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  • CLASSES

    Anthracyclines

    BOXED WARNING

    Infusion-related reactions

    Infusion-related reactions have been reported with liposomal doxorubicin; some cases were life-threatening or fatal. These reactions typically occur during the first infusion. Medications to treat infusion-related reactions and cardiopulmonary resuscitative equipment should be available for immediate use prior to starting the liposomal doxorubicin infusion. Monitor patients for symptoms of infusion-related reactions (e.g., flushing, shortness of breath, facial swelling, headache, chills, chest pain, back pain, tightness in the chest and throat, fever, tachycardia, pruritus, rash, cyanosis, syncope, bronchospasm, asthma, apnea, and hypotension). Hold the liposomal doxorubicin infusion in patients who develop grade 1, 2, or 3 infusion-related reactions and resume at a reduced rate; discontinue therapy in patients who have grade 4 or a life-threatening reaction.[29359]

    Cardiac disease, cardiomyopathy, cardiotoxicity, radiation therapy

    Cardiotoxicity (e.g., congestive heart failure, acute left ventricular failure) has been reported with the use of liposomal doxorubicin. Monitor cardiac function (e.g., echocardiograms, multigated radionuclide (MUGA) scans) before initiation of therapy, during treatment, and after completion of therapy. The risk of cardiomyopathy may be higher in patients with cumulative anthracycline exposure (450 to 550 mg/m2), prior radiation therapy to the mediastinum, or treatment with concomitant use of other cardiotoxic agents. Other anthracycline and anthracenedione use should be included in the calculation of the cumulative anthracycline dose. Perform a risk/benefit analysis before administering liposomal doxorubicin in patients with a history of cardiac disease.[29359]

    DEA CLASS

    Rx

    DESCRIPTION

    Liposomal formulation of a cytotoxic anthracycline antibiotic that inhibits nucleotide replication and repair
    Approved for use in multiple myeloma in combination with bortezomib, ovarian cancer, and AIDS-related Kaposi's sarcoma
    Cardiomyopathy and infusion-related reactions have been reported

    COMMON BRAND NAMES

    Doxil, Lipodox

    HOW SUPPLIED

    Doxil/Doxorubicin, Liposomal/Lipodox Intravenous Inj Lipos: 1mL, 2mg

    DOSAGE & INDICATIONS

    For the treatment of HIV-related Kaposi's sarcoma in patients with disease that has progressed on prior combination chemotherapy or in patients who are intolerant to other therapy.
    Intravenous dosage (Doxil)
    Adults

    20 mg/m2 IV over 60 minutes once every 21 days, until disease progression or unacceptable toxicity. Begin infusion at a rate of 1 mg/minute and increase the rate as tolerated. In an open-label, single-arm, multicenter study, 27% of evaluable patients with disease progression on, or intolerance to, prior systemic combination chemotherapy who received liposomal doxorubicin (n = 34) had a partial response (PR) and 29% had stable disease (SD); the median time to PR was 43 days and duration of PR was 73 days. Of patients who had previously received conventional doxorubicin (n = 20), 30% experienced PR and 40% had SD; the median time to PR and duration of PR were 53 days and 89 days, respectively.

    For the treatment of ovarian cancer that has progressed or recurred after platinum-based chemotherapy.
    NOTE: Doxil has been designated an orphan drug by the FDA for this indication.
    NOTE: Refractory disease is defined as progression while on therapy or within 6 months of completing treatment.
    Intravenous dosage (Doxil)
    Adults

