hour on days 1, 2, and 3 plus doxorubicin 20 mg/m2 per day as an IV bolus or CIV on days 1, 2, and 3; ifosfamide 2.5 grams/m2 per day IV over 3 hours on days 1, 2 and 3; and mesna 2.5 grams/m2 per day CIV on days 1, 2, and 3) in patients with inoperable locally advanced or metastatic soft-tissue sarcoma in another randomized, phase III study. FDA approved labeling for doxorubicin states to avoid concomitant use with CYP3A4, CYP2D6, and P-glycoprotein inhibitors and inducers and that cumulative doses above 550 mg/m2 are associated with an increased risk of cardiomyopathy.

    For the treatment of metastatic neuroblastoma.
    For the treatment of intermediate-risk neuroblastoma in combination with etoposide, cyclophosphamide, and carboplatin.
    Intravenous dosage
    Children and Infants

    Doxorubicin has been given in combination with carboplatin, cyclophosphamide, and etoposide. In Cycles 1 and 7: Carboplatin 560 mg/m2 IV on day 1 (18 mg/kg per day in children less than 12 kg) plus etoposide 120 mg/m2 per day IV on days 1, 2, and 3 (4 mg/kg per day in children less than 12 kg). Cycles 2 and 6: Carboplatin 560 mg/m2 IV on day 1 (18 mg/kg per day in children less than 12 kg) plus cyclophosphamide 1,000 mg/m2 IV on day 1 (33 mg/kg per day in children less than 12 kg), and doxorubicin 30 mg/m2 IV on day 1 (1 mg/kg per day in children less than 12 kg). Cycles 3 and 5: Cyclophosphamide 1,000 mg/m2 IV on day 1 (33 mg/kg per day in children less than 12 kg) plus etoposide 120 mg/m2 per day IV on days 1, 2, and 3 (4 mg/kg/day in children less than 12 kg). Cycle 4: Carboplatin 560 mg/m2 IV on day 1 (18 mg/kg per day in children less than 12 kg) plus etoposide 120 mg/m2 per day IV on days 1, 2, and 3 (4 mg/kg per day in children less than 12 kg), and doxorubicin 30 mg/m2 IV on day 1 (1 mg/kg per day in children less than 12 kg). Cycle 8: Cyclophosphamide 1,000 mg/m2 IV on day 1 (33 mg/kg per day in children less than 12 kg) plus doxorubicin 30 mg/m2 IV on day 1 (1 mg/kg per day in children less than 12 kg). All cycles given at 3 week intervals. Patients with favorable biologic features received 4 cycles; if incomplete response after 4 cycles, patients were given an additional 4 cycles. Patients with unfavorable biologic features received 8 cycles. Infants aged less than 60 days of age received granulocyte colony-stimulating factor after each cycle. FDA approved labeling for doxorubicin states to avoid concomitant use with CYP3A4, CYP2D6, and P-glycoprotein inhibitors and inducers and that cumulative doses above 550 mg/m2 are associated with an increased risk of cardiomyopathy.

    Intravenous dosage
    Adults

    60 to 75 mg/m2 IV repeated every 21 days as a single agent; 40 to 75 mg/m2 IV repeated every 21 to 28 days in combination with other chemotherapy agents. Cumulative doses above 550 mg/m2 are associated with an increased risk of cardiomyopathy. Avoid concomitant use with CYP3A4, CYP2D6, and P-glycoprotein inhibitors and inducers.

    Infants

    35 mg/m2 IV on day 8 in combination with cyclophosphamide (150 mg/m2 per day PO on days 1 to 7) repeated every 21 days for 5 cycles. In a clinical trial, 135 patients with hyperdiploid tumors exhibited a complete response rate of 67%. Patients with diploid tumors or patients with hyperdiploid tumors who had a suboptimal response to treatment were switched to cisplatin and etoposide. FDA approved labeling for doxorubicin states to avoid concomitant use with CYP3A4, CYP2D6, and P-glycoprotein inhibitors and inducers and that cumulative doses above 550 mg/m2 are associated with an increased risk of cardiomyopathy.

    For the treatment of metastatic thyroid cancer.
    Intravenous dosage
    Adults

    60 to 75 mg/m2 IV repeated every 21 days as a single agent; 40 to 75 mg/m2 IV repeated every 21 to 28 days in combination with other chemotherapy agents. Cumulative doses above 550 mg/m2 are associated with an increased risk of cardiomyopathy. Avoid concomitant use with CYP3A4, CYP2D6, and P-glycoprotein inhibitors and inducers.

    For the treatment of metastatic Wilms' tumor.
    Intravenous dosage
    Adults, Adolescents, Children, and Infants

    60 to 75 mg/m2 IV repeated every 21 days as a single agent; 40 to 75 mg/m2 IV repeated every 21 to 28 days in combination with other chemotherapy agents. Cumulative doses above 550 mg/m2 are associated with an increased risk of cardiomyopathy. Avoid concomitant use with CYP3A4, CYP2D6, and P-glycoprotein inhibitors and inducers.

    For the treatment of advanced or recurrent endometrial cancer† in combination with cisplatin and paclitaxel.
    Intravenous dosage
    Adults

    45 mg/m2 IV on day 1, given immediately before cisplatin (50 mg/m2) on day 1, then give paclitaxel (160 mg/m2) on day 2; repeated every 21 days. In clinical trials, treatment was continued for up to 7 cycles or until disease progression, and filgrastim (5 mcg/kg) was administered on days 3 to 12. A phase III trial showed an increase in response rate, progression-free survival, and overall survival in patients receiving paclitaxel, doxorubicin, and cisplatin (TAP) compared with cisplatin and doxorubicin alone. Thrombocytopenia and neuropathy were higher in the TAP arm. FDA approved labeling for doxorubicin states to avoid concomitant use with CYP3A4, CYP2D6, and P-glycoprotein inhibitors and inducers and that cumulative doses above 550 mg/m2 are associated with an increased risk of cardiomyopathy.

    For induction therapy prior to autologous stem-cell transplantation in patients with newly diagnosed multiple myeloma†, in combination with vincristine and dexamethasone.
    Intravenous dosage
    Adults 18 to 65 years

    9 mg/m2 per day IV and vincristine 0.4 mg per day IV on days 1, 2, 3, and 4 plus dexamethasone (VAD regimen) repeated every 4 weeks for 3 to 4 cycles as induction therapy prior to autologous stem-cell transplantation has been studied in previously untreated multiple myeloma patients. Doxorubicin and vincristine were administered as a continuous IV infusion over 24 hours per day or as a daily IV infusion. Dexamethasone was given as 40 mg PO daily on days 1, 2, 3, and 4; 9, 10, 11, and 12; and 17, 18, 19, and 20 or as 40 mg PO daily days 1, 2, 3, and 4 on all cycles and days 9, 10, 11, and 12 and 17, 18, 19, and 20 on cycles 1 and 2 only. FDA approved labeling for doxorubicin states to avoid concomitant use with CYP3A4, CYP2D6, and P-glycoprotein inhibitors and inducers and that cumulative doses above 550 mg/m2 are associated with an increased risk of cardiomyopathy.

    For the treatment of advanced stage hepatocellular cancer† in combination with cisplatin.
    Intra-arterial dosage†
    Adults

    30 mg/m2 in combination with cisplatin 100 mg/m2, has been administered via intra-arterial administration as a solution or emulsified with the use of Lipiodol. Treatment was repeated every 2 months for at least 3 cycles. FDA approved labeling for doxorubicin states to avoid concomitant use with CYP3A4, CYP2D6, and P-glycoprotein inhibitors and inducers and that cumulative doses above 550 mg/m2 are associated with an increased risk of cardiomyopathy.

    For the treatment of thymoma†.
    For the treatment of unresectable, advanced thymoma in combination with cyclophosphamide and cisplatin†.
    Intravenous dosage
    Adults

    50 mg/m2 IV on day 1 plus cisplatin 50 mg/m2 IV on day 1 and cyclophosphamide 500 mg/m2 IV on day 1 (with 1 liter of hydration before and after chemotherapy) repeated every 21 days (PAC regimen) for up to 8 cycles (median of 7 cycles) in patients with previously untreated, unresectable, extensive-stage thymoma or for 2 or 4 cycles (median of 4 cycles; range, 1 to 7 cycles) followed by radiotherapy in patients with previously untreated, unresectable, limited-stage thymoma who had stable disease or better was evaluated in a nonrandomized study. Additionally, multimodality treatment with 3 cycles of doxorubicin 30 mg/m2 per day continuous IV infusion over 24 hours on days 1, 2, and 3; cisplatin 30 mg/m2 per day IV on days 1, 2, and 3; cyclophosphamide 500 mg/m2 IV on day 1; and prednisone 100 mg PO on days 1 to 5 repeated every 3 to 4 weeks followed by surgery and radiation therapy and then consolidation chemotherapy with doxorubicin, cisplatin, and cyclophosphamide given at 80% of the original doses and prednisone (given at 100%) repeated every 3 to 4 weeks for 3 cycles was evaluated in another nonrandomized study. In these studies, overall response rates and overall survival rates were favorable. FDA approved labeling for doxorubicin states to avoid concomitant use with CYP3A4, CYP2D6, and P-glycoprotein inhibitors and inducers and that cumulative doses above 550 mg/m2 are associated with an increased risk of cardiomyopathy.

    For the treatment of unresectable, advanced thymoma in combination with cisplatin, cyclophosphamide, and vincristine†.
    Intravenous dosage
    Adults

    40 mg/m2 IV on day 1 plus cisplatin 50 mg/m2 IV on day 1, vincristine 0.6 mg/m2 IV on day 3, and cyclophosphamide 700 mg/m2 IV on day 4 repeated every 3 weeks (median of 5 cycles; range, 3 to 7 cycles) resulted in a favorable overall response rate in a nonrandomized study of 37 patients. FDA approved labeling for doxorubicin states to avoid concomitant use with CYP3A4, CYP2D6, and P-glycoprotein inhibitors and inducers and that cumulative doses above 550 mg/m2 are associated with an increased risk of cardiomyopathy.

    For the treatment of AIDS-related Kaposi's sarcoma† in combination with bleomycin and vincristine.
    Intravenous dosage
    Adults

    10 mg/m2 IV on day 1 in combination with bleomycin (15 units IV on day 1) and vincristine (1 mg IV on day 1), repeated every 2 weeks. Alternately, doxorubicin 20 mg/m2 IV on day 1 has been given in combination with bleomycin (10 mg/m2 IV on day 1) and vincristine (1 mg IV on day 1), repeated every 2 weeks for 6 cycles. FDA approved labeling for doxorubicin states to avoid concomitant use with CYP3A4, CYP2D6, and P-glycoprotein inhibitors and inducers and that cumulative doses above 550 mg/m2 are associated with an increased risk of cardiomyopathy.

    For the first-line treatment of rhabdomyosarcoma† in combination with vincristine, dactinomycin, and ifosfamide.
    Intravenous dosage
    Adolescents and Children

    40 mg/m2 per day IV on days 29 and 30 in combination with ifosfamide 6,000 mg/m2 continuous IV (CIV) over 48 hours on days 1, 29, and 50; mesna 6,000 mg/m2 CIV over 48 hours on days 1, 29, and 50; dactinomycin 0.5 mg/m2 per day IV on days 1, 2, and 3 and 50, 51, and 52; and vincristine 1.5 mg/m2 IV on days 1, 8, 15, and 22. The duration of therapy was dependent on stage at diagnosis (stage I: 16 weeks; II: 26 weeks; III: 40 weeks; IV: 48 weeks). FDA approved labeling for doxorubicin states to avoid concomitant use with CYP3A4, CYP2D6, and P-glycoprotein inhibitors and inducers and that cumulative doses above 550 mg/m2 are associated with an increased risk of cardiomyopathy.

    For the treatment of metastatic liver lesions from malignant melanoma†.
    Intra-arterial dosage†
    Adults

    Doxorubicin 150 mg of 100 to 300 micron beads (given as 2 vials, each 2 mL in volume and containing 75 mg of doxorubicin) via intra-arterial chemoembolization. The maximum dose of doxorubicin was 150 mg/procedure. The beads were mixed with contrast before the procedure and injected slowly in 1 mL aliquots using a "sandwich technique" (i.e., beads then contrast) to identify and minimize reflux.

    For the treatment of biliary tract cancer† (unresectable intrahepatic cholangiocarcinoma) in combination with cisplatin, mitomycin, ethiodol, and polyvinyl alcohol.
    Intra-arterial dosage†
    Adults

    Chemoembolization material consisted of mitomycin 10 mg, doxorubicin 50 mg, and cisplatin 100 mg dissolved in sterile contrast (8.5 mL) and diluted with 1.5 mL of sterile water. This was emulsified in a 1:1 ratio with ethiodol. Added to the final aliquot of the emulsion or separately following administration of the emulsion was 0.2 mL of 150- to 250-l polyvinyl alcohol particles. Normal saline at 200 to 300 mL per hour until the completion of the procedure, followed by normal saline at 150 mL per hour for a total of 3 liters. No diuretics were given. Prophylactic antiemetics (ondansetron 24 mg and dexamethasone 10 mg intravenously) and antibiotics (cefazolin 1 g and metronidazole 500 mg) were given.

