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  • CLASSES

    Small Molecule Antineoplastic Histone Deacetylase (HDAC) Inhibitors

    DEA CLASS

    Rx

    DESCRIPTION

    Histone deacetylase (HDAC) inhibitor
    Used for cutaneous T-cell lymphoma in adults who have received at least 1 prior systemic therapy
    ECG abnormalities have been reported; ensure potassium and magnesium levels are within normal range before administering therapy

    COMMON BRAND NAMES

    Istodax

    HOW SUPPLIED

    Istodax Intravenous Inj Pwd F/Sol: 11mg
    Romidepsin Intravenous Inj Pwd: 11mg
    Romidepsin Intravenous Inj Sol: 1mL, 5mg

    DOSAGE & INDICATIONS

    For the treatment of cutaneous T-cell lymphoma (CTCL) in patients who have received at least 1 prior systemic therapy.
    NOTE: Romidepsin has been designated an orphan drug by the FDA for the treatment of non-Hodgkin T-cell lymphomas.
    Intravenous dosage
    Adults

    14 mg/m2 IV over 4 hours on days 1, 8, and 15 repeated every 28 days until disease progression. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Interruption or discontinuation of therapy and/or a dose reduction may be necessary in patients who develop toxicities.[37292] The overall response rate (ORR; primary end point) was 34% following treatment with romidepsin in patients with stage Ib to IVa CTCL who had 1 or more systemic therapy failures in a multinational, single-arm, phase 2 trial (n = 96). The median number of prior systemic therapies was 3 (range, 1 to 8 therapies); 77% of patients had previously received chemotherapy. Romidepsin therapy was given for up to 6 cycles, but treatment could continue beyond 6 cycles in patients who had a response or stable disease. The complete response (CR) rate was 6%. For all responders, the median time to response was 2 months (range, 0.9 to 4.8 months), the median duration of response (DOR) was 15 months (range, up to 19.8+ months), and the median time to progression (TTP) was 8 months (range, up to 21.7+ months). Pruritus was evaluated using a 100-mm visual analog scale (VAS) score of 1 to 100 millimeters (mm). In 65 patients with a VAS score of 30 mm or higher (moderate to severe pruritus), a clinically meaningful reduction in pruritus, defined as a decrease in VAS score of at least 30 mm or a score of 0 for at least 2 consecutive cycles, occurred in 43% of patients.[58218] The ORR was 34% in patients with relapsed, refractory, or advanced (stage IIb to IVb) CTCL who received romidepsin (median of 4 cycles; range, 1 to 72 cycles) in a multicenter, 2-cohort, phase 2 study (n = 71); 6% of these patients achieved a CR. The median number of prior therapies was 4 (range, 0 to 14 therapies); 65% of patients had previously received chemotherapy. For all responders, the median time to response was 2 months (range, 1 to 6 months), the median DOR was 13.7 months, and the median TTP was 15.1 months.[58219]

    For the treatment of peripheral T-cell lymphoma (PTCL)† in patients who have received at least 1 prior therapy.
    NOTE: Romidepsin has been designated an orphan drug by the FDA for the treatment of non-Hodgkin T-cell lymphomas.
    NOTE: The manufacturer removed the PTCL indication from the Istodax label in July 2021 after initially receiving accelerated approval; romidepsin failed to meet the primary end point of progression-free survival in a phase 3 trial.
    Intravenous dosage
    Adults

    Dosage not established.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    14 mg/m2 IV.

    Geriatric

    14 mg/m2 IV.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Baseline Hepatic Impairment
    Mild (bilirubin level at or below the ULN and AST level greater than the ULN, or bilirubin level greater than the ULN to 1.5 times the ULN and any AST level): No romidepsin dosage adjustment is necessary.Moderate (bilirubin levels greater than 1.5 to 3 times the ULN): Reduce the dose to 7 mg/m2 IV on days 1, 8, and 15.Severe (bilirubin levels greater than 3 times the ULN): Reduce the dose to 5 mg/m2 IV on days 1, 8, and 15.[37292]

    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
    Moderate
    Administer routine antiemetic prophylaxis prior to treatment.