    50 mg/m2 IV over 60 minutes on day 1 every 28 days, until disease progression or unacceptable toxicity. Begin infusion at a rate of 1 mg/minute and increase the rate as tolerated. In a phase II trial, the overall response rate was 25.7% in patients with progressive disease following either cisplatin or carboplatin and paclitaxel or at least 1 platinum-based and 1 paclitaxel-based regimen. The majority of patients in this trial required dose reductions to at least 40 mg/m2 IV every 4 weeks due to severe mucositis and skin toxicity. In a randomized, multicenter, open-label, phase III trial of patients with recurrent ovarian cancer (n = 474), patients treated with liposomal doxorubicin did not have improved time to progression (primary outcome) after treatment with liposomal doxorubicin compared with topotecan (4.1 months vs. 4.2 months; p = 0.62). However, secondary endpoints of overall survival (14.4 months vs. 13.7 months; p = 0.05) and overall response rate (19.7% vs. 17%) were improved with liposomal doxorubicin. The median duration of response was 6.9 months vs. 5.9 months, respectively. For women treated with pegylated liposomal doxorubicin, there was an 18% reduction in risk of death for those with platinum-refractory disease while a 30% reduction in risk of death was noted for women with platinum-sensitive disease.

    For the treatment of relapsed or refractory multiple myeloma in patients who have received at least 1 prior therapy, in combination with bortezomib.
    Intravenous dosage (Doxil)
    Adults

    30 mg/m2 IV over 1 hour on day 4 repeated every 3 weeks in combination with bortezomib 1.3 mg/m2/dose IV bolus over 3 to 5 seconds on days 1, 4 , 8, and 11 of each cycle; give doxorubicin liposomal after bortezomib receipt on day 4. Begin liposomal doxorubicin infusion at a rate of 1 mg/minute and increase the rate as tolerated. Administer up to 8 treatment cycles or until disease progression or unacceptable toxicity occurs. At a planned interim analysis (median follow-up of 7.2 months), the primary endpoint of median time to progression was significantly improved with bortezomib plus pegylated liposomal doxorubicin (PLD) compared with bortezomib alone (9.3 months vs 6.5 months; p < 0.000004) in patients with relapsed or refractory multiple myeloma who had received at least 1 prior therapy in a multinational, randomized, phase III trial (n = 646). OS was not significantly improved with bortezomib plus PLD compared with bortezomib alone (33 months vs. 31 months; HR 0.96; 95% CI, 0.8 to 1.14) in the final survival analysis.

    For the treatment of locally advanced or metastatic breast cancer†.
    NOTE: In a phase III trial comparing conventional doxorubicin to liposomal doxorubicin (Myocet; not available in the United States), the estimated median cumulative lifetime dose of doxorubicin for the first appearance of cardiotoxicity was > 2220 mg/m2 for the liposomal doxorubicin and 480 mg/m2 for conventional doxorubicin.
    Intravenous dosage
    Adults

    50 mg/m2 IV on day 1, every 4 weeks. In a phase III non-inferiority trial, 509 patients were randomized to receive PLD 50 mg/m2 IV or doxorubicin (60 mg/m2 IV on day 1, every 3 weeks) until disease progression. PLD was non-inferior to doxorubicin in progression-free survival (PFS), the primary endpoint (6.9 months vs. 7.8 months [HR 1.00, 95% CI 0.82 to 1.22]). Overall survival was also similar between the treatment arms (21 months vs. 22 months [HR 0.94, 95% CI 0.74 to 1.19]). Cardiotoxic events occurred more frequently in the doxorubicin arm (48 events vs. 10 events) and the overall risk of cardiotoxicity versus cumulative dose of anthracycline was also higher in the doxorubicin arm (HR 3.16, 95% CI 1.58 to 6.31, p < 0.001). Of note, in a phase II trial of 46 patients with previously treated metastatic breast cancer, PLD 40 mg/m2 IV on day 1 every 4 weeks, reduced the incidence of severe palmar-plantar erythrodysesthesia and mucositis, while providing comparable efficacy to historical controls administered standard dose PLD.