    For the treatment of systemic anaplastic large-cell lymphoma (sALCL)†.
    For the treatment of previously untreated sALCL, in combination with brentuximab vedotin, cyclophosphamide, and prednisone†.
    NOTE: Brentuximab vedotin is FDA approved in combination with cyclophosphamide, doxorubicin, and prednisone for this indication.
    Intravenous dosage
    Adults

    50 mg/m2 IV on day 1 in combination with brentuximab vedoin 1.8 mg/kg (not to exceed 180 mg/dose) IV on day 1, cyclophosphamide 750 mg/m2 IV on day 1, and prednisone 100 mg orally daily on days 1, 2, 3, 4, and 5 given every 21 days for 6 to 8 cycles of therapy. The progression-free survival (PFS) time (evaluated via an independent review facility) was significantly improved in patients with CD30-expressing sALCL or peripheral T-cell lymphoma who received brentuximab vedotin plus cyclophosphamide, doxorubicin, and prednisone (CHP) compared with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) (48.2 months vs. 20.8 months; hazard ratio (HR) = 0.71; 95% CI, 0.54 to 0.93) in a multicenter, randomized, double-blind, phase 3 trial (the ECHELON-2 trial; n = 452). Overall survival was also significantly improved in the brentuximab vedotin-containing arm (HR = 0.66; 95% CI, 0.46 to 0.95). In patients with sALCL (n = 314; anaplastic lymphoma kinase (ALK)-negative sALCL, 48%; ALK-positive sALCL, 22%), the PFS times were 55.7 months and 54.2 months in patients who received brentuximab vedotin plus CHP and CHOP, respectively (HR = 0.59; 95% CI, 0.42 to 0.84).

    For the treatment of peripheral T-cell lymphoma (PTCL)†.
    For the treatment of previously untreated CD30-expressing PTCL, in combination with brentuximab vedotin, cyclophosphamide, and prednisone†.
    NOTE: Brentuximab vedotin is FDA approved in combination with cyclophosphamide, doxorubicin, and prednisone for this indication.
    Intravenous dosage
    Adults

    50 mg/m2 IV on day 1 in combination with brentuximab vedotin 1.8 mg/kg (not to exceed 180 mg/dose) IV on day 1, cyclophosphamide 750 mg/m2 IV on day 1, and prednisone 100 mg orally daily on days 1, 2, 3, 4, and 5 given every 21 days for 6 to 8 cycles of therapy. The progression-free survival time (evaluated via an independent review facility) was significantly improved in patients with CD30-expressing systemic anaplastic large-cell lymphoma (sALCL) or PTCL who received brentuximab vedotin plus cyclophosphamide, doxorubicin, and prednisone (CHP) compared with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) (48.2 months vs. 20.8 months; hazard ratio (HR) = 0.71; 95% CI, 0.54 to 0.93) in a multicenter, randomized, double-blind, phase 3 trial (the ECHELON-2 trial; n = 452). Overall survival was also significantly improved in the brentuximab vedotin-containing arm (HR = 0.66; 95% CI, 0.46 to 0.95). In this trial, 70% of patients had sALCL and 30% of patients had PTCL (e.g., including PTCL not otherwise specified (16%), angioimmunoblastic T-cell lymphoma (12%), adult T-cell leukemia/lymphoma (2%), and enteropathy-associated T-cell lymphoma (less than 1%))[45378]

    †Indicates off-label use

    MAXIMUM DOSAGE

    The suggested maximum tolerated dose (MTD) for doxorubicin, which is dependent on performance status, other chemotherapy agents or radiation given in combination, and disease state, is as follows:
    NOTE: The correct dose of doxorubicin will vary from protocol to protocol. Clinicians should consult the appropriate references to verify the dose.

    Adults

    Maximum lifetime cumulative dosage of doxorubicin is 550 mg/m2 IV; 450 mg/m2 IV in patients who have received previous mediastinal radiation.

    Geriatric

    Maximum lifetime cumulative dosage of doxorubicin is 550 mg/m2 IV; 450 mg/m2 IV in patients who have received previous mediastinal radiation.

    Adolescents

    Maximum lifetime cumulative dosage of doxorubicin is 550 mg/m2 IV; 450 mg/m2 IV in patients who have received previous mediastinal radiation.

    Children

    Maximum lifetime cumulative dosage of doxorubicin is 550 mg/m2 IV; 450 mg/m2 IV in patients who have received previous mediastinal radiation. The dose should be based on body weight for children with a BSA < 0.5 m2. Children are more susceptible to cardiotoxicity and require long term follow-up.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    A doxorubicin dosage adjustment is necessary in patients with hepatic impairment as follows:
    Serum bilirubin level of 1.2 to 3 mg/dL: decrease the doxorubicin dose by 50%.
    Serum bilirubin level of 3.1 to 5 mg/dL: decrease the doxorubicin dose by 75%.
    Severe hepatic impairment (Child-Pugh Class C) or serum bilirubin level greater than 5 mg/dL: doxorubicin use is contraindicated.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    Observe and exercise appropriate precautions for handling, preparing, and administering cytotoxic drugs.
    Treat accidental contact with the skin or eyes immediately. Wash with water, soap and water, or sodium bicarbonate solution. Do not use a scrub brush on skin. Promptly seek medical attention.

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intravenous Administration

    Doxorubicin is available as a lyophilized powder vial or a 2 mg/mL injectable solution.
    Do not mix doxorubicin with other drugs.
    If extravasation occurs or is suspected (e.g., blood return is present on aspiration of the infusion needle), manage as follows: 1) immediately terminate the injection or infusion; 2) elevate the extremity (if applicable); 3) apply ice to the site for 15 minutes 4 times daily for 3 days; 4) consider dexrazoxane administration as soon as possible and within the first 6 hours; and 4) do NOT remove the needle (until attempts are made to aspirate extravasated fluid), flush the line, or apply pressure to the site.
     
    Reconstitution of the Lyophilized Powder Vial:
    Add 5 mL of 0.9% Sodium Chloride Injection to the 10-mg vial and 25 mL of 0.9% Sodium Chloride Injection to the 50-mg vial for a final concentration of 2 mg/mL.
    Gently shake the vial until the powder is dissolved.
    Protect from light.
    Formation of a gelled product may occur if the vial is refrigerated; allow the gelled product to sit out at room temperature (15 to 30 degrees C; 59 to 86 degrees F) for 2 to 4 hours to return the product to a slightly viscous, liquid solution.
    Storage of reconstituted vial: store up to 7 days at room temperature or up to 15 days in the refrigerator (2 to 8 degrees C).
    Intravenous (IV) Injection:
    Administer doxorubicin IV over 3 to 10 minutes through a central IV line or a secure and free-flowing peripheral venous line containing 0.9% Sodium Chloride Injection, 0.45% Sodium Chloride Injection, or 5% Dextrose Injection.
    Decrease the rate of injection if erythematous streaking along the vein proximal to the site of infusion or facial flushing occur.
     
    Continuous IV infusion:
    Dilute doxorubicin in 0.9% Sodium Chloride Injection or 5% Dextrose Injection and administer IV over 24 hours through a central IV line.
    Decrease the rate of infusion if erythematous streaking along the vein proximal to the site of infusion or facial flushing occur.
    Protect from light until the infusion is complete.

    Other Injectable Administration

    Intraarterial Administration
     
    NOTE: Doxorubicin is not approved by the FDA for intraarterial administration.
    Hepatic artery chemoembolization:
    Withdraw the appropriate volume of doxorubicin from the reconstituted or solution vial; administer within 1 hour of preparation.
    Place catheter in the hepatic artery by the femoral route and infuse doxorubicin over 30 minutes; remove catheter.
    Administer hydration (e.g., 5% Dextrose and 0.45% Sodium Chloride Injection with 0.02 mEq/mL of potassium chloride) for 2 hours prior to catheter placement and for 6 hours after chemotherapy.
    Furosemide 40 mg IV and mannitol 12.5 grams IV were given when hydration was started.

    STORAGE

    Generic:
    - Discard unused portion. Do not store for later use.
    - Protect from light
    - Store in carton until time of use
    - Store unreconstituted product at 68 to 77 degrees F
    Adriamycin:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Protect from light
    - Refrigerate (between 36 and 46 degrees F)
    - Store in carton until time of use
    Adriamycin PFS:
    - Protect from light
    - Refrigerate (between 36 and 46 degrees F)
    - See package insert for detailed storage information
    - Store in carton until contents are used
    Adriamycin RDF:
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Rubex:
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    Anthracycline hypersensitivity

    Doxorubicin is contraindicated in patients who have had a severe hypersensitivity reaction (e.g., anaphylaxis) to doxorubicin. Use doxorubicin with caution in patients who have an anthracycline hypersensitivity (or anthracenedione hypersensitivity) to another agent in the class.

    Hepatic disease

    Doxorubicin is contraindication in patients with severe hepatic impairment (defined as Child-Pugh class C or serum bilirubin levels greater than 5 mg/dL). Use doxorubicin with caution in patients with mild or moderate hepatic disease/impairment (serum bilirubin levels of 1.2 to 5 mg/dL); a dose reduction is recommended in these patients. Monitor liver function tests prior to starting doxorubicin and during therapy.

    Cardiomyopathy, cardiotoxicity, heart failure, maximum cumulative lifetime dose, myocardial infarction, myocarditis, pericarditis

    Cardiotoxicity (e.g., cardiomyopathy, pericarditis, myocarditis, and left ventricular heart failure) has been reported with doxorubicin therapy. Doxorubicin use is contraindicated in patients with severe myocardial insufficiency or recent (occurring within the past 4 to 6 weeks) myocardial infarction. Assess left ventricular function (e.g., MUGA or echocardiogram) before starting doxorubicin therapy and then regularly during and after therapy; use the same method of assessment at all time points. If the cumulative doxorubicin dose exceeds 300 mg/m2 in a patient that will continue to receive therapy, increase the frequency of cardiac assessment and consider starting dexrazoxane to reduce the incidence and severity of cardiomyopathy. Increased cumulative anthracycline (or anthracenediones) doses, concomitant cardiotoxicity medication (e.g., cyclophosphamide, trastuzumab), and prior mediastinum radiotherapy increase the risk of cardiotoxicity. The incidence of cardiotoxicity is highest in patients who exceed the maximum cumulative lifetime dose of 550 mg/m2. Cardiomyopathy may develop during treatment or up to several years after the completion of treatment. The estimated risk of developing cardiomyopathy (when doxorubicin is given every 3 weeks) is 1% to 2% at a cumulative dose of 300 mg/m2, 3% to 5% at a cumulative dose of 400 mg/m2, and 6% to 20% at a cumulative dose of 500 mg/m2.

    Bone marrow suppression, infection, leukopenia, neutropenia, thrombocytopenia

    Severe myelosuppression/bone marrow suppression (leukopenia, neutropenia, thrombocytopenia) has been reported with doxorubicin therapy; serious infection, septic shock, blood or platelet transfusions, hospitalization, and death may occur due to severe myelosuppression. Doxorubicin use is contraindicated in patients with severe persistent drug-induced myelosuppression. Monitor complete blood counts (CBC) prior to starting doxorubicin; monitor CBC and for signs of clinical complications (e.g., infection, bleeding) during therapy. A reversible, dose-dependent neutropenia is the most common doxorubicin-induced hematologic toxicity. When doxorubicin is given every 3 weeks, the neutrophil count nadir is typically reached 10 to 14 days following the dose.

    Extravasation, tissue necrosis

    Extravasation and severe local tissue necrosis have been reported with doxorubicin therapy; wide excision of the affected area and skin grafting may be necessary if severe tissue injury occurs. Immediately stop the injection or infusion of doxorubicin if signs or symptoms of extravasation occur. If extravasation occurs or is suspected, apply ice at the site for 15 minutes 4 times daily for 3 days; administer dexrazoxane at the site as soon as possible and within the first 6 hours following extravasation. Extravasation may occur in the absence of typical symptoms (e.g., stinging or burning sensation) or when patients have adequate blood return on aspiration of the infusion needle. If doxorubicin is administered through a peripheral IV line, infuse doxorubicin over 10 minutes or less to minimize the risk of extravasation.

    New primary malignancy

    A new primary malignancy, including acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS), has been reported with doxorubicin therapy. In patients who received doxorubicin as adjuvant treatment for breast cancer, the cumulative incidence of secondary malignancy ranged from 0.2% at 5 years to 1.5% at 10 years in 2 separate trials; AML/MDS typically occurred within 1 to 3 years following treatment.

    Radiation therapy

    Increased toxicity to the myocardium, mucosa, skin, and liver may occur when doxorubicin is used concurrently with radiation therapy. Additionally, a radiation recall reaction that may include cutaneous or pulmonary toxicity has been reported in doxorubicin-treated patients who received prior radiation therapy.

    Tumor lysis syndrome (TLS)

    Tumor lysis syndrome (TLS) may occur in doxorubicin-treated patients with rapidly growing tumors. Monitor serum electrolytes (e.g., potassium, calcium, phosphorus), uric acid levels, and serum creatinine prior to and during initial treatment. Administer hydration, urine alkalinization, and uric acid lowering therapy (e.g., allopurinol) as appropriate to minimize the risk of complications associated with TLS.

    Females

    Females may have an increased risk of anthracycline-induced cardiotoxicity. Female patients had a significantly greater reduction in cardiac contractility compared with male patients based on echocardiogram evaluations in a study in 120 children and adults who had been treated with bolus doses of doxorubicin (cumulative doses of 244 to 550 mg/m2) in childhood.