    Injectable Administration

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

    Intravenous Administration

    Romidepsin is available in a 10-mg lyophilized powder vial or as a 5 mg/mL solution for injection.
    Reconstitution (lyophilized powder vial only):
    Reconstitute the romidepsin 10-mg lyophilized powder vial with 2.2 mL of the supplied diluent for a final volume of 2 mL and a final vial concentration of 5 mg/mL; note that diluent vials contain overfill (2.4 mL total volume).
    Slowly inject the diluent into the powder vial; swirl the vial until the solution is clear with no visible particles.
    Storage following reconstitution: vials may be stored at room temperature for up to 8 hours.
    Dilution:
    Dilute the appropriate amount of romidepsin in 500 mL 0.9% sodium chloride for injection.
    The diluted solution may be contained in polyvinyl chloride (PVC), ethylene vinyl acetate (EVA), polyethylene (PE) infusion bags or glass bottles.
    Storage following dilution: administer the diluted admixture as soon as possible; however, the admixture may be stored at room temperature for up to 24 hours.
    Intravenous (IV) infusion:
    Administer the romidepsin admixture as an IV infusion over 4 hours.

    STORAGE

    Generic:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Protect from light
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    - Store in carton
    Istodax :
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Reconstituted product is stable for up to 8 hours at room temperature (77 degrees F)
    - Store at controlled room temperature (between 68 and 77 degrees F)
    - Store diluted product in accordance with package insert instructions
    - Store reconstituted product in accordance with package insert instructions

    CONTRAINDICATIONS / PRECAUTIONS

    Hepatic disease

    Reduce the romidepsin dose in patients with baseline moderate (bilirubin levels greater than 1.5 to 3 times the ULN) or severe (bilirubin levels greater than 3 times the ULN) hepatic disease. Monitor patients with hepatic impairment frequently for romidepsin toxicity, particularly during the first cycle of therapy.

    Hepatitis, infection, viral infection

    Serious bacterial infection (e.g., pneumonia, sepsis) and reactivation of viral infection (e.g., Epstein Barr virus (EBV) and hepatitis B virus (HBV)) have been reported with romidepsin therapy in clinical trials; some cases were fatal. Infectious events may occur during or following romidepsin treatment. Patients who received prior treatment with monoclonal antibodies directed against lymphocyte antigens or who have bone marrow disease involvement may be at higher risk of developing a life-threatening infection. Monitor patients who have a history of HBV infections for reactivation; consider antiviral prophylaxis in these patients.

    Apheresis, AV block, bradycardia, cardiac disease, cardiomyopathy, celiac disease, females, fever, geriatric, heart failure, human immunodeficiency virus (HIV) infection, hyperparathyroidism, hypocalcemia, hypokalemia, hypomagnesemia, hypothermia, hypothyroidism, long QT syndrome, myocardial infarction, pheochromocytoma, QT prolongation, rheumatoid arthritis, sickle cell disease, sleep deprivation, stroke, systemic lupus erythematosus (SLE)

    Electrocardiographic (ECG) changes (e.g., QT prolongation and T-wave and ST-segment changes) have been reported with romidepsin therapy. Correct electrolyte imbalances (e.g., hypokalemia, hypomagnesemia) prior to starting romidepsin. Use with caution, and consider ECG monitoring at baseline and periodically during treatment, in patients with congenital long QT syndrome, a history of significant cardiac disease, or who are taking antiarrhythmic medicines or other medications that may lead to significant QT prolongation. Use romidepsin with caution in patients with conditions that may increase the risk of QT prolongation including bradycardia, AV block, heart failure, stress-related cardiomyopathy, myocardial infarction, stroke, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Females, geriatric patients, patients with sleep deprivation, pheochromocytoma, sickle cell disease, hypothyroidism, hyperparathyroidism, hypothermia, systemic inflammation (e.g., human immunodeficiency virus (HIV) infection, fever, and some autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus (SLE), and celiac disease) and patients undergoing apheresis procedures (e.g., plasmapheresis [plasma exchange], cytapheresis) may also be at increased risk for QT prolongation.[28432] [28457] [37292] [56592]