    For the treatment of refractory or transformed cutaneous T-cell lymphoma (CTCL)†, including mycosis fungoides† and Sezary syndrome†.
    Intravenous dosage
    Adults

    20 or 40 mg/m2 IV once every 4 weeks for up to 8 cycles with overall response rates of 84.2% (20 mg/m2 dose) and 56% (40 mg/m2 dose) have been evaluated in small, nonrandomized clinical trials. Pyridoxine 300 mg/day PO starting with pegylated liposomal doxorubicin therapy and continuing for 1 month after therapy was given to prevent palmar-plantar erythrodysesthesia in 1 trial.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    ovarian cancer, 50 mg/m2 IV every 4 weeks; AIDS-related Kaposi's sarcoma, 20 mg/m2 IV every 3 weeks; multiple myeloma, 30 mg/m2 IV every 21 days.

    Geriatric

    ovarian cancer, 50 mg/m2 IV every 4 weeks; AIDS-related Kaposi's sarcoma, 20 mg/m2 IV every 3 weeks; multiple myeloma, 30 mg/m2 IV every 21 days.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Reduce the dose of liposomal doxorubicin for a serum bilirubin level of 1.2 mg/dL or more.[29359]
    NOTE: Previous data have recommended decreasing the dose by 50% for a total bilirubin level of 1.2 to 3 mg/dL and by 75% for a total bilirubin level greater than 3 mg/dL.[59426]

    Renal Impairment

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

    ADMINISTRATION

    Hazardous Drugs Classification
    NIOSH 2016 List: Group 1
    NIOSH (Draft) 2020 List: Table 1
    Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
    Use double chemotherapy gloves and a protective gown. Prepare in a biological safety cabinet or compounding aseptic containment isolator with a closed system drug transfer device. Eye/face and respiratory protection may be needed during preparation and administration.
    Emetic Risk
    Pediatrics
    IV Doses 50 mg/m2 or less: Minimal
    Administer prn antiemetics as necessary.
    Adults
    Low
    Administer routine antiemetic prophylaxis prior to treatment.
    Extravasation Risk
    Irritant

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Liposomal doxorubicin is a translucent, red liposomal dispersion.

    Intravenous Administration

    Liposomal doxorubicin is available as a 2 mg/mL injectable solution.
    Do not mix liposomal doxorubicin with other drugs.
    If extravasation occurs or is suspected, hold the infusion, elevate the extremity (if applicable), and apply ice to the site for 15 minutes 4 times daily for 3 days; do NOT remove the needle (until attempts are made to aspirate extravasated fluid), flush the line, or apply pressure to the site.
    Dilution:
    Dilute liposomal doxorubicin in 250 mL of 5% Dextrose injection for doses of 90 mg or less and in 500 mL of 5% Dextrose injection for doses greater than 90 mg.
    Storage following dilution: Store refrigerated (2 to 8 degrees C;36 to 46 degrees F); administer within 24 hours of dilution.
    Intravenous infusion:
    Administer the first dose at an initial rate of 1 mg/minute to decrease the risk of infusion reactions. If no infusion-related adverse effects occur, the rate can be increased to complete the infusion over 1 hour.
    Do not filter; do not rapidly flush the infusion line.[29359]

    STORAGE

    Doxil:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Do not freeze
    - Store in carton until time of use
    - Store reconstituted product in refrigerator (36 to 46 degrees F) and administer within 24 hours
    - Store unopened containers in refrigerator (36 to 46 degrees F)
    Lipodox:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Do not freeze
    - Store in carton until time of use
    - Store reconstituted product in refrigerator (36 to 46 degrees F) and administer within 24 hours
    - Store unopened containers in refrigerator (36 to 46 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    Anthracycline hypersensitivity, serious rash

    Doxorubicin liposome is contraindicated in patients who have a history of anthracycline hypersensitivity, specifically a doxorubicin hypersensitivity, or a hypersensitivity to any component of the doxorubicin hydrochloride liposome product. Serious rash (i.e., palmar-plantar erythrodysesthesia (hand and foot syndrome)) has been reported with liposomal doxorubicin therapy. Therapy interruption, dose reduction, or discontinuation may be necessary in patients who develop hand and foot syndrome.