    Children, growth inhibition, infants

    Pediatric patients including adolescents, children, and infants are at risk for developing late cardiovascular dysfunction with anthracycline therapy. Pediatric patients should receive long-term, periodic cardiac evaluations after receiving doxorubicin. Risk factors include young age at treatment (especially in children less than 5 years of age), high cumulative doses, and a history of receiving combined modality therapy. Prepubertal growth inhibition/failure and gonadal impairment have been reported in pediatric patients who received doxorubicin as part of intensive chemotherapy; gonadal impairment was usually reversible.

    Pregnancy

    Doxorubicin is pregnancy category D. It may cause fetal harm when administered to a pregnant woman. Females of reproductive potential should avoid pregnancy during doxorubicin therapy. Apprise the patient of the potential hazard to a fetus if doxorubicin is used during pregnancy or if the patient becomes pregnant while taking doxorubicin. In animal studies in rats and rabbits, doxorubicin was teratogenic (e.g., esophageal and intestinal atresia, tracheo-esophageal fistula, hypoplasia of the urinary bladder, and cardiovascular anomalies) and embryotoxic at doses approximately 0.07-times (based on body surface area) the recommended human dose of 60 mg/m2.

    Contraception requirements, infertility, male-mediated teratogenicity, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during doxorubicin treatment. Females of reproductive potential should use effective contraception during and for 6 months after treatment with doxorubicin. Due to male-mediated teratogenicity, men with female partners of reproductive potential should use effective contraception during therapy and for 6 months following the final dose of doxorubicin. Doxorubicin may cause infertility; amenorrhea has been reported in females and oligospermia, azoospermia, and permanent loss of fertility have been reported in males. Sperm counts returned to normal levels in some men who received doxorubicin, sometimes several years after the end of treatment.

    Breast-feeding

    Doxorubicin has been detected in breast milk and should not be administered in breast-feeding women. Peak milk concentrations in 1 patient were approximately 4.4-times greater than plasma concentrations 24 hours after treatment. Doxorubicin was detectable in breast milk up to 72 hours after therapy. Due to the potential for serious adverse reactions in nursing infants from doxorubicin, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

    Vaccination

    Vaccination with live vaccines should be avoided during treatment with doxorubicin due to the risk of serious or fatal infections. Killed or inactivated vaccines may be administered; however, patient response may be diminished due to immunosuppression.[43236] [61628]

    ADVERSE REACTIONS

    Severe

    heart failure / Delayed / 0-20.0
    cardiomyopathy / Delayed / 1.0-20.0
    leukopenia / Delayed / 3.7-3.7
    thrombocytopenia / Delayed / 0.1-0.1
    cardiotoxicity / Delayed / Incidence not known
    pericarditis / Delayed / Incidence not known
    myocarditis / Delayed / Incidence not known
    typhlitis / Delayed / Incidence not known
    peptic ulcer / Delayed / Incidence not known
    GI bleeding / Delayed / Incidence not known
    keratitis / Delayed / Incidence not known
    tissue necrosis / Early / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    tumor lysis syndrome (TLS) / Delayed / Incidence not known
    new primary malignancy / Delayed / Incidence not known
    seizures / Delayed / Incidence not known
    coma / Early / Incidence not known

    Moderate

    bleeding / Early / Incidence not known
    neutropenia / Delayed / Incidence not known
    bone marrow suppression / Delayed / Incidence not known
    dehydration / Delayed / Incidence not known
    stomatitis / Delayed / Incidence not known
    esophagitis / Delayed / Incidence not known
    colitis / Delayed / Incidence not known
    oral ulceration / Delayed / Incidence not known
    erythema / Early / Incidence not known
    palmar-plantar erythrodysesthesia (hand and foot syndrome) / Delayed / Incidence not known
    conjunctivitis / Delayed / Incidence not known
    phlebitis / Rapid / Incidence not known
    skin ulcer / Delayed / Incidence not known
    radiation recall reaction / Delayed / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known
    peripheral neuropathy / Delayed / Incidence not known

    Mild

    vomiting / Early / 5.0-37.0
    infection / Delayed / 2.0-2.0
    chills / Rapid / Incidence not known
    fever / Early / Incidence not known
    diarrhea / Early / Incidence not known
    abdominal pain / Early / Incidence not known
    nausea / Early / Incidence not known
    anorexia / Delayed / Incidence not known
    photosensitivity / Delayed / Incidence not known
    rash / Early / Incidence not known
    nail discoloration / Delayed / Incidence not known
    skin hyperpigmentation / Delayed / Incidence not known
    pruritus / Rapid / Incidence not known
    onycholysis / Delayed / Incidence not known
    urticaria / Rapid / Incidence not known
    urine discoloration / Early / Incidence not known
    lacrimation / Early / Incidence not known
    injection site reaction / Rapid / Incidence not known
    amenorrhea / Delayed / Incidence not known
    oligospermia / Delayed / Incidence not known
    azoospermia / Delayed / Incidence not known
    gonadal suppression / Delayed / Incidence not known
    spermatogenesis inhibition / Delayed / Incidence not known
    asthenia / Delayed / Incidence not known
    malaise / Early / Incidence not known
    Co-Enzyme Q-10 deficiency / Delayed / Incidence not known