    Tumor lysis syndrome (TLS)

    Tumor lysis syndrome (TLS) has been reported with romidepsin therapy. Patients with advanced-stage disease and/or high tumor burden are at increased risk for developing TLS. Closely monitor these patients; take appropriate precautions (e.g., hydration, TLS prophylaxis) and start treatment for TLS if needed.

    Anemia, leukopenia, neutropenia, thrombocytopenia

    Myelosuppression including thrombocytopenia, leukopenia, neutropenia, lymphopenia, and anemia has been reported with romidepsin therapy in clinical trials. Regularly monitor blood counts during romidepsin treatment. Interruption of therapy and/or a dose reduction may be necessary in patients who develop hematologic toxicity.

    Pregnancy

    Romidepsin may cause fetal harm when administered during pregnancy, based on its mechanism of action and data from animal studies. Females of reproductive potential should avoid becoming pregnant while taking romidepsin. Discuss the potential hazard to the fetus if a patient becomes pregnant while taking this drug. Although romidepsin has not been evaluated in pregnant women, fetal toxicity including reduced fetal weight, folded retina, rotated limbs, and incomplete sternal ossification occurred when pregnant rats received a romidepsin dose resulting in 0.2 times or greater the exposure that was observed in humans who received the recommended dose.[37292]

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

    Counsel patients about the reproductive risk and contraception requirements during romidepsin treatment. Pregnancy testing should be performed in women of reproductive potential within 7 days prior to initiating therapy. These women should use effective contraception during therapy and for 1 month after the final romidepsin dose. Romidepsin may reduce the effectiveness of estrogen-containing contraceptives; therefore, advise women to use alternative methods of contraception (e.g., condoms and intrauterine devices). Due to the risk of male-mediated teratogenicity, male patients should use effective contraception to avoid potential drug exposure in female partners of reproductive potential during therapy and for 1 month after the final romidepsin dose. The risk of infertility with romidepsin has not been studied in humans, although findings from animal studies suggest that impaired fertility may occur in male and female patients.[37292]

    Breast-feeding

    It is not known if romidepsin or its metabolites are secreted in human milk or if it has effects on the breast-fed infant or on milk production. Because there is a potential for adverse reactions in nursing infants from romidepsin, women should be advised against breast-feeding during romidepsin therapy and for 1 week after the last dose.[37292]

    ADVERSE REACTIONS

    Severe

    lymphopenia / Delayed / 0-37.0
    infection / Delayed / 0-33.0
    neutropenia / Delayed / 4.0-27.0
    leukopenia / Delayed / 0-22.0
    anemia / Delayed / 3.0-16.0
    thrombocytopenia / Delayed / 0-14.0
    asthenia / Delayed / 8.0-14.0
    fatigue / Early / 8.0-14.0
    hypophosphatemia / Delayed / 0-10.0
    vomiting / Early / 0-10.0
    hypermagnesemia / Delayed / 0-8.0
    exfoliative dermatitis / Delayed / 0-8.0
    hyperuricemia / Delayed / 0-8.0
    hypocalcemia / Delayed / 0-6.0
    nausea / Early / 3.0-6.0
    pruritus / Rapid / 0-6.0
    edema / Delayed / 0-5.0
    hypotension / Rapid / 3.0-4.0
    anorexia / Delayed / 0-4.0
    elevated hepatic enzymes / Delayed / 0-4.0
    hypoalbuminemia / Delayed / 0-4.0
    dyspnea / Early / 0-4.0
    dehydration / Delayed / 4.0-4.0
    fever / Early / 1.0-4.0
    hyponatremia / Delayed / 0-2.0
    hypokalemia / Delayed / 0-2.0
    constipation / Delayed / 0-2.0
    hyperglycemia / Delayed / 1.0-2.0
    hepatitis B exacerbation / Delayed / 1.0-1.0
    hypomagnesemia / Delayed / 0-1.0
    diarrhea / Early / 0-1.0
    renal failure / Delayed / 0-1.0
    tumor lysis syndrome (TLS) / Delayed / 1.0-1.0
    acute respiratory distress syndrome (ARDS) / Early / Incidence not known