    Infusion-related reactions

    Infusion-related reactions have been reported with liposomal doxorubicin; some cases were life-threatening or fatal. These reactions typically occur during the first infusion. Medications to treat infusion-related reactions and cardiopulmonary resuscitative equipment should be available for immediate use prior to starting the liposomal doxorubicin infusion. Monitor patients for symptoms of infusion-related reactions (e.g., flushing, shortness of breath, facial swelling, headache, chills, chest pain, back pain, tightness in the chest and throat, fever, tachycardia, pruritus, rash, cyanosis, syncope, bronchospasm, asthma, apnea, and hypotension). Hold the liposomal doxorubicin infusion in patients who develop grade 1, 2, or 3 infusion-related reactions and resume at a reduced rate; discontinue therapy in patients who have grade 4 or a life-threatening reaction.[29359]

    Cardiac disease, cardiomyopathy, cardiotoxicity, radiation therapy

    Cardiotoxicity (e.g., congestive heart failure, acute left ventricular failure) has been reported with the use of liposomal doxorubicin. Monitor cardiac function (e.g., echocardiograms, multigated radionuclide (MUGA) scans) before initiation of therapy, during treatment, and after completion of therapy. The risk of cardiomyopathy may be higher in patients with cumulative anthracycline exposure (450 to 550 mg/m2), prior radiation therapy to the mediastinum, or treatment with concomitant use of other cardiotoxic agents. Other anthracycline and anthracenedione use should be included in the calculation of the cumulative anthracycline dose. Perform a risk/benefit analysis before administering liposomal doxorubicin in patients with a history of cardiac disease.[29359]

    Neutropenia, thrombocytopenia

    Myelosuppression (e.g., neutropenia and thrombocytopenia) has been reported with doxorubicin liposome use. Obtain complete blood counts prior to starting therapy, frequently during therapy, and at least prior to each liposomal doxorubicin dose. Therapy interruption, dose reduction, or discontinuation may be necessary in patients who develop hematologic toxicity. Some patients may require granulocyte colony-stimulation factor support.[29359]

    Extravasation

    Take precautions to avoid extravasation. If a burning or stinging sensation occurs, or other evidence indicating an extravasation occurs, discontinue the infusion. Do not remove the needle until attempts to aspirate extravasated fluid are made. Do not flush the line or apply pressure to the site. If the extravasation is in an extremity, elevate the extremity. Apply ice to the site for 15 minutes 4 times daily for 3 days.

    Hepatic disease

    Use doxorubicin liposome with caution in patients with hepatic disease. A reduced doxorubicin liposome dose is recommended in patients with hepatic impairment (e.g., hyperbilirubinemia). Evaluate hepatic function (e.g., liver function tests) prior to doxorubicin liposome therapy.

    New primary malignancy, stomatitis

    New primary malignancy (e.g., acute myelogenous leukemia and oral cancer) has been reported with liposomal doxorubicin therapy. Secondary oral cancer has occurred up to 6 years after the last dose. Monitor patients regularly for signs of oral ulceration or stomatitis; advise patients to report symptoms of oral discomfort. Therapy interruption, dose reduction, or discontinuation may be necessary in patients who develop grade 2 or higher stomatitis.[29359]

    Ensure correct formulation selection

    Ensure correct formulation selection for the patient. Do not prescribe or substitute doxorubicin in place of doxorubicin liposomal.[29359]

    Pregnancy

    Liposomal doxorubicin may cause fetal harm when administered during pregnancy, based on its mechanism of action and data from animal studies. Avoid the use of liposomal doxorubicin during pregnancy in the first trimester; available data is not conclusive regarding the risk of major birth defects or miscarriage when liposomal doxorubicin is used during the second or third trimester of pregnancy. Women who become pregnant while receiving liposomal doxorubicin should be apprised of the potential hazard to the fetus. Liposomal doxorubicin was embryotoxic in rats and abortifacient in rabbits when administered during organogenesis at doses of approximately 0.12-times the recommended clinical dose.[29359]