    DRUG INTERACTIONS

    Abacavir; Lamivudine, 3TC; Zidovudine, ZDV: (Major) Avoid concomitant administration of zidovudine, ZDV, and doxorubicin as an antagonistic relationship has been demonstrated in vitro.
    Abiraterone: (Major) Avoid coadministration of doxorubicin with abiraterone due to increased plasma concentrations of doxorubicin. Doxorubicin is a CYP2D6 substrate and abiraterone is a moderate CYP2D6 inhibitor. Clinically significant interactions have been reported with inhibitors of CYP2D6, resulting in increased concentration and clinical effect of doxorubicin.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Major) Barbiturates induce CYP3A4 and doxorubicin is a major substrate of CYP3A4. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy. Avoid coadministration of barbiturates and doxorubicin if possible. If not possible, monitor doxorubicin closely for efficacy.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Major) Chlorpheniramine is a CYP2D6 inhibitor and doxorubicin is a major CYP2D6 substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP2D6, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of chlorpheniramine and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Major) Chlorpheniramine is a CYP2D6 inhibitor and doxorubicin is a major CYP2D6 substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP2D6, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of chlorpheniramine and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: (Major) Chlorpheniramine is a CYP2D6 inhibitor and doxorubicin is a major CYP2D6 substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP2D6, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of chlorpheniramine and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Acetaminophen; Diphenhydramine: (Minor) Diphenhydramine is a CYP2D6 inhibitor and doxorubicin is a major substrate of CYP2D6. However, these drugs are often used together in treatment.
    Amiodarone: (Major) Avoid the concomitant use of doxorubicin and amiodarone; use of these drugs together may increase doxorubicin concentrations and increase the risk of doxorubicin-induced toxicity. Doxorubicin is a substrate of CYP2D6, CYP3A4, and P-glycoprotein (P-gp); amiodarone is a CYP2D6 inhibitor, a CYP3A4 substrate and inhibitor, and a P-gp inhibitor.
    Amlodipine; Celecoxib: (Major) Avoid coadministration of celecoxib and doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Celecoxib is a CYP2D6 inhibitor, and doxorubicin is a CYP2D6 substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP2D6, resulting in increased concentration and clinical effect of doxorubicin.
    Amobarbital: (Major) Barbiturates induce CYP3A4 and doxorubicin is a major substrate of CYP3A4. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy. Avoid coadministration of barbiturates and doxorubicin if possible. If not possible, monitor doxorubicin closely for efficacy.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Avoid coadministration of clarithromycin with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Clarithromycin is a strong CYP3A4 inhibitor and a P-glycoprotein (P-gp) inhibitor; doxorubicin is a major substrate of CYP3A4 and P-gp. Concurrent use of CYP3A4 inhibitors or P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid coadministration of clarithromycin with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Clarithromycin is a strong CYP3A4 inhibitor and a P-glycoprotein (P-gp) inhibitor; doxorubicin is a major substrate of CYP3A4 and P-gp. Concurrent use of CYP3A4 inhibitors or P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
    Apalutamide: (Major) Avoid coadministration of doxorubicin with apalutamide due to decreased doxorubicin plasma concentrations. Doxorubicin is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy.
    Aprepitant, Fosaprepitant: (Moderate) Aprepitant, fosaprepitant is indicated for the prophylaxis of chemotherapy-induced nausea/vomiting and is often used in combination with doxorubicin. However, use caution and monitor for a possible increase in non-emetogenic doxorubicin-related adverse effects for several days after administration of a multi-day aprepitant regimen. Of note, doxorubicin was included in treatment regimens used in four of the multicenter, randomized, double-blind, controlled clinical trials evaluating the efficacy of aprepitant in highly emetogenic (HEC) and moderately emetogenic chemotherapy (MEC). Doxorubicin is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and theoretically could increase plasma concentrations of doxorubicin. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
    Aspirin, ASA; Butalbital; Caffeine: (Major) Barbiturates induce CYP3A4 and doxorubicin is a major substrate of CYP3A4. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy. Avoid coadministration of barbiturates and doxorubicin if possible. If not possible, monitor doxorubicin closely for efficacy.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) Barbiturates induce CYP3A4 and doxorubicin is a major substrate of CYP3A4. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy. Avoid coadministration of barbiturates and doxorubicin if possible. If not possible, monitor doxorubicin closely for efficacy.
    Atazanavir: (Major) Atazanavir is a strong CYP3A4 inhibitor; doxorubicin is a major substrate of CYP3A4. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP3A4, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of atazanavir and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Atazanavir; Cobicistat: (Major) Atazanavir is a strong CYP3A4 inhibitor; doxorubicin is a major substrate of CYP3A4. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP3A4, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of atazanavir and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity. (Major) Avoid coadministration of cobicistat and doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Cobicistat is a strong inhibitor of CYP3A4 and an inhibitor of CYP2D6 and P-glycoprotein (P-gp); doxorubicin is a major CYP2D6, CYP3A4, and P-gp substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP2D6, CYP3A4, and/or P-gp, resulting in increased concentration and clinical effect of doxorubicin.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Major) Phenobarbital is a potent inducer of CYP3A4 and P-glycoprotein (P-gp); doxorubicin is a major CYP3A4 and P-gp substrate. Primidone and mephobarbital, both metabolized to phenobartital, are also potent CYP3A4 inducers. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy. Avoid coadministration of doxorubicin with phenobarbital, primidone, and mephobarbital if possible. If not possible, monitor doxorubicin closely for efficacy.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Phenobarbital is a potent inducer of CYP3A4 and P-glycoprotein (P-gp); doxorubicin is a major CYP3A4 and P-gp substrate. Primidone and mephobarbital, both metabolized to phenobartital, are also potent CYP3A4 inducers. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy. Avoid coadministration of doxorubicin with phenobarbital, primidone, and mephobarbital if possible. If not possible, monitor doxorubicin closely for efficacy.
    Berotralstat: (Major) Avoid coadministration of doxorubicin with berotralstat due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Doxorubicin is a CYP3A4, CYP2D6, and P-gp substrate; berotralstat is a CYP3A4, CYP2D6, and P-gp inhibitor. Concurrent use of CYP3A4, CYP2D6, and P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
    Bexarotene: (Major) Avoid coadministration of doxorubicin with bexarotene due to decreased doxorubicin plasma concentrations. Doxorubicin is a CYP3A4 substrate and bexarotene is a moderate CYP3A4 inducer. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy.
    Boceprevir: (Major) Boceprevir is a strong CYP3A4 inhibitor and a mild inhibitor of P-glycoprotein (P-gp); doxorubicin is a major substrate of both CYP3A4 and P-gp. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP3A4 and/or P-gp, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of boceprevir and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Bosentan: (Major) Bosentan is a CYP3A4 inducer and doxorubicin is a major substrate of CYP3A4. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy. Avoid coadministration of bosentan and doxorubicin if possible. If not possible, monitor doxorubicin closely for efficacy.
    Brigatinib: (Moderate) Monitor for an increase in doxorubicin-related adverse reactions if coadministration with brigatinib is necessary. Doxorubicin is a substrate of P-glycoprotein (P-gp). Brigatinib inhibits P-gp in vitro and may have the potential to increase concentrations of P-gp substrates. Concurrent use of P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
    Bupropion: (Major) In vitro, bupropion is a mild CYP2D6 inhibitor and doxorubicin is a major CYP2D6 substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP2D6, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of bupropion and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Bupropion; Naltrexone: (Major) In vitro, bupropion is a mild CYP2D6 inhibitor and doxorubicin is a major CYP2D6 substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP2D6, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of bupropion and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Butabarbital: (Major) Barbiturates induce CYP3A4 and doxorubicin is a major substrate of CYP3A4. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy. Avoid coadministration of barbiturates and doxorubicin if possible. If not possible, monitor doxorubicin closely for efficacy.
    Butalbital; Acetaminophen: (Major) Barbiturates induce CYP3A4 and doxorubicin is a major substrate of CYP3A4. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy. Avoid coadministration of barbiturates and doxorubicin if possible. If not possible, monitor doxorubicin closely for efficacy.
    Butalbital; Acetaminophen; Caffeine: (Major) Barbiturates induce CYP3A4 and doxorubicin is a major substrate of CYP3A4. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy. Avoid coadministration of barbiturates and doxorubicin if possible. If not possible, monitor doxorubicin closely for efficacy.
    Cabozantinib: (Minor) Monitor for an increase in doxorubicin-related adverse reactions if coadministration with cabozantinib is necessary. Doxorubicin is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown.
    Capmatinib: (Major) Avoid coadministration of capmatinib with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Capmatinib is a P-gp inhibitor and doxorubicin is a P-gp substrate. Concurrent use of P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
    Carbamazepine: (Major) As carbamazepine is metabolized by CYP3A4, the potential exists for an interaction between carbamazepine and doxorubicin HCl, which isexpected to decrease plasma concentrations of carbamazepine. A 36-year old female with a seizure disorder and cancer had a seizure due to subtherapeutic carbamazepine, phenytoin, and valproate concentrations after 2 days of doxorubicin and cisplatin receipt. The exact mechanism of the interaction is unknown, but decreased absorption or accelerated elimination of carbamazepine may be the cause. Additionally, carbamazepine is a potent inducer of CYP3A4 and P-glycoprotein (P-gp); doxorubicin is a major substrate of both CYP3A4 and P-gp. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy. Avoid coadministration of carbamazepine and doxorubicin if possible. If not possible, monitor doxorubicin closely for efficacy; additionally, closely monitor the serum carbamazepine concentration, as the dose may need to be increased.
    Carbetapentane; Chlorpheniramine: (Major) Chlorpheniramine is a CYP2D6 inhibitor and doxorubicin is a major CYP2D6 substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP2D6, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of chlorpheniramine and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Carbetapentane; Chlorpheniramine; Phenylephrine: (Major) Chlorpheniramine is a CYP2D6 inhibitor and doxorubicin is a major CYP2D6 substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP2D6, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of chlorpheniramine and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Carbetapentane; Diphenhydramine; Phenylephrine: (Minor) Diphenhydramine is a CYP2D6 inhibitor and doxorubicin is a major substrate of CYP2D6. However, these drugs are often used together in treatment.
    Carvedilol: (Moderate) Increased concentrations of doxorubicin may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and doxorubicin is a P-gp substrate.
    Celecoxib: (Major) Avoid coadministration of celecoxib and doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Celecoxib is a CYP2D6 inhibitor, and doxorubicin is a CYP2D6 substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP2D6, resulting in increased concentration and clinical effect of doxorubicin.
    Cenobamate: (Major) Avoid coadministration of doxorubicin with cenobamate due to decreased doxorubicin plasma concentrations. Doxorubicin is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy.
    Ceritinib: (Major) Avoid coadministration of ceritinib with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Ceritinib is a strong CYP3A4 inhibitor and doxorubicin is a major substrate of CYP3A4. Concurrent use of CYP3A4 inhibitors with doxorubicin has resulted in clinically significant interactions.
    Chloramphenicol: (Major) Chloramphenicol is a CYP3A4 inhibitor and doxorubicin is a major CYP3A4 substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP3A4, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of chloramphenicol and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Chlorpheniramine: (Major) Chlorpheniramine is a CYP2D6 inhibitor and doxorubicin is a major CYP2D6 substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP2D6, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of chlorpheniramine and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Chlorpheniramine; Codeine: (Major) Chlorpheniramine is a CYP2D6 inhibitor and doxorubicin is a major CYP2D6 substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP2D6, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of chlorpheniramine and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Chlorpheniramine; Dextromethorphan: (Major) Chlorpheniramine is a CYP2D6 inhibitor and doxorubicin is a major CYP2D6 substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP2D6, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of chlorpheniramine and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Major) Chlorpheniramine is a CYP2D6 inhibitor and doxorubicin is a major CYP2D6 substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP2D6, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of chlorpheniramine and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Major) Chlorpheniramine is a CYP2D6 inhibitor and doxorubicin is a major CYP2D6 substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP2D6, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of chlorpheniramine and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Major) Chlorpheniramine is a CYP2D6 inhibitor and doxorubicin is a major CYP2D6 substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP2D6, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of chlorpheniramine and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) Chlorpheniramine is a CYP2D6 inhibitor and doxorubicin is a major CYP2D6 substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP2D6, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of chlorpheniramine and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Chlorpheniramine; Hydrocodone: (Major) Chlorpheniramine is a CYP2D6 inhibitor and doxorubicin is a major CYP2D6 substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP2D6, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of chlorpheniramine and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Major) Chlorpheniramine is a CYP2D6 inhibitor and doxorubicin is a major CYP2D6 substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP2D6, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of chlorpheniramine and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Major) Chlorpheniramine is a CYP2D6 inhibitor and doxorubicin is a major CYP2D6 substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP2D6, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of chlorpheniramine and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Chlorpheniramine; Phenylephrine: (Major) Chlorpheniramine is a CYP2D6 inhibitor and doxorubicin is a major CYP2D6 substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP2D6, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of chlorpheniramine and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Chlorpheniramine; Pseudoephedrine: (Major) Chlorpheniramine is a CYP2D6 inhibitor and doxorubicin is a major CYP2D6 substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP2D6, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of chlorpheniramine and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Chlorpromazine: (Major) Avoid coadministration of chlorpromazine with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Chlorpromazine is a CYP2D6 inhibitor, and doxorubicin is a major substrate of CYP2D6. Concurrent use of CYP2D6 inhibitors with doxorubicin has resulted in clinically significant interactions.
    Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
    Cimetidine: (Major) Cimetidine is a mild inhibitor of CYP2D6 and CYP3A4; doxorubicin is a major CYP2D6 and CYP3A4 substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP2D6 and/or CYP3A4, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of cimetidine and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Cinacalcet: (Major) Cinacalcet is a CYP2D6 inhibitor and doxorubicin is a major CYP2D6 substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP2D6, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of cinacalcet and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Ciprofloxacin: (Major) Avoid coadministration of ciprofloxacin with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Ciprofloxacin is a moderate CYP3A4 inhibitor, and doxorubicin is a major substrate of CYP3A4. Concurrent use of CYP3A4 inhibitors with doxorubicin has resulted in clinically significant interactions.
    Clarithromycin: (Major) Avoid coadministration of clarithromycin with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Clarithromycin is a strong CYP3A4 inhibitor and a P-glycoprotein (P-gp) inhibitor; doxorubicin is a major substrate of CYP3A4 and P-gp. Concurrent use of CYP3A4 inhibitors or P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
    Clobazam: (Major) Avoid coadministration of doxorubicin and clobazam due to the potential for altered doxorubicin exposure. Doxorubicin is a major substrate of CYP3A4 and CYP2D6. Clobazam is a weak inhibitor of CYP2D6 and a weak inducer of CYP3A4. Clinically significant interactions have been reported with inhibitors of CYP2D6 resulting in increased concentration and clinical effect of doxorubicin while inducers of CYP3A4 may decrease the concentration of doxorubicin.
    Cobicistat: (Major) Avoid coadministration of cobicistat and doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Cobicistat is a strong inhibitor of CYP3A4 and an inhibitor of CYP2D6 and P-glycoprotein (P-gp); doxorubicin is a major CYP2D6, CYP3A4, and P-gp substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP2D6, CYP3A4, and/or P-gp, resulting in increased concentration and clinical effect of doxorubicin.
    Cocaine: (Major) Cocaine is a potent CYP2D6 inhibitor and a mild inhibitor of CYP3A4; doxorubicin is a major CYP2D6 and CYP3A4 substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP2D6 and/or CYP3A4, resulting in increased concentration and clinical effect of doxorubicin. Increased side effects of doxorubicin, including myelosuppression and cardiotoxicity, might occur. Avoid coadministration of cocaine and doxorubicin when possible. Local, limited topical use of cocaine in medical procedures is not expected to produce interactions.
    Conivaptan: (Major) Avoid coadministration of conivaptan, a CYP3A4/P-glycoprotein (P-gp) inhibitor and doxorubicin, a CYP3A4/P-gp substrate. Concurrent use may result in increased serum concentrations of doxorubicin. According to the manufacturer of conivaptan, concomitant use of conivaptan with drugs that are primarily metabolized by CYP3A4, such as doxorubicin, should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy. Coadministration of conivaptan with other CYP3A substrates (midazolam, simvastatin, amlodipine) has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with doxorubicin.
    Crizotinib: (Major) Avoid coadministration of crizotinib with doxorubicin due to the risk of increased doxorubicin exposure resulting in increased treatment-related adverse reactions. Crizotinib is a moderate CYP3A inhibitor and doxorubicin is a major substrate of CYP3A4; clinically significant interactions have been reported with other CYP3A4 inhibitors, resulting in increased concentration and clinical effect of doxorubicin.
    Cyclophosphamide: (Moderate) Monitor for signs and symptoms of cardiac dysfunction if coadministration of cyclophosphamide with anthracyclines is necessary as there is an additive or potentially synergistic increase in the risk of cardiomyopathy.