    Moderate

    ST-T wave changes / Rapid / 2.0-63.0
    QT prolongation / Rapid / Incidence not known

    Mild

    dysgeusia / Early / 15.0-40.0
    cough / Delayed / 0-19.0

    DRUG INTERACTIONS

    Aldesleukin, IL-2: (Moderate) Romidepsin is a substrate for CYP3A4. Aldesleukin, IL-2 is a mild inhibitor of CYP3A4. Concurrent administration of romidepsin with a mild CYP3A4 inhibitor may cause an increase in systemic romidepsin concentrations. Use caution when concomitant administration of these agents is necessary.
    Alfuzosin: (Moderate) Consider monitoring electrolytes and ECGs at baseline and periodically during treatment if romidepsin is administered with alfuzosin. Romidepsin has been reported to prolong the QT interval and alfuzosin may also prolong the QT interval in a dose-dependent manner.
    Amiodarone: (Major) The concomitant use of romidepsin, a CYP3A4 substrate and a P-glycoprotein (P-gp) substrate, and amiodarone, a CYP3A4 inhibitor and a P-gp inhibitor, may increase romidepsin plasma exposure. If these agents are used together, monitor patients for signs and symptoms of romidepsin toxicity including hematologic toxicity, infection, and electrocardiogram (ECG) changes; therapy interruption or discontinuation or a dosage reduction may be required if toxicity develops. In addition, romidepsin has been reported to prolong the QT interval. Amiodarone also prolongs the QT interval. If romidepsin and amiodarone must be continued, appropriate cardiovascular monitoring precautions should be considered, such as the monitoring of electrolytes and ECGs at baseline and periodically during treatment.
    Amisulpride: (Major) Monitor ECG and electrolytes if amisulpride is coadministered with romidepsin due to the potential for additive QT prolongation. Amisulpride causes dose- and concentration- dependent QT prolongation. Romidepsin has been reported to prolong the QT interval.
    Amobarbital: (Moderate) Romidepsin is a substrate for CYP3A4. Coadministration of CYP3A4 inducers, like barbiturates, may decrease systemic concentrations of romidepsin. Use caution when concomitant administration of these agents is necessary.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) The concomitant use of romidepsin, a CYP3A4 substrate and a P-glycoprotein (P-gp) substrate, and clarithromycin, a strong CYP3A4 inhibitor and a P-gp inhibitor, may increase romidepsin plasma exposure. If these agents are used together, monitor patients for signs and symptoms of romidepsin toxicity including hematologic toxicity, infection, and electrocardiogram (ECG) changes; therapy interruption or discontinuation or a dosage reduction may be required if toxicity develops. In addition, romidepsin has been reported to prolong the QT interval. Clarithromycin may also prolong the QT interval. If romidepsin and the clarithromycin must be continued, appropriate cardiovascular monitoring precautions should be considered, such as the monitoring of electrolytes and ECGs at baseline and periodically during treatment.
    Amprenavir: (Moderate) The concomitant use of romidepsin, a CYP3A4 substrate, and amprenavir, a strong CYP3A4 inhibitor, may increase romidepsin plasma exposure. If these agents are used together, monitor patients for signs and symptoms of romidepsin toxicity including hematologic toxicity, infection, and electrocardiogram changes; therapy interruption or discontinuation or a dosage reduction may be required if toxicity develops.
    Anagrelide: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include romidepsin.
    Apalutamide: (Major) Avoid coadministration of romidepsin with apalutamide if possible due to decreased plasma concentrations of romidepsin. Romidepsin is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. The effect of strong CYP3A4 inducers on the exposure of romidepsin is unknown.
    Apomorphine: (Moderate) Use apomorphine and romidepsin together with caution due to the risk of additive QT prolongation. Dose-related QTc prolongation is associated with therapeutic apomorphine exposure. Consider monitoring electrolytes and ECGs at baseline and periodically during treatment if romidepsin is administered with apomorphine. Romidepsin has been reported to prolong the QT interval.