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

    Counsel patients about the reproductive risk and contraception requirements during liposomal doxorubicin treatment. Pregnancy testing should be performed prior to starting liposomal doxorubicin in female patients of reproductive potential. These patients should use effective contraception during and for 6 months after the last dose. Due to the risk of male-mediated teratogenicity, male patients with a female partner of reproductive potential should use effective contraception during liposomal doxorubicin therapy and for 6 months after the last dose. Women who become pregnant while receiving liposomal doxorubicin should be apprised of the potential hazard to the fetus. There is a risk of temporary or permanent infertility with liposomal doxorubicin therapy. In females, amenorrhea and premature menopause can occur, with recovery of menses and ovulation being related to age at treatment. In males, treatment with liposomal doxorubicin may result in oligospermia, azoospermia, and permanent loss of fertility. Sperm counts may return to normal levels in some men up to several years after therapy discontinuation.[29359]

    Breast-feeding

    No information is available regarding the presence of liposomal doxorubicin in human milk. Due to the potential for serious adverse reactions in the nursing infant, breast-feeding is not recommended during liposomal doxorubicin therapy.[29359]

    ADVERSE REACTIONS

    Severe

    neutropenia / Delayed / 12.2-57.0
    thrombocytopenia / Delayed / 1.3-24.0
    palmar-plantar erythrodysesthesia (hand and foot syndrome) / Delayed / 0-24.0
    anemia / Delayed / 5.4-16.0
    cardiomyopathy / Delayed / 0-11.0
    cardiac arrest / Early / 0-10.0
    GI bleeding / Delayed / 1.0-10.0
    ileus / Delayed / 1.0-10.0
    exfoliative dermatitis / Delayed / 1.0-10.0
    thrombosis / Delayed / 0-10.0
    vomiting / Early / 0-8.0
    stomatitis / Delayed / 2.0-8.0
    diarrhea / Early / 2.5-7.0
    peripheral neuropathy / Delayed / 0-7.0
    fatigue / Early / 0-7.0
    asthenia / Delayed / 0-7.0
    nausea / Early / 0-5.0
    rash / Early / 1.0-4.2
    dyspnea / Early / 0-4.1
    anorexia / Delayed / 0-2.5
    infection / Delayed / 0-2.1
    heart failure / Delayed / 0-2.0
    back pain / Delayed / 0-1.7
    abdominal pain / Early / 0-1.0
    constipation / Delayed / 0-1.0
    paresthesias / Delayed / 0-1.0
    dysesthesia / Delayed / 0-1.0
    fever / Early / 0-1.0
    dyspepsia / Early / 0-0.8
    headache / Early / 0-0.8
    toxic epidermal necrolysis / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    new primary malignancy / Delayed / Incidence not known
    leukemia / Delayed / Incidence not known
    pulmonary embolism / Delayed / Incidence not known
    apnea / Delayed / Incidence not known
    bronchospasm / Rapid / Incidence not known
    cyanosis / Early / Incidence not known

    Moderate

    infusion-related reactions / Rapid / 11.0-11.0
    hypotension / Rapid / 1.0-10.0
    peripheral vasodilation / Rapid / 1.0-10.0
    sinus tachycardia / Rapid / 1.0-10.0
    esophagitis / Delayed / 1.0-10.0
    dysphagia / Delayed / 1.0-10.0
    oral ulceration / Delayed / 1.0-10.0
    furunculosis / Delayed / 1.0-10.0
    bullous rash / Early / 1.0-10.0
    conjunctivitis / Delayed / 0-10.0
    candidiasis / Delayed / 1.0-10.0
    hyperbilirubinemia / Delayed / 1.0-10.0
    hypokalemia / Delayed / 1.0-10.0
    hyponatremia / Delayed / 1.0-10.0
    hypercalcemia / Delayed / 1.0-10.0
    dehydration / Delayed / 0-10.0
    hematuria / Delayed / 1.0-10.0
    chest pain (unspecified) / Early / 1.0-5.0
    elevated hepatic enzymes / Delayed / 1.0-5.0
    palpitations / Early / 0-1.0
    bundle-branch block / Early / 0-1.0
    radiation recall reaction / Delayed / 0-1.0
    hepatitis / Delayed / 0-1.0
    phlebitis / Rapid / 0-1.0
    depression / Delayed / Incidence not known