    Cyclosporine: (Major) Concurrent use of doxorubicin with other agents which cause bone marrow or immune suppression such as other immunosuppressives may result in additive effects. In addition, high doses of cyclosporine (starting at 16 mg/kg/day IV) may increase exposure to anthracyclines (e.g. doxorubicin) in cancer patients. Cyclosporine is a substrate and inhibitor of P-glycoprotein, an energy-dependent drug efflux pump encoded for by the multidrug resistance gene-1 (MDR1). Overexpression of this protein has been described as a mechanism of resistance to naturally-occurring (non-synthetic) chemotherapy agents. Cyclosporine can block MDR1-mediated resistance when given at much higher doses than those used in transplantation and may also enhance the efficacy of doxorubicin by inhibiting this protein. Valspodar is a cyclosporine analog with less renal and immunosuppressive effects than cyclosporine while retaining effects on MDR. The addition of cyclosporine or valspodar to doxorubicin therapy may result in increases in AUC for both doxorubicin and doxorubicinol possibly due to a decrease in clearance of parent drug, a decrease in metabolism of doxorubicinol, or an increase in intracellular doxorubicin concentrations. Literature reports suggest that adding cyclosporine to doxorubicin results in more profound and prolonged hematologic toxicity than doxorubicin alone; coma and/or seizures have also been described.
    Dabrafenib: (Major) Dabrafenib is a CYP3A4 inducer and doxorubicin is a major substrate of CYP3A4. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy. Avoid coadministration of dabrafenib and doxorubicin if possible. If not possible, monitor doxorubicin closely for efficacy.
    Daclatasvir: (Moderate) Systemic exposure of doxorubicin, a substrate of the drug transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), may be increased when administered concurrently with daclatasvir, a P-gp and BCRP inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of doxorubicin; monitor patients for potential adverse effects.
    Daclizumab: (Major) Concurrent use of doxorubicin with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
    Dacomitinib: (Major) Avoid coadministration of dacomitinib with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Doxorubicin is a substrate of CYP2D6; dacomitinib is a strong CYP2D6 inhibitor. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP2D6, resulting in increased concentration and clinical effects of doxorubicin.
    Dalfopristin; Quinupristin: (Major) Avoid coadministration of dalfopristin; quinupristin with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Dalfopristin; quinupristin is a weak CYP3A4 inhibitor and doxorubicin is a major substrate of CYP3A4. Concurrent use of CYP3A4 inhibitors with doxorubicin has resulted in clinically significant interactions.
    Danazol: (Major) Danazol is a CYP3A4 inhibitor and doxorubicin is a major CYP3A4 substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP3A4, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of danazol and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Darifenacin: (Major) Avoid coadministration of darifenacin with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Darifenacin is a moderate CYP2D6 inhibitor and doxorubicin is a major substrate of CYP2D6. Concurrent use of CYP2D6 inhibitors with doxorubicin has resulted in clinically significant interactions.
    Darunavir: (Major) Avoid coadministration of darunavir with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Darunavir is a strong CYP3A4 inhibitor and doxorubicin is a major substrate of CYP3A4. Concurrent use of CYP3A4 inhibitors with doxorubicin has resulted in clinically significant interactions.
    Darunavir; Cobicistat: (Major) Avoid coadministration of cobicistat and doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Cobicistat is a strong inhibitor of CYP3A4 and an inhibitor of CYP2D6 and P-glycoprotein (P-gp); doxorubicin is a major CYP2D6, CYP3A4, and P-gp substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP2D6, CYP3A4, and/or P-gp, resulting in increased concentration and clinical effect of doxorubicin. (Major) Avoid coadministration of darunavir with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Darunavir is a strong CYP3A4 inhibitor and doxorubicin is a major substrate of CYP3A4. Concurrent use of CYP3A4 inhibitors with doxorubicin has resulted in clinically significant interactions.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Avoid coadministration of cobicistat and doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Cobicistat is a strong inhibitor of CYP3A4 and an inhibitor of CYP2D6 and P-glycoprotein (P-gp); doxorubicin is a major CYP2D6, CYP3A4, and P-gp substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP2D6, CYP3A4, and/or P-gp, resulting in increased concentration and clinical effect of doxorubicin. (Major) Avoid coadministration of darunavir with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Darunavir is a strong CYP3A4 inhibitor and doxorubicin is a major substrate of CYP3A4. Concurrent use of CYP3A4 inhibitors with doxorubicin has resulted in clinically significant interactions.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid coadministration of ritonavir with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Ritonavir is a strong CYP3A4 inhibitor and a P-gp inhibitor; doxorubicin is a CYP3A4 and P-gp substrate. Concurrent use of CYP3A4 and/or P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
    Delavirdine: (Major) Delavirdine is a potent CYP3A4 inhibitor as well as a CYP2D6 inhibitor; doxorubicin is a major CYP2D6 and CYP3A4 substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP2D6 and/or CYP3A4, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of delavirdine and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Dexrazoxane: (Moderate) Dexrazoxane is a cardioprotectant administered prior to doxorubicin-containing chemotherapy regimens in women with metastatic breast cancer who have received a cumulative doxorubicin dose of 300 mg/m2 and who will continue to receive doxorubicin therapy. Monitor blood counts if these agents are used together; additive myelosuppression may occur. Do not use dexrazoxane as a cardioprotectant when doxorubicin therapy is first begun; significantly lower tumor response rates and a shorter time to disease progression were reported in women with metastatic breast cancer who received dexrazoxane at the start of doxorubicin therapy in a randomized trial.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Minor) Diphenhydramine is a CYP2D6 inhibitor and doxorubicin is a major substrate of CYP2D6. However, these drugs are often used together in treatment.
    Dextromethorphan; Quinidine: (Major) Avoid coadministration of quinidine with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Quinidine is a potent CYP2D6 inhibitor and P-glycoprotein (P-gp) inhibitor; doxorubicin is a major substrate of CYP2D6 and P-gp. Concurrent use of CYP2D6 or P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
    Diltiazem: (Major) Avoid coadministration of diltiazem and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity. Diltiazem is a moderate CYP3A4 inhibitor; doxorubicin is a major CYP3A4 substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP3A4, resulting in increased concentration and clinical effect of doxorubicin.
    Diphenhydramine: (Minor) Diphenhydramine is a CYP2D6 inhibitor and doxorubicin is a major substrate of CYP2D6. However, these drugs are often used together in treatment.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Minor) Diphenhydramine is a CYP2D6 inhibitor and doxorubicin is a major substrate of CYP2D6. However, these drugs are often used together in treatment.
    Diphenhydramine; Ibuprofen: (Minor) Diphenhydramine is a CYP2D6 inhibitor and doxorubicin is a major substrate of CYP2D6. However, these drugs are often used together in treatment.
    Diphenhydramine; Naproxen: (Minor) Diphenhydramine is a CYP2D6 inhibitor and doxorubicin is a major substrate of CYP2D6. However, these drugs are often used together in treatment.
    Diphenhydramine; Phenylephrine: (Minor) Diphenhydramine is a CYP2D6 inhibitor and doxorubicin is a major substrate of CYP2D6. However, these drugs are often used together in treatment.
    Docetaxel: (Minor) Docetaxel appears to cause sequence-related drug interactions with doxorubicin. Antagonism may occur if docetaxel and doxorubicin are administered simultaneously, and when doxorubicin was added prior to docetaxel.
    Dronedarone: (Major) Avoid coadministration of dronedarone with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Dronedarone is a CYP3A4, CYP2D6, and P-glycoprotein (P-gp) inhibitor; doxorubicin is a major substrate of CYP3A4, CYP2D6, and P-gp. Concurrent use of CYP3A4, CYP2D6, or P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
    Drospirenone; Ethinyl Estradiol: (Moderate) Ethinyl Estradiol is a mild CYP3A4 inhibitor and doxorubicin is a major CYP3A4 substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP3A4, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of ethinyl estradiol and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Moderate) Ethinyl Estradiol is a mild CYP3A4 inhibitor and doxorubicin is a major CYP3A4 substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP3A4, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of ethinyl estradiol and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Duloxetine: (Major) Duloxetine is a CYP2D6 inhibitor and doxorubicin is a major CYP2D6 substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP2D6, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of duloxetine and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Duvelisib: (Major) Avoid coadministration of duvelisib with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Duvelisib is a moderate CYP3A4 inhibitor and doxorubicin is a major substrate of CYP3A4. Concurrent use of CYP3A4 inhibitors with doxorubicin has resulted in clinically significant interactions.
    Efavirenz: (Major) Avoid coadministration of efavirenz with doxorubicin due to decreased doxorubicin plasma concentrations. Efavirenz is a CYP3A4 inducer and doxorubicin is a major substrate of CYP3A4. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy.
    Efavirenz; Emtricitabine; Tenofovir: (Major) Avoid coadministration of efavirenz with doxorubicin due to decreased doxorubicin plasma concentrations. Efavirenz is a CYP3A4 inducer and doxorubicin is a major substrate of CYP3A4. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of efavirenz with doxorubicin due to decreased doxorubicin plasma concentrations. Efavirenz is a CYP3A4 inducer and doxorubicin is a major substrate of CYP3A4. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy.
    Elbasvir; Grazoprevir: (Moderate) Administering doxorubicin with elbasvir; grazoprevir may result in elevated doxorubicin plasma concentrations. Doxorubicin is a substrate of CYP3A and the drug transporter breast cancer resistance protein (BCRP). Elbasvir and grazoprevir are inhibitors of BCRP, and grazoprevir is also a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
    Elexacaftor; tezacaftor; ivacaftor: (Major) Ivacaftor is a mild inhibitor of CYP3A and P-glycoprotein (P-gp); doxorubicin is a major CYP3A4 and P-gp substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP3A4 and/or P-gp, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of ivacaftor and doxorubicin if possible. If avoidance is not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Eliglustat: (Major) Avoid coadministration of eliglustat with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Eliglustat is a CYP2D6 and P-glycoprotein (P-gp) inhibitor, and doxorubicin is a major substrate of CYP3A4 and P-gp. Concurrent use of CYP3A4 or P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid coadministration of cobicistat and doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Cobicistat is a strong inhibitor of CYP3A4 and an inhibitor of CYP2D6 and P-glycoprotein (P-gp); doxorubicin is a major CYP2D6, CYP3A4, and P-gp substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP2D6, CYP3A4, and/or P-gp, resulting in increased concentration and clinical effect of doxorubicin.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of cobicistat and doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Cobicistat is a strong inhibitor of CYP3A4 and an inhibitor of CYP2D6 and P-glycoprotein (P-gp); doxorubicin is a major CYP2D6, CYP3A4, and P-gp substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP2D6, CYP3A4, and/or P-gp, resulting in increased concentration and clinical effect of doxorubicin.
    Enasidenib: (Major) Avoid coadministration of enasidenib with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Enasidenib is a P-gp inhibitor and doxorubicin is a P-gp substrate. Concurrent use of P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
    Enzalutamide: (Major) Avoid coadministration of doxorubicin with enzalutamide due to decreased doxorubicin plasma concentrations. Doxorubicin is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy.
    Erythromycin: (Major) Avoid coadministration of erythromycin with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Erythromycin is a CYP3A4 and P-glycoprotein (P-gp) inhibitor; doxorubicin is a major substrate of CYP3A4 and P-gp. Concurrent use of CYP3A4 or P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
    Erythromycin; Sulfisoxazole: (Major) Avoid coadministration of erythromycin with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Erythromycin is a CYP3A4 and P-glycoprotein (P-gp) inhibitor; doxorubicin is a major substrate of CYP3A4 and P-gp. Concurrent use of CYP3A4 or P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
    Escitalopram: (Major) Avoid coadministration of escitalopram with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Escitalopram is a moderate CYP2D6 inhibitor and doxorubicin is a major substrate of CYP3D6. Concurrent use of CYP2D6 inhibitors with doxorubicin has resulted in clinically significant interactions.
    Eslicarbazepine: (Major) Eslicarbazepine is a CYP3A4 inducer and doxorubicin is a major substrate of CYP3A4. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy. Avoid coadministration of eslicarbazepine and doxorubicin if possible. If not possible, monitor doxorubicin closely for efficacy
    Estradiol; Progesterone: (Minor) Enhanced doxorubicin-induced neutropenia and thrombocytopenia may occur if coadministered with progesterone.
    Ethinyl Estradiol: (Moderate) Ethinyl Estradiol is a mild CYP3A4 inhibitor and doxorubicin is a major CYP3A4 substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP3A4, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of ethinyl estradiol and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Ethinyl Estradiol; Desogestrel: (Moderate) Ethinyl Estradiol is a mild CYP3A4 inhibitor and doxorubicin is a major CYP3A4 substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP3A4, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of ethinyl estradiol and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Ethinyl Estradiol; Ethynodiol Diacetate: (Moderate) Ethinyl Estradiol is a mild CYP3A4 inhibitor and doxorubicin is a major CYP3A4 substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP3A4, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of ethinyl estradiol and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Ethinyl Estradiol; Etonogestrel: (Moderate) Ethinyl Estradiol is a mild CYP3A4 inhibitor and doxorubicin is a major CYP3A4 substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP3A4, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of ethinyl estradiol and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Ethinyl Estradiol; Levonorgestrel: (Moderate) Ethinyl Estradiol is a mild CYP3A4 inhibitor and doxorubicin is a major CYP3A4 substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP3A4, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of ethinyl estradiol and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Ethinyl Estradiol; Levonorgestrel; Ferrous bisglycinate: (Moderate) Ethinyl Estradiol is a mild CYP3A4 inhibitor and doxorubicin is a major CYP3A4 substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP3A4, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of ethinyl estradiol and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Moderate) Ethinyl Estradiol is a mild CYP3A4 inhibitor and doxorubicin is a major CYP3A4 substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP3A4, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of ethinyl estradiol and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Ethinyl Estradiol; Norelgestromin: (Moderate) Ethinyl Estradiol is a mild CYP3A4 inhibitor and doxorubicin is a major CYP3A4 substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP3A4, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of ethinyl estradiol and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Ethinyl Estradiol; Norethindrone Acetate: (Moderate) Ethinyl Estradiol is a mild CYP3A4 inhibitor and doxorubicin is a major CYP3A4 substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP3A4, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of ethinyl estradiol and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: (Moderate) Ethinyl Estradiol is a mild CYP3A4 inhibitor and doxorubicin is a major CYP3A4 substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP3A4, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of ethinyl estradiol and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Ethinyl Estradiol; Norgestrel: (Moderate) Ethinyl Estradiol is a mild CYP3A4 inhibitor and doxorubicin is a major CYP3A4 substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP3A4, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of ethinyl estradiol and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Ethotoin: (Major) Patients receiving antineoplastic agents concurrently with hydantoins may be at risk for toxicity or loss of clinical efficacy and seizures; anticonvulsant therapy should be monitored closely during and after administration of antineoplastic agents. Phenytoin concentrations may be decreased by doxorubicin. Fosphenytoin, a prodrug of phenytoin, may also be susceptible to this interaction with doxorubicin; as well as ethotoin, another anticonvulsant hydantoin. Additionally, phenytoin and fosphenytoin are potent inducers of CYP3A4; doxorubicin is a major CYP3A4 substrate. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy. Avoid coadministration of doxorubicin with phenytoin or fosphenytoin if possible. If not possible, monitor doxorubicin closely for efficacy.
    Etravirine: (Major) Etravirine is a CYP3A4 inducer/substrate and a P-glycoprotein (P-gp) inhibitor; doxorubicin is a CYP3A4 and P-gp substrate. Inducers of CYP3A4 my decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of P-gp and/or CYP3A4, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of etravirine and doxorubicin if possible. If not possible, closely monitor for doxorubicin efficacy, as well as increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Fedratinib: (Major) Avoid coadministration of fedratinib with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Fedratinib is a moderate CYP3A4 and CYP2D6 inhibitor and doxorubicin is a major substrate of CYP3A4 and CYP2D6. Concurrent use of CYP3A4/CYP2D6 inhibitors with doxorubicin has resulted in clinically significant interactions.
    Felbamate: (Major) Felbamate is a mild CYP3A4 inhibitor and doxorubicin is a major CYP3A4 substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP3A4, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of felbamate and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Fluconazole: (Major) Avoid coadministration of fluconazole with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Fluconazole is a moderate CYP3A4 inhibitor, and doxorubicin is a major substrate of CYP3A4. Concurrent use of CYP3A4 inhibitors with doxorubicin has resulted in clinically significant interactions.
    Flutamide: (Major) In vitro, flutamide is a CYP3A4 inhibitor; doxorubicin is a major CYP3A4 substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP3A4, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of flutamide and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Fluvoxamine: (Major) Avoid coadministration of fluvoxamine with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Fluvoxamine is a CYP3A4 inhibitor, and doxorubicin is a major substrate of CYP3A4. Concurrent use of CYP3A4 inhibitors with doxorubicin has resulted in clinically significant interactions.
    Fosamprenavir: (Major) Fosamprenavir is a potent CYP3A4 inhibitor as well as a CYP3A4 inducer; doxorubicin is a major CYP3A4 substrate. Inducers of CYP3A4 my decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP3A4, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of fosamprenavir and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Fosphenytoin: (Major) Patients receiving antineoplastic agents concurrently with hydantoins may be at risk for toxicity or loss of clinical efficacy and seizures; anticonvulsant therapy should be monitored closely during and after administration of antineoplastic agents. Phenytoin concentrations may be decreased by doxorubicin. Fosphenytoin, a prodrug of phenytoin, may also be susceptible to this interaction with doxorubicin; as well as ethotoin, another anticonvulsant hydantoin. Additionally, phenytoin and fosphenytoin are potent inducers of CYP3A4; doxorubicin is a major CYP3A4 substrate. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy. Avoid coadministration of doxorubicin with phenytoin or fosphenytoin if possible. If not possible, monitor doxorubicin closely for efficacy.