    Aprepitant, Fosaprepitant: (Moderate) Use caution if romidepsin and aprepitant, fosaprepitant are used concurrently and monitor for an increase in romidepsin-related adverse effects for several days after administration of a multi-day aprepitant regimen. Romidepsin 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 may increase plasma concentrations of romidepsin. 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.
    Aripiprazole: (Moderate) Consider monitoring electrolytes and ECGs at baseline and periodically during treatment if romidepsin is administered with aripiprazole. Romidepsin has been reported to prolong the QT interval. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose.
    Arsenic Trioxide: (Major) If possible, drugs that are known to prolong the QT interval should be discontinued prior to initiating arsenic trioxide therapy. QT prolongation should be expected with the administration of arsenic trioxide. Torsade de pointes (TdP) and complete atrioventricular block have been reported. Romidepsin has been reported to prolong the QT interval. If romidepsin must be coadministered with arsenic trioxide, appropriate cardiovascular monitoring precautions should be considered, such as the monitoring of electrolytes and ECGs at baseline and periodically during treatment.
    Artemether; Lumefantrine: (Major) Concurrent use of romidepsin and artemether; lumefantrine should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). If these drugs must be coadministered, appropriate cardiovascular monitoring precautions should be considered, such as the monitoring of electrolytes and ECGs at baseline and periodically during treatment. Both romidepsin and artemether; lumefantrine are associated with prolongation of the QT interval.
    Asenapine: (Major) Asenapine has been associated with QT prolongation. According to the manufacturer of asenapine, the drug should be avoided in combination with other agents also known to have this effect, such as romidepsin. Romidepsin has been reported to prolong the QT interval. If romidepsin and asenapine must be coadministered, appropriate cardiovascular monitoring precautions should be considered, such as the monitoring of electrolytes and ECGs at baseline and periodically during treatment.
    Aspirin, ASA; Butalbital; Caffeine: (Moderate) Romidepsin is a substrate for CYP3A4. Coadministration of CYP3A4 inducers, like barbiturates, may decrease systemic concentrations of romidepsin. Use caution when concomitant administration of these agents is necessary.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Romidepsin is a substrate for CYP3A4. Coadministration of CYP3A4 inducers, like barbiturates, may decrease systemic concentrations of romidepsin. Use caution when concomitant administration of these agents is necessary.
    Atazanavir: (Moderate) The concomitant use of romidepsin, a CYP3A4 substrate, and atazanavir, a strong CYP3A4 inhibitor, may increase romidepsin plasma exposure. If these agents are used together, monitor patients for signs and symptoms of romidepsin toxicity including hematologic toxicity, infection, and electrocardiogram changes; therapy interruption or discontinuation or a dosage reduction may be required if toxicity develops.
    Atazanavir; Cobicistat: (Moderate) Monitor for toxicity related to increased romidepsin exposure and follow the dose modifications for toxicity during initial administration of romidepsin with cobicistat. Romidepsin is a CYP3A4 and P-gp substrate; cobicistat is a P-gp inhibitor and strong CYP3A4 inhibitor. In a pharmacokinetic drug interaction trial a strong CYP3A4 inhibitor increased romidepsin AUC by approximately 25%. (Moderate) The concomitant use of romidepsin, a CYP3A4 substrate, and atazanavir, a strong CYP3A4 inhibitor, may increase romidepsin plasma exposure. If these agents are used together, monitor patients for signs and symptoms of romidepsin toxicity including hematologic toxicity, infection, and electrocardiogram changes; therapy interruption or discontinuation or a dosage reduction may be required if toxicity develops.