    Mild

    alopecia / Delayed / 0-19.0
    cough / Delayed / 0-18.0
    pharyngitis / Delayed / 0-16.0
    weight loss / Delayed / 1.0-12.0
    dysgeusia / Early / 0-10.0
    rhinitis / Early / 1.0-10.0
    sinusitis / Delayed / 1.0-10.0
    vesicular rash / Delayed / 1.0-10.0
    skin discoloration / Delayed / 1.0-10.0
    acne vulgaris / Delayed / 1.0-10.0
    maculopapular rash / Early / 0-10.0
    xerosis / Delayed / 1.0-10.0
    pruritus / Rapid / 1.0-10.0
    drowsiness / Early / 1.0-10.0
    dizziness / Early / 1.0-10.0
    xerophthalmia / Early / 1.0-10.0
    epistaxis / Delayed / 1.0-10.0
    ecchymosis / Delayed / 1.0-10.0
    chills / Rapid / 1.0-5.0
    muscle cramps / Delayed / Incidence not known
    Co-Enzyme Q-10 deficiency / Delayed / Incidence not known
    flushing / Rapid / Incidence not known
    syncope / Early / 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.
    Abrocitinib: (Major) Avoid coadministration of abrocitinib with doxorubicin due to the risk for increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Doxorubicin is a P-gp substrate and abrocitinib is a P-gp inhibitor. Concurrent use of P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
    Acetaminophen; 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.
    Acetaminophen; 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.
    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 : (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; 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.
    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.
    Butalbital; Acetaminophen; 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.
    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.
    Cannabidiol: (Major) Avoid coadministration of cannabidiol with doxorubicin due to the risk for increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Doxorubicin is a P-gp substrate and cannabidiol is a P-gp inhibitor. Concurrent use of P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
    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.
    Celecoxib; Tramadol: (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; 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.
    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; Ibuprofen; 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 doxorubicin with conivaptan due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Doxorubicin is a substrate of CYP3A and P-gp and conivaptan is a moderate CYP3A and P-gp inhibitor.
    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.
    Desogestrel; 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.
    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; 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; 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.
    Ethynodiol Diacetate; 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.
    Etonogestrel; 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.
    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.
    Gilteritinib: (Major) Avoid coadministration of gilteritinib with doxorubicin due to the risk for increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Doxorubicin is a P-gp substrate and gilteritinib is a P-gp inhibitor. Concurrent use of P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
    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.
    Lansoprazole; Amoxicillin; 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.
    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.
    Levoketoconazole: (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.
    Levonorgestrel; 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.
    Levonorgestrel; Ethinyl Estradiol; 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.
    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.
    Maribavir: (Major) Avoid coadministration of maribavir with doxorubicin due to the risk for increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Doxorubicin is a P-gp substrate and maribavir is a P-gp inhibitor. Concurrent use of P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
    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.
    Mitapivat: (Major) Avoid coadministration of mitapivat with doxorubicin due to the risk for increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Doxorubicin is a P-gp substrate and mitapivat is a P-gp inhibitor. Concurrent use of P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
    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.
    Nanoparticle Albumin-Bound 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.
    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.
    Nirmatrelvir; 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.
    Norethindrone Acetate; 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.
    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.
    Pacritinib: (Major) Avoid coadministration of pacritinib with doxorubicin due to the risk for increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Doxorubicin is a P-gp substrate and pacritinib is a P-gp inhibitor. Concurrent use of P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
    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.
    Phenobarbital; Hyoscyamine; Atropine; 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.
    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.
    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.
    Voxelotor: (Major) Avoid coadministration of doxorubicin with voxelotor due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Doxorubicin is a major substrate of CYP3A and voxelotor is a moderate CYP3A inhibitor. Concurrent use of CYP3A 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