    Fostamatinib: (Major) Avoid coadministration of fostamatinib and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity. Fostamatinib is a P-gp inhibitor, and the active metabolite of fostamatinib, R406, is a CYP3A4 inhibitor; doxorubicin is a major substrate of both CYP3A4 and P-gp. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP3A4 and/or P-gp, resulting in increased concentration and clinical effect of doxorubicin.
    Gadobenate Dimeglumine: (Moderate) Gadobenate dimeglumine is a substrate for the canalicular multi-specific organic anion transporter (MOAT). Use with other MOAT substrates, such as anthracyclines, may result in prolonged systemic exposure of the coadministered drug. Caution is advised if these drugs are used together.
    Ganciclovir: (Moderate) Use ganciclovir and doxorubicin together only if the potential benefits outweigh the risks; bone marrow suppression, spermatogenesis inhibition, skin toxicity, and gastrointestinal toxicity may be additive as both drugs inhibit rapidly dividing cells.
    Glecaprevir; Pibrentasvir: (Moderate) Caution is advised with the coadministration of glecaprevir and doxorubicin as coadministration may increase serum concentrations of doxorubicin and increase the risk of adverse effects. Doxorubicin is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP); glecaprevir is an inhibitor of P-gp and BCRP. (Moderate) Caution is advised with the coadministration of pibrentasvir and doxorubicin as coadministration may increase serum concentrations of doxorubicin and increase the risk of adverse effects. Doxorubicin is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP); pibrentasvir is an inhibitor of P-gp and BCRP.
    Grapefruit juice: (Major) Grapefruit juice is a potent CYP3A4 inhibitor, a moderate inhibitor of P-glycoprotein (P-gp), and an in vitro inhibitor of CYP2D6; doxorubicin is a major substrate of CYP2D6, CYP3A4, and P-gp. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP2D6, CYP3A4, and/or P-gp, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of grapefruit juice and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Hydantoins: (Major) Patients receiving antineoplastic agents concurrently with hydantoins may be at risk for toxicity or loss of clinical efficacy and seizures; anticonvulsant therapy should be monitored closely during and after administration of antineoplastic agents. Phenytoin concentrations may be decreased by doxorubicin. Fosphenytoin, a prodrug of phenytoin, may also be susceptible to this interaction with doxorubicin; as well as ethotoin, another anticonvulsant hydantoin. Additionally, phenytoin and fosphenytoin are potent inducers of CYP3A4; doxorubicin is a major CYP3A4 substrate. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy. Avoid coadministration of doxorubicin with phenytoin or fosphenytoin if possible. If not possible, monitor doxorubicin closely for efficacy.
    Idelalisib: (Major) Avoid coadministration of doxorubicin with idelalisib due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Idelalisib is a strong CYP3A4 inhibitor and doxorubicin is a major substrate of CYP3A4. Concurrent use of CYP3A4 inhibitors with doxorubicin has resulted in clinically significant interactions.
    Imatinib: (Major) Imatinib, STI-571 is an inhibitor of CYP2D6 and CYP3A4; doxorubicin is a major CYP2D6 and CYP3A4 substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP2D6 and/or CYP3A4, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of imatinib and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Indinavir: (Major) Indinavir is a potent inhibitor of CYP3A4 and in vitro, a mild CYP2D6 inhibitor; doxorubicin is a major CYP2D6 and CYP3A4 substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP2D6 and/or CYP3A4, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of indinavir and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with doxorubicin may result in increased serum concentrations of doxorubicin. Doxorubicin is a substrate of the hepatic isoenzyme CYP3A4 and drug transporter P-glycoprotein (P-gp); isavuconazole, the active moiety of isavuconazonium, is an inhibitor of CYP3A4 and P-gp. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP3A4 and/or P-gp, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of isavuconazonium and doxorubicin if possible. If avoidance is not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Isoniazid, INH: (Major) Avoid coadministration of isoniazid with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Isoniazid is a weak CYP3A4 inhibitor and doxorubicin is a major substrate of CYP3A4. Concurrent use of CYP3A4 inhibitors with doxorubicin has resulted in clinically significant interactions.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid coadministration of isoniazid with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Isoniazid is a weak CYP3A4 inhibitor and doxorubicin is a major substrate of CYP3A4. Concurrent use of CYP3A4 inhibitors with doxorubicin has resulted in clinically significant interactions. (Major) Rifampin is a potent CYP3A4 inducer, a moderate inducer of P-glycoprotein (P-gp), and a mild inducer of CYP2D6. Doxorubicin is a major substrate of CYP3A4, P-gp, and CYP2D6. Inducers of CYP3A4, CYP2D6, and/or P-gp may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy. Avoid coadministration of rifampin and doxorubicin if possible. If not possible, monitor doxorubicin closely for efficacy.
    Isoniazid, INH; Rifampin: (Major) Avoid coadministration of isoniazid with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Isoniazid is a weak CYP3A4 inhibitor and doxorubicin is a major substrate of CYP3A4. Concurrent use of CYP3A4 inhibitors with doxorubicin has resulted in clinically significant interactions. (Major) Rifampin is a potent CYP3A4 inducer, a moderate inducer of P-glycoprotein (P-gp), and a mild inducer of CYP2D6. Doxorubicin is a major substrate of CYP3A4, P-gp, and CYP2D6. Inducers of CYP3A4, CYP2D6, and/or P-gp may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy. Avoid coadministration of rifampin and doxorubicin if possible. If not possible, monitor doxorubicin closely for efficacy.
    Istradefylline: (Major) Avoid coadministration of istradefylline with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Istradefylline is a P-gp inhibitor and doxorubicin is a P-gp substrate. Concurrent use of P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
    Itraconazole: (Major) Avoid coadministration of itraconazole with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Itraconazole is a strong CYP3A4 inhibitor and an inhibitor of P-glycoprotein (P-gp). Doxorubicin is a major substrate of CYP3A4 and P-gp. Concurrent use of CYP3A4 or P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
    Ivacaftor: (Major) Ivacaftor is a mild inhibitor of CYP3A and P-glycoprotein (P-gp); doxorubicin is a major CYP3A4 and P-gp substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP3A4 and/or P-gp, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of ivacaftor and doxorubicin if possible. If avoidance is not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Ixabepilone: (Minor) Ixabepilone is a weak inhibitor of P-glycoprotein (Pgp). Doxorubicin is a Pgp substrate, and concomitant use of ixabepilone with a Pgp substrate may cause an increase in doxorubicin concentrations. Use caution if ixabepilone is coadministered with a Pgp substrate.
    Ketoconazole: (Major) Avoid coadministration of ketoconazole with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Ketoconazole is a potent CYP3A4 inhibitor, and a P-glycoprotein (P-gp) inhibitor; doxorubicin is a major substrate of CYP3A4 and P-gp. Concurrent use of CYP3A4 or P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
    Lamivudine, 3TC; Zidovudine, ZDV: (Major) Avoid concomitant administration of zidovudine, ZDV, and doxorubicin as an antagonistic relationship has been demonstrated in vitro.
    Lapatinib: (Major) Avoid coadministration of lapatinib with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Lapatinib is a CYP3A4 and P-glycoprotein (P-gp) inhibitor; doxorubicin is a major substrate of CYP3A4 and P-gp. Concurrent use of CYP3A4 or P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
    Larotrectinib: (Major) Avoid coadministration of larotrectinib with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Larotrectinib is a weak CYP3A4 inhibitor and doxorubicin is a major substrate of CYP3A4. Concurrent use of CYP3A4 inhibitors with doxorubicin has resulted in clinically significant interactions.
    Ledipasvir; Sofosbuvir: (Moderate) Ledipsavir is a P-glycoprotein (P-gp) inhibitor and doxorubicin is a major P-gp substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of P-gp, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of ledipsavir and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Lefamulin: (Major) Avoid coadministration of oral lefamulin with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Doxorubicin is a major substrate of CYP3A4 and oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin. Concurrent use of CYP3A4 inhibitors with doxorubicin has resulted in clinically significant interactions.
    Letermovir: (Major) Avoid use of letermovir with doxorubicin, as concurrent use may increase doxorubicin concentration and risk for adverse events. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine. Doxorubicin is a substrate of CYP3A4. Letermovir is a moderate CYP3A4 inhibitor. The combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
    Lonafarnib: (Major) Avoid coadministration of doxorubicin with lonafarnib due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Doxorubicin is a CYP3A4 and P-gp substrate; lonafarnib is a P-gp and strong CYP3A4 inhibitor. Concurrent use of CYP3A4 and P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
    Lopinavir; Ritonavir: (Major) Avoid coadministration of ritonavir with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Ritonavir is a strong CYP3A4 inhibitor and a P-gp inhibitor; doxorubicin is a CYP3A4 and P-gp substrate. Concurrent use of CYP3A4 and/or P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
    Lorcaserin: (Major) Lorcaserin is a mild CYP2D6 inhibitor and doxorubicin is a major CYP2D6 substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP2D6, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of locaserin and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Lorlatinib: (Major) Avoid coadministration of doxorubicin with lorlatinib due to decreased doxorubicin plasma concentrations. Doxorubicin is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy.
    Lumacaftor; Ivacaftor: (Major) Concomitant administration of doxorubicin and lumacaftor; ivacaftor may alter the exposure of doxorubicin; avoid concurrent use. Doxorubicin is a major substrate of CYP3A4 and P-glycoprotein (P-gp). Lumacaftor is a strong CYP3A inducer; in vitro data also suggest lumacaftor; ivacaftor may induce and/or inhibit P-gp.
    Lumacaftor; Ivacaftor: (Major) Ivacaftor is a mild inhibitor of CYP3A and P-glycoprotein (P-gp); doxorubicin is a major CYP3A4 and P-gp substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP3A4 and/or P-gp, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of ivacaftor and doxorubicin if possible. If avoidance is not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Margetuximab: (Major) Avoid administration of anthracyclines during margetuximab therapy and for up to 4 months after the last dose of margetuximab due to the risk of increased cardiac dysfunction. If concomitant use is unavoidable, closely monitor cardiac function. This interaction has not been studied with margetuximab; however, clinical data from other HER2-directed antibodies warrants consideration.
    Mephobarbital: (Major) Barbiturates induce CYP3A4 and doxorubicin is a major substrate of CYP3A4. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy. Avoid coadministration of barbiturates and doxorubicin if possible. If not possible, monitor doxorubicin closely for efficacy.
    Mercaptopurine, 6-MP: (Moderate) Use mercaptopurine and doxorubicin together with caution; doxorubicin may potentiate mercaptopurine-induced hepatotoxicity. If these drugs are used together, monitor patients for signs and symptoms of hepatic dysfunction. Additionally, a mercaptopurine dosage reduction may be required when it is used in combination with other myelosuppressive agents such as doxorubicin. Hepatic dysfunction (i.e., hyperbilirubinemia, elevated AST and alkaline phosphatase levels) occurred in all 11 patients with refractory leukemia who received mercaptopurine (500 mg/m2 IV daily for 5 days) and doxorubicin (50 mg/m2 IV) repeated every 2 to 3 weeks; some patients also received vincristine and prednisone. Hepatotoxicity was observed in 19 of 20 patients who received mercaptopurine and doxorubicin as induction therapy for resistant leukemia in another report.
    Methohexital: (Major) Barbiturates induce CYP3A4 and doxorubicin is a major substrate of CYP3A4. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy. Avoid coadministration of barbiturates and doxorubicin if possible. If not possible, monitor doxorubicin closely for efficacy.
    Mifepristone: (Moderate) Avoid coadministration of mifepristone and doxorubicin if possible. Mifepristone is an inhibitor of CYP3A4 and may also inhibit P-glycoprotein (P-gp); doxorubicin is a major substrate of both P-gp and CYP3A4. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP3A4 and/or P-gp, resulting in increased concentration and clinical effect of doxorubicin. When mifepristone is used chronically for hormonal conditions, as in the treatment of Cushing's disease, increased concentrations of CYP3A substrates are expected, and any drug interactions that do occur may be prolonged due to mifepristone's long duration of action. If not possible to avoid use of these drugs together, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Mirabegron: (Major) Mirabegron is a moderate CYP2D6 inhibitor; doxorubicin is a substrate of both CYP2D6 and CYP3A4. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP2D6, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of mirabegron and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Mitotane: (Major) Concomitant use of mitotane with doxorubicin should be undertaken with caution as it could result in decreased plasma concentrations of doxorubicin, leading to reduced efficacy. Mitotane is a strong CYP3A4 inducer and doxorubicin is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of doxorubicin.
    Modafinil: (Major) Modafinil is a CYP3A4 inducer and doxorubicin is a major substrate of CYP3A4. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy. Avoid coadministration of modafinil and doxorubicin if possible. If not possible, monitor doxorubicin closely for efficacy.
    Mycophenolate: (Major) Concurrent use of doxorubicin with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
    Nafcillin: (Major) In vitro, nafcillin is a CYP3A4 inducer; doxorubicin is a major substrate of CYP3A4. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy. Avoid coadministration of nafcillin and doxorubicin if possible. If not possible, monitor doxorubicin closely for efficacy.
    Nefazodone: (Major) Nefazodone is a potent CYP3A4 inhibitor and doxorubicin is a major substrate of CYP3A4. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP3A4, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of nefazodone and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Nelfinavir: (Major) Nelfinavir is a potent CYP3A4 inhibitor and a moderate inhibitor of P-glycoprotein (P-gp); doxorubicin is a major substrate of both CYP3A4 and P-gp. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP3A4 and/or P-gp, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of nelfinavir and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Neratinib: (Major) Avoid coadministration of neratinib with doxorubicin due to the risk for increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Neratinib is a P-glycoprotein (P-gp) inhibitor and doxorubicin is a P-gp substrate. Concurrent use of P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
    Nevirapine: (Major) Nevirapine is a CYP3A4 inducer and doxorubicin is a major substrate of CYP3A4. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy. Avoid coadministration of nevirapine and doxorubicin if possible. If not possible, monitor doxorubicin closely for efficacy.
    Nicardipine: (Major) Avoid coadministration of nicardipine and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity. Nicardipine is a CYP2D6 and CYP3A4 inhibitor; doxorubicin is a major substrate of CYP2D6 and CYP3A4. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP2D6 and CYP3A4, resulting in increased concentration and clinical effect of doxorubicin.
    Nicotine: (Major) Nicotine is a mild CYP2D6 inducer and doxorubicin is a major substrate of CYP2D6. Inducers of CYP2D6 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy. Avoid coadministration of nicotine and doxorubicin if possible. If not possible, monitor doxorubicin closely for efficacy.
    Nilotinib: (Major) Avoid coadministration of nilotinib with doxorubicin due to the risk of increased doxorubicin exposure. Nilotinib is a moderate CYP3A4 inhibitor and doxorubicin is a major substrate of CYP3A4; clinically significant interactions have been reported with other CYP3A4 inhibitors, resulting in increased concentration and clinical effect of doxorubicin.
    Norethindrone; Ethinyl Estradiol: (Moderate) Ethinyl Estradiol is a mild CYP3A4 inhibitor and doxorubicin is a major CYP3A4 substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP3A4, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of ethinyl estradiol and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Moderate) Ethinyl Estradiol is a mild CYP3A4 inhibitor and doxorubicin is a major CYP3A4 substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP3A4, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of ethinyl estradiol and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Norgestimate; Ethinyl Estradiol: (Moderate) Ethinyl Estradiol is a mild CYP3A4 inhibitor and doxorubicin is a major CYP3A4 substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP3A4, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of ethinyl estradiol and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid coadministration of ritonavir with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Ritonavir is a strong CYP3A4 inhibitor and a P-gp inhibitor; doxorubicin is a CYP3A4 and P-gp substrate. Concurrent use of CYP3A4 and/or P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
    Omeprazole; Amoxicillin; Rifabutin: (Major) Rifabutin is a CYP3A4 inducer and doxorubicin is a major substrate of CYP3A4. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy. Avoid coadministration of rifabutin and doxorubicin if possible. If not possible, monitor doxorubicin closely for efficacy.
    Oritavancin: (Major) Doxorubicin is metabolized by CYP3A4 and CYP2D6; oritavancin is a weak CYP3A4 and CYP2D6 inducer. Inducers of CYP2D6 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy. Avoid coadministration of oritavancin and doxorubicin if possible. If not possible, monitor the patient for signs of lack of efficacy.
    Osimertinib: (Major) Avoid coadministration of osimertinib with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Osimertinib is a P-gp inhibitor and doxorubicin is a P-gp substrate. Concurrent use of P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
    Oxcarbazepine: (Major) Oxcarbazepine is a CYP3A4 inducer and doxorubicin is a major substrate of CYP3A4. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy. Avoid coadministration of oxcarbazepine and doxorubicin if possible. If not possible, monitor doxorubicin closely for efficacy.
    Paclitaxel: (Moderate) Use paclitaxel and doxorubicin together with caution. Administer doxorubicin prior to paclitaxel; the AUC values of doxorubicin and its metabolites may increase if paclitaxel is given first. Paclitaxel and doxorubicin are both CYP3A4 substrates.
    Palbociclib: (Major) Avoid coadministration of palbociclib with doxorubicin due to the risk of increased doxorubicin exposure. Palbociclib is a weak time-dependent inhibitor of CYP3A. Doxorubicin is a major substrate of CYP3A4; clinically significant interactions have been reported with other CYP3A4 inhibitors, resulting in increased concentration and clinical effect of doxorubicin.
    Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
    Paroxetine: (Major) Avoid coadministration of paroxetine with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Paroxetine is a strong CYP2D6 inhibitor and doxorubicin is a major substrate of CYP3D6. Concurrent use of CYP2D6 inhibitors with doxorubicin has resulted in clinically significant interaction
    Pazopanib: (Major) Avoid coadministration of pazopanib with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Pazopanib is a CYP2D6 and CYP3A4 inhibitor; doxorubicin is a major substrate of CYP2D6 and CYP3A4. Concurrent use of CYP2D6 or CYP3A4 inhibitors with doxorubicin has resulted in clinically significant interactions.