    Liposomal doxorubicin may cause fetal harm when administered during pregnancy, based on its mechanism of action and data from animal studies. Avoid the use of liposomal doxorubicin during pregnancy in the first trimester; available data is not conclusive regarding the risk of major birth defects or miscarriage when liposomal doxorubicin is used during the second or third trimester of pregnancy. Women who become pregnant while receiving liposomal doxorubicin should be apprised of the potential hazard to the fetus. Liposomal doxorubicin was embryotoxic in rats and abortifacient in rabbits when administered during organogenesis at doses of approximately 0.12-times the recommended clinical dose.[29359]

    No information is available regarding the presence of liposomal doxorubicin in human milk. Due to the potential for serious adverse reactions in the nursing infant, breast-feeding is not recommended during liposomal doxorubicin therapy.[29359]

    MECHANISM OF ACTION

    Doxorubicin is the active cytotoxic agent in Doxorubicin Liposomal. Doxorubicin complexes with DNA by intercalating between DNA base pairs, causing the helix to change shape. This simple act of changing the conformation of DNA can interfere with strand elongation by inhibiting DNA polymerase and can inhibit protein synthesis due to affects on RNA polymerase. Doxorubicin may also form complexes with iron or copper. These complexes have high association constants and may contribute to doxorubicin-induced cardiotoxicity by enhancing redox cycling to produce membrane and mitochondria damage. Doxorubicin also affects topoisomerase II, an enzyme responsible for DNA strand breaks during transcription. Doxorubicin stabilizes the initial DNA-enzyme complex leading to double-strand DNA breaks. Doxorubicin also undergoes one-electron reduction to form oxygen free radical intermediates. In the presence of oxygen and metal catalysts such as Fe2+, doxorubicin undergoes reduction to the semiquinone radical. In the presence of oxygen, the semiquinone radical can form a superperoxide that in the presence of hydrogen peroxide forms hydroxyl radicals. Doxorubicin-derived free radicals can induce membrane lipid peroxidation, DNA strand scission, and direct oxidation of purine or pyrimidine bases, thiols and amines. Doxorubicin is considered cell cycle non-specific; although, it has maximum cytotoxic effects in the S-phase. Cells exposed to doxorubicin in G1 may proceed through the S-phase but then are blocked and die in the G2 phase.
     
    Resistance to doxorubicin may occur through several mechanisms. One of the most important mechanisms of resistance is the multidrug resistance (MDR) mechanism that is mediated through an overexpression of a P170-glycoprotein. This membrane protein functions as an energy-dependent drug efflux pump in resistance cells. Several compounds including cyclosporine, cyclosporine analogs and verapamil may block this protein and reverse resistance. Other mechanisms of resistance include changes in topoisomerase II and glutathione activity. Liposomal doxorubicin formulations are less susceptible to tumor resistance via MDR.
     
    Doxorubicin-induced free radical formation also contributes to its cardiotoxicity. Once doxorubicin enters cardiac cells, it is reduced to an anthracycline free radical that is rapidly oxidized with oxygen to form the original drug and superoxide anions. Normally, these superoxide radicals are converted back to oxygen via glutathione peroxidase (GP); however, the heart is essentially devoid of this enzyme. Administration of doxorubicin destroys any GP activity present in cardiac cells. Consequently, H2O2 is forced to react with ferrous ions (Fe2+) to form the highly toxic superhydroxide free radical that causes severe lipid peroxidation leading to extensive mitochondrial destruction. Both cardiac and malignant cells are rich in mitochondria. Additionally, these free radicals crosslink sulfhydryl groups of calcium-release channels and inhibit Ca-ATPase which leads to extensive depletion of sarcoplasmic reticulum (SR) calcium stores and prevention of restoration of calcium stores in the SR, respectively.