    Peginterferon Alfa-2b: (Major) Monitor for adverse effects associated with increased exposure to doxorubicin if peginterferon alfa-2b is coadministered. Peginterferon alfa-2b is a CYP2D6 inhibitor, while doxorubicin is a CYP2D6 substrate.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Pentobarbital: (Major) Barbiturates induce CYP3A4 and doxorubicin is a major substrate of CYP3A4. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy. Avoid coadministration of barbiturates and doxorubicin if possible. If not possible, monitor doxorubicin closely for efficacy.
    Perampanel: (Major) In vitro, perampanel is a mild CYP3A4 inhibitor; doxorubicin is a major substrate of CYP3A4. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP3A4, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of perampanel and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Pertuzumab; Trastuzumab; Hyaluronidase: (Major) Avoid coadministration of anthracyclines and trastuzumab products due to the risk of increased cardiac dysfunction; if possible, continue to avoid for up to 7 months after the last dose of trastuzumab. If concomitant use is unavoidable, carefully monitor cardiac function. Anthracycline treatment after therapy with trastuzumab product may increase the risk of cardiac dysfunction due to the long washout period of trastuzumab.
    Pexidartinib: (Major) Avoid coadministration of doxorubicin with pexidartinib due to decreased doxorubicin plasma concentrations. Doxorubicin is a CYP3A4 substrate and pexidartinib is a moderate CYP3A4 inducer. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy.
    Phenobarbital: (Major) Phenobarbital is a potent inducer of CYP3A4 and P-glycoprotein (P-gp); doxorubicin is a major CYP3A4 and P-gp substrate. Primidone and mephobarbital, both metabolized to phenobartital, are also potent CYP3A4 inducers. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy. Avoid coadministration of doxorubicin with phenobarbital, primidone, and mephobarbital if possible. If not possible, monitor doxorubicin closely for efficacy.
    Phentermine; Topiramate: (Major) Topiramate is a mild CYP3A4 inducer; doxorubicin is a major substrate of CYP3A4. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy. Avoid coadministration of topiramate and doxorubicin if possible. If not possible, monitor doxorubicin closely for efficacy.
    Phenytoin: (Major) Patients receiving antineoplastic agents concurrently with hydantoins may be at risk for toxicity or loss of clinical efficacy and seizures; anticonvulsant therapy should be monitored closely during and after administration of antineoplastic agents. Phenytoin concentrations may be decreased by doxorubicin. Fosphenytoin, a prodrug of phenytoin, may also be susceptible to this interaction with doxorubicin; as well as ethotoin, another anticonvulsant hydantoin. Additionally, phenytoin and fosphenytoin are potent inducers of CYP3A4; doxorubicin is a major CYP3A4 substrate. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy. Avoid coadministration of doxorubicin with phenytoin or fosphenytoin if possible. If not possible, monitor doxorubicin closely for efficacy.
    Posaconazole: (Major) Avoid coadministration of posaconazole with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Posaconazole is a strong CYP3A4 inhibitor and P-glycoprotein (P-gp) inhibitor; doxorubicin is a major substrate of CYP3A4 and P-gp. Concurrent use of CYPsA4 or P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
    Primidone: (Major) Phenobarbital is a potent inducer of CYP3A4 and P-glycoprotein (P-gp); doxorubicin is a major CYP3A4 and P-gp substrate. Primidone and mephobarbital, both metabolized to phenobartital, are also potent CYP3A4 inducers. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy. Avoid coadministration of doxorubicin with phenobarbital, primidone, and mephobarbital if possible. If not possible, monitor doxorubicin closely for efficacy.
    Progesterone: (Minor) Enhanced doxorubicin-induced neutropenia and thrombocytopenia may occur if coadministered with progesterone.
    Propafenone: (Major) Avoid coadministration of propafenone with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Propafenone is a CYP2D6 and P-gp inhibitor and doxorubicin is a CYP2D6 and P-gp substrate. Concurrent use of CYP2D6 and/or P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
    Quinidine: (Major) Avoid coadministration of quinidine with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Quinidine is a potent CYP2D6 inhibitor and P-glycoprotein (P-gp) inhibitor; doxorubicin is a major substrate of CYP2D6 and P-gp. Concurrent use of CYP2D6 or P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
    Quinine: (Major) Avoid coadministration of quinine with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Quinine is a CYP3A4, CYP2D6, and P-glycoprotein (P-gp) inhibitor; doxorubicin is a major substrate of CYP3A4, CYP2D6, and P-gp. Concurrent use of CYP3A4, CYP2D6, or P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
    Ranolazine: (Major) Avoid coadministration of ranolazine with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Ranolazine is a CYP3A4, CYP2D6, and P-glycoprotein (P-gp) inhibitor; doxorubicin is a major substrate of CYP3A4, CYP2D6, and P-gp. Concurrent use of CYP3A4, CYP2D6, or P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
    Ribociclib: (Major) Avoid coadministration of ribociclib with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Ribociclib is a strong CYP3A4 inhibitor and doxorubicin is a major substrate of CYP3A4. Concurrent use of CYP3A4 inhibitors with doxorubicin has resulted in clinically significant interactions.
    Ribociclib; Letrozole: (Major) Avoid coadministration of ribociclib with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Ribociclib is a strong CYP3A4 inhibitor and doxorubicin is a major substrate of CYP3A4. Concurrent use of CYP3A4 inhibitors with doxorubicin has resulted in clinically significant interactions.
    Rifabutin: (Major) Rifabutin is a CYP3A4 inducer and doxorubicin is a major substrate of CYP3A4. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy. Avoid coadministration of rifabutin and doxorubicin if possible. If not possible, monitor doxorubicin closely for efficacy.
    Rifampin: (Major) Rifampin is a potent CYP3A4 inducer, a moderate inducer of P-glycoprotein (P-gp), and a mild inducer of CYP2D6. Doxorubicin is a major substrate of CYP3A4, P-gp, and CYP2D6. Inducers of CYP3A4, CYP2D6, and/or P-gp may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy. Avoid coadministration of rifampin and doxorubicin if possible. If not possible, monitor doxorubicin closely for efficacy.
    Rifapentine: (Major) Avoid coadministration of doxorubicin with rifapentine due to decreased doxorubicin plasma concentrations. Doxorubicin is a CYP3A4 substrate and rifapentine is a strong CYP3A4 inducer. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy.
    Rifaximin: (Major) Avoid coadministration of rifaximin and doxorubicin if possible. If not possible, monitor doxorubicin closely for increased side effects including myelosuppression and cardiotoxicity. Oral rifaximin is largely unabsorbed and should not result in drug interactions. In vitro, rifaximin is a mild inhibitor of P-glycoprotein (P-gp). Doxorubicin is a major substrate of P-gp. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of P-gp, resulting in increased concentration and clinical effect of doxorubicin.
    Ritonavir: (Major) Avoid coadministration of ritonavir with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Ritonavir is a strong CYP3A4 inhibitor and a P-gp inhibitor; doxorubicin is a CYP3A4 and P-gp substrate. Concurrent use of CYP3A4 and/or P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
    Rolapitant: (Major) Avoid coadministration of doxorubicin and rolapitant because it can result in doxorubicin-related adverse effects, including cardiac effects. Doxorubicin is a major substrate of CYP2D6, and is also metabolized via P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP); rolapitant inhibits CYP2D6, P-gp, and BCRP. The inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured. The Cmax and AUC of another BCRP substrate were increased by 140% and 130%, respectively, on day 1 and 17% and 32%, respectively, on day 8 after rolapitant administration. When rolapitant was administered with another P-gp substrate, the day 1 Cmax and AUC were increased by 70% and 30%, respectively; the Cmax and AUC on day 8 were not studied. Of note, in a multicenter, randomized, double-blind, placebo-controlled clinical trial showing efficacy of rolapitant in patients treated with moderately emetogenic chemotherapy (n = 1369), at least 50% of patients received a combination of anthracycline and cyclophosphamide. In a similarly designed study of patients receiving highly emetogenic chemotherapy (n = 532), 6% received doxorubicin. Non-gastrointestinal adverse effects are not reported by the manufacturer; however, an increased incidence of hematologic toxicity is possible, as well as an unknown impact on short- and long-term cardiotoxicity.
    Rucaparib: (Major) Avoid coadministration of rucaparib with doxorubicin due to the risk of increased doxorubicin exposure. Rucaparib is a CYP3A4 inhibitor and doxorubicin is a major substrate of CYP3A4; clinically significant interactions have been reported with other CYP3A4 inhibitors, resulting in increased concentration and clinical effect of doxorubicin.
    Saquinavir: (Major) Avoid coadministration of saquinavir with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Saquinavir is a strong CYP3A4 inhibitor and a P-glycoprotein (P-gp) inhibitor; doxorubicin is a major substrate of CYP3A4 and P-gp. Concurrent use of CYP3A4 inhibitors or P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
    Sarecycline: (Major) Avoid coadministration of sarecycline with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Doxorubicin is a substrate of P-glycoprotein (P-gp); sarecycline is a P-gp inhibitor. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of P-gp, resulting in increased concentration and clinical effects of doxorubicin.
    SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
    Secobarbital: (Major) Barbiturates induce CYP3A4 and doxorubicin is a major substrate of CYP3A4. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy. Avoid coadministration of barbiturates and doxorubicin if possible. If not possible, monitor doxorubicin closely for efficacy.
    Segesterone Acetate; Ethinyl Estradiol: (Moderate) Ethinyl Estradiol is a mild CYP3A4 inhibitor and doxorubicin is a major CYP3A4 substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP3A4, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of ethinyl estradiol and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Simeprevir: (Major) Simeprevir, a breast cancer resistance protein (BCRP) inhibitor, P-glycoprotein inhibitor (P-gp), and a mild intestinal CYP3A4 inhibitor, may increase the side effects of doxorubicin, which is a BCRP, P-gp and CYP3A4 substrate. Avoid coadministration of simeprevir and doxorubicin if possible. If avoidance is not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Sirolimus: (Major) Concurrent use of doxorubicin with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Major) Avoid concurrent administration of voxilaprevir with doxorubicin. Taking these medications together may increase doxorubicin plasma concentrations, potentially increasing the risk for adverse events. Doxorubicin is a substrate for the drug transporters P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP). Voxilaprevir is a P-gp and BCRP inhibitor.
    Sorafenib: (Major) Avoid coadministration of sorafenib with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Sorafenib is a P-glycoprotein (P-gp) inhibitor; doxorubicin is a major substrate of P-gp. Concurrent use of P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
    Sotorasib: (Major) Avoid coadministration of doxorubicin with sotorasib due to altered doxorubicin plasma concentrations, which may lead to increased toxicity or decreased efficacy. Doxorubicin is a CYP3A4 and P-gp substrate; sotorasib is a moderate CYP3A4 inducer and P-gp inhibitor. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy.
    St. John's Wort, Hypericum perforatum: (Major) St. John's Wort, Hypericum perforatum, is a potent inducer of CYP3A4 and a moderate P-glycoprotein (P-gp) inducer; doxorubicin is a major substrate of both CYP3A4 and P-gp. Inducers of CYP3A4 and/or P-gp may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy. Avoid coadministration of St. John's Wort and doxorubicin if possible. If not possible, monitor doxorubicin closely for efficacy.
    Stavudine, d4T: (Moderate) It appears that doxorubicin inhibits the phosphorylation of stavudine in vitro. The clinical significance of this in vitro data is unknown and, therefore, concomitant use of stavudine and doxorubicin should be undertaken with caution.
    Streptogramins: (Major) Avoid coadministration of dalfopristin; quinupristin with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Dalfopristin; quinupristin is a weak CYP3A4 inhibitor and doxorubicin is a major substrate of CYP3A4. Concurrent use of CYP3A4 inhibitors with doxorubicin has resulted in clinically significant interactions.
    Streptozocin: (Moderate) Streptozocin reduces doxorubicin's clearance possibly through inhibition of hepatic metabolism of doxorubicin. Enhanced toxicity can be seen.
    Telaprevir: (Major) Avoid coadministration of telaprevir and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity. Telaprevir is a potent CYP3A4 inhibitor and a mild inhibitor of P-glycoprotein; doxorubicin is a major substrate of both CYP3A4 and P-gp. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP3A4 and/or P-gp, resulting in increased concentration and clinical effect of doxorubicin.
    Telithromycin: (Major) Avoid coadministration of telithromycin with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Telithromycin is a strong CYP3A4 inhibitor and P-glycoprotein (P-gp) inhibitor; doxorubicin is a major substrate of CYP3A4 and P-gp. Concurrent use of CYP3A4 or P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
    Temsirolimus: (Major) Avoid coadministration of doxorubicin with temsirolimus due to the potential for increased doxorubicin exposure. Doxorubicin is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Clinically significant interactions have been reported with inhibitors of P-gp, resulting in increased concentration and clinical effect of doxorubicin.
    Tepotinib: (Major) Avoid coadministration of tepotinib with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Doxorubicin is a P-gp substrate and tepotinib is a P-gp inhibitor. Concurrent use of P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
    Tezacaftor; Ivacaftor: (Major) Ivacaftor is a mild inhibitor of CYP3A and P-glycoprotein (P-gp); doxorubicin is a major CYP3A4 and P-gp substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP3A4 and/or P-gp, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of ivacaftor and doxorubicin if possible. If avoidance is not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Thiopental: (Major) Barbiturates induce CYP3A4 and doxorubicin is a major substrate of CYP3A4. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy. Avoid coadministration of barbiturates and doxorubicin if possible. If not possible, monitor doxorubicin closely for efficacy.
    Thioridazine: (Major) Avoid coadministration of thioridazine with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Thioridazine is a CYP2D6 inhibitor and doxorubicin is a major substrate of CYP2D6. Concurrent use of CYP2D6 inhibitors with doxorubicin has resulted in clinically significant interactions.
    Thiothixene: (Major) In vitro, thiothixene is a mild CYP2D6 inhibitor; doxorubicin is a major substrate of CYP2D6. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP2D6, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of thiothixene and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Tipranavir: (Major) Tipranavir is a potent CYP2D6 and CYP3A4 inhibitor; it is also a potent inducer of P-glycoprotein (P-gp). Doxorubicin is a major substrate of CYP2D6, CYP3A4 and P-gp. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP3A4 and/or CYP2D6, resulting in increased concentration and clinical effect of doxorubicin. Inducers of P-gp may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy. Avoid coadministration of tipranavir and doxorubicin if possible. If not possible, closely monitor for doxorubicin efficacy and increased side effects of doxorubicin, including myelosuppression and cardiotoxicity.
    Topiramate: (Major) Topiramate is a mild CYP3A4 inducer; doxorubicin is a major substrate of CYP3A4. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy. Avoid coadministration of topiramate and doxorubicin if possible. If not possible, monitor doxorubicin closely for efficacy.
    Trandolapril; Verapamil: (Major) Avoid the concomitant use of doxorubicin and verapamil; use of these drugs together may increase doxorubicin concentrations and increase the risk of doxorubicin-induced toxicity. Doxorubicin is a substrate of CYP3A4 and P-glycoprotein (P-gp); verapamil is a substrate and inhibitor of CYP3A4 and P-gp.
    Trastuzumab: (Major) Avoid coadministration of anthracyclines and trastuzumab products due to the risk of increased cardiac dysfunction; if possible, continue to avoid for up to 7 months after the last dose of trastuzumab. If concomitant use is unavoidable, carefully monitor cardiac function. Anthracycline treatment after therapy with trastuzumab product may increase the risk of cardiac dysfunction due to the long washout period of trastuzumab.
    Trastuzumab; Hyaluronidase: (Major) Avoid coadministration of anthracyclines and trastuzumab products due to the risk of increased cardiac dysfunction; if possible, continue to avoid for up to 7 months after the last dose of trastuzumab. If concomitant use is unavoidable, carefully monitor cardiac function. Anthracycline treatment after therapy with trastuzumab product may increase the risk of cardiac dysfunction due to the long washout period of trastuzumab.
    Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
    Tucatinib: (Major) Avoid coadministration of doxorubicin with tucatinib due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Doxorubicin is a CYP3A4 and P-glycoprotein (P-gp) substrate; tucatinib is a strong CYP3A4 inhibitor and P-gp inhibitor. Concurrent use of CYP3A4 inhibitors with doxorubicin has resulted in clinically significant interactions.
    Valganciclovir: (Moderate) Use valganciclovir and doxorubicin together only if the potential benefits outweigh the risks; bone marrow suppression, spermatogenesis inhibition, skin toxicity, and gastrointestinal toxicity may be additive as both drugs inhibit rapidly dividing cells.
    Valproic Acid, Divalproex Sodium: (Major) In vitro, valproic acid, divalproex soidum is a mild CYP3A4 and P-glycoprotein (P-gp) inducer; it is also a mild CYP3A4 inhibitor. Doxorubicin is a major substrate of CYP2D6, CYP3A4 and P-gp. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP3A4, resulting in increased concentration and clinical effect of doxorubicin. Inducers of CYP3A4 and/or P-gp may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy. Avoid coadministration of valproic acid and doxorubicin if possible. If not possible, closely monitor for doxorubicin efficacy and increased side effects of doxorubicin, including myelosuppression and cardiotoxicity.
    Vemurafenib: (Major) Avoid coadministration of vemurafenib with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Vemurafenib is a P-glycoprotein (P-gp) inhibitor, and doxorubicin is a major substrate of P-gp. Concurrent use of P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
    Verapamil: (Major) Avoid the concomitant use of doxorubicin and verapamil; use of these drugs together may increase doxorubicin concentrations and increase the risk of doxorubicin-induced toxicity. Doxorubicin is a substrate of CYP3A4 and P-glycoprotein (P-gp); verapamil is a substrate and inhibitor of CYP3A4 and P-gp.
    Voclosporin: (Major) Avoid coadministration of voclosporin with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Doxorubicin is a P-gp substrate and voclosporin is a P-gp inhibitor. Concurrent use of P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
    Voriconazole: (Major) Avoid coadministration of voriconazole with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. voriconazole is a strong CYP3A4 inhibitor and doxorubicin is a major substrate of CYP3A4. Concurrent use of CYP3A4 inhibitors with doxorubicin has resulted in clinically significant interactions.
    Zafirlukast: (Major) In vitro, zafirlukast is a CYP3A4 inhibitor; doxorubicin is a major substrate of CYP3A4. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP3A4, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of zafirlukast and doxorubicin if possible. If not possible, closely monitor increased side effects of doxorubicin, including myelosuppression and cardiotoxicity.
    Zalcitabine, ddC: (Moderate) Doxorubicin caused a decrease in zalcitabine, ddC phosphorylation, with a > 50% inhibition of total phosphate formation in vitro. Although there may be decreased zalcitabine activity because of lessened active metabolite formation, the clinical significance of this interaction is unknown.
    Zidovudine, ZDV: (Major) Avoid concomitant administration of zidovudine, ZDV, and doxorubicin as an antagonistic relationship has been demonstrated in vitro.
    Zonisamide: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and doxorubicin is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.