    PHARMACOKINETICS

    Pegylated liposomal doxorubicin (Doxil) is administered intravenously. Pegylated liposomal doxorubicin distributes to the liver, spleen, and lymphatic system, but less extensively to the heart, kidneys, and lungs. In a pharmacokinetic study which administered a single dose of liposomal doxorubicin at 10 mg/m2 and 20 mg/m2 (n = 23), the volume of distribution (Vd) was 2.83 +/- 0.145 L/m2 and 2.72 +/- 0.120 L/m2, respectively; the small volume of distribution relative to conventional doxorubicin suggests that liposomal doxorubicin is mainly confined to vascular fluid. In the pharmacokinetic study, liposomal doxorubicin exhibited linear pharmacokinetics, with an alpha half life of 4.7 and 5.2 hours and a terminal half life of 52.3 and 55 hours for doses of 10 and 20 mg/m2, respectively. At doses > 50 mg/m2 the pharmacokinetics are non-linear and the elimination half-life is longer. Plasma clearance was 0.056 +/- 0.01 L/h/m2 and 0.041 +/- 0.004 L/h/m2, respectively; comparatively, plasma clearance after administration of conventional doxorubicin is 24 to 35 L/h/m2.
     
    Liposomal doxorubicin formulations are made up of microscopic liposomes, which exhibit unique characteristics that influence the pharmacokinetics of the product. A liposome is a closed, spherical vehicle consisting of a single or multiple phospholipid bilayer. As high concentrations of phospholipids are mixed in an aqueous solution, the hydrophobic tails gather together to avoid water molecules, resulting in the binding of the hydrophilic heads thus forming a liposome. Liposomes may encapsulate water-soluble and fat-soluble drugs within different areas of the lipid bilayer. Liposomes are effective drug carriers due to increases blood circulation time and small size allow which allows penetration into areas of inflammation or malignant disease. These areas tend to have leaky capillaries or enlarged spaces within the lining of blood vessels which allows the liposome to pass. The pegylated liposomal doxorubicin products uses Stealth liposomes which are formulated with surface-bound methoxypolyethylene glycol (MGEG) to avoid detection by the reticuloendothelial system (RES) and increase blood circulation time.
     
    Once inside the tumor, the liposomal covering allows release of the encapsulated doxorubicin. Although the exact mechanism of drug release from the liposome has not been determined, several processes which may be important to the process have been reported including endocytosis and lysosome degradation which releases their contents, lipid exchange between the liposome and the cell membrane resulting in delivery of the liposome contents to the cell and fusion of the liposome to the cellular membrane. Liposomes also attach to the cell surface allowing the contents of the liposome to diffuse across the cell membrane into the cytoplasm. The concentration of liposomal doxorubicin in Kaposi's sarcoma lesions is up to 22-times that in normal skin.
     
    Doxorubicin is extensively metabolized in the liver and eliminated primarily as glucuronide or hydroxylated conjugates. Doxorubicinol is the primary metabolite and has 1/20th cytotoxic properties of doxorubicin; however, it may be a more potent cardiotoxin than doxorubicin. The formation of doxorubicinol following administration of pegylated liposomal doxorubicin is dramatically reduced resulting in very low plasma concentrations.
     
    Affected cytochrome P450 isoenzymes: none

    Intravenous Route

    In a single-dose pharmacokinetic study of patients with AIDS-related Kaposi's sarcoma who received liposomal doxorubicin 10 mg/m2 or 20 mg/m2, the peak plasma concentration was 4.12 +/- 0.215 mcg/mL and 8.34 +/- 0.49 mcg/mL, and the AUC 277 +/- 32.9 h x mcg/mL and 590 +/- 58.7 h x mcg/mL, respectively.