    PREGNANCY AND LACTATION

    Pregnancy

    Doxorubicin is pregnancy category D. It may cause fetal harm when administered to a pregnant woman. Females of reproductive potential should avoid pregnancy during doxorubicin therapy. Apprise the patient of the potential hazard to a fetus if doxorubicin is used during pregnancy or if the patient becomes pregnant while taking doxorubicin. In animal studies in rats and rabbits, doxorubicin was teratogenic (e.g., esophageal and intestinal atresia, tracheo-esophageal fistula, hypoplasia of the urinary bladder, and cardiovascular anomalies) and embryotoxic at doses approximately 0.07-times (based on body surface area) the recommended human dose of 60 mg/m2.

    Doxorubicin has been detected in breast milk and should not be administered in breast-feeding women. Peak milk concentrations in 1 patient were approximately 4.4-times greater than plasma concentrations 24 hours after treatment. Doxorubicin was detectable in breast milk up to 72 hours after therapy. Due to the potential for serious adverse reactions in nursing infants from doxorubicin, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

    MECHANISM OF ACTION

    Doxorubicin is a cytotoxic anthracycline antibiotic derived from Streptomyces peucetius. It prevents the replication of rapidly growing cells by intercalating between base pairs of the DNA/RNA strand and inhibiting DNA and RNA synthesis. Doxorubicin is also a topoisomerase II inhibitor that works by stabilizing the covalently bound form of the topoisomerase II enzyme with DNA causing increased topoisomerase II cross-linked DNA strand breaks. Several mechanisms of doxorubicin-induced cardiotoxicity have been proposed including iron-catalyzed induction of cardiac oxidative stress, altered calcium homeostasis, impaired gene expression of cardiac proteins, dysregulation of protein degradation by the ubiquitin–proteasome system, induction of mitochondrial DNA lesions, and interference with topoisomerase II. Doxorubicin undergoes one-electron reduction to form oxygen free radical intermediates. In the presence of oxygen and metal catalysts such as iron (Fe2+), doxorubicin undergoes reduction to the semiquone radical. In the presence of oxygen, the semiquone radical can form a superperoxide that in the presence of hydrogen peroxide forms hydroxyl radicals. Mitochondria appear to be an important target for anthracycline-induced cardiotoxicity; anthracyclines are found in high concentrations in the mitochondrial compartment. Doxorubicin binds with high-affinity to cardiolipin, a major phospholipid component of heart mitochondrial inner membranes.

    PHARMACOKINETICS

    Doxorubicin is administered intravenously (IV). Doxorubicin and its major metabolite, doxorubicinol, are approximately 75% bound to plasma proteins; binding is independent of plasma concentration up to 1.1 mcg/mL. It does not cross the blood brain barrier. In pharmacokinetic analyses of doxorubicin, the steady-state volume of distribution was 809 to 1,214 L/m2, the plasma clearance was 324 to 809 mL/min/m2, and the terminal half-life was 20 to 48 hours. Doxorubicin is primarily excreted in the bile. Following a doxorubicin IV dose, about 40% of the dose is found in the bile and 5% to 12% of the parent drug and its metabolites appear in the urine within 5 days. Less than 3% of the dose is recovered as doxorubicinol in the urine within 7 days. The AUC ratio between doxorubicinol and doxorubicin is about 0.5.
     
    Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: CYP2D6, CYP3A4, P-gp
    Doxorubicin is metabolized via CYP3A4 and CYP2D6; it is also a P-glycoprotein (P-gp) substrate. Avoid concomitant use with CYP3A4, CYP2D6, or P-gp inhibitors and inducers.

    Intravenous Route

    In cancer patients, doxorubicin exhibits multiphasic disposition after an IV injection. It had dose independent pharmacokinetics in 4 patients receiving doxorubicin 30 to 70 mg/m2.