    Atomoxetine: (Moderate) Consider monitoring electrolytes and ECGs at baseline and periodically during treatment if romidepsin is administered with atomoxetine. Romidepsin has been reported to prolong the QT interval. QT prolongation has also occurred during hterapeutic use of atomoxetine and following overdose.
    Azithromycin: (Major) Avoid coadministration of azithromycin with romidepsin due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. QT prolongation and torsade de pointes (TdP) have been spontaneously reported during azithromycin postmarketing surveillance. Romidepsin has been reported to prolong the QT interval.
    Bedaquiline: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering bedaquiline with romidepsin. Both drugs have been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline electrocardiogram (ECG). An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) The concomitant use of romidepsin, a CYP3A4 substrate, and phenobarbital, a strong CYP3A4 inducer, may result in significantly altered romidepsin plasma exposure. Therefore, avoid using romidepsin with potent CYP3A4 inducers if possible.
    Bexarotene: (Moderate) Romidepsin is a substrate for CYP3A4. Coadministration of a CYP3A4 inducer, like bexarotene, may decrease systemic concentrations of romidepsin. Use caution when concomitant administration of these agents is necessary.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Moderate) Concomitant use of metronidazole and romidepsin may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Concomitant use of metronidazole and romidepsin may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
    Boceprevir: (Moderate) The concomitant use of romidepsin, a CYP3A4 substrate and a P-glycoprotein (P-gp) substrate, and boceprevir, a strong CYP3A4 inhibitor and a P-gp substrate and inhibitor, may increase romidepsin plasma exposure. If these agents are used together, monitor patients for signs and symptoms of romidepsin toxicity including hematologic toxicity, infection, and electrocardiogram changes; therapy interruption or discontinuation or a dosage reduction may be required if toxicity develops.
    Bosentan: (Moderate) Romidepsin is a substrate for CYP3A4. Coadministration of a CYP3A4 inducer, like bosentan, may decrease systemic concentrations of romidepsin. Use caution when concomitant administration of these agents is necessary.
    Brigatinib: (Moderate) Monitor for an increase in romidepsin-related adverse reactions if coadministration with brigatinib is necessary. Romidepsin 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.
    Buprenorphine: (Major) Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval, such as romidepsin. If coadministration is necessary, monitor electrolytes and ECG at baseline and periodically during treatment.
    Buprenorphine; Naloxone: (Major) Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval, such as romidepsin. If coadministration is necessary, monitor electrolytes and ECG at baseline and periodically during treatment.
    Butabarbital: (Moderate) Romidepsin is a substrate for CYP3A4. Coadministration of CYP3A4 inducers, like barbiturates, may decrease systemic concentrations of romidepsin. Use caution when concomitant administration of these agents is necessary.
    Butalbital; Acetaminophen: (Moderate) Romidepsin is a substrate for CYP3A4. Coadministration of CYP3A4 inducers, like barbiturates, may decrease systemic concentrations of romidepsin. Use caution when concomitant administration of these agents is necessary.
    Butalbital; Acetaminophen; Caffeine: (Moderate) Romidepsin is a substrate for CYP3A4. Coadministration of CYP3A4 inducers, like barbiturates, may decrease systemic concentrations of romidepsin. Use caution when concomitant administration of these agents is necessary.
    Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Romidepsin is a substrate for CYP3A4. Coadministration of CYP3A4 inducers, like barbiturates, may decrease systemic concentrations of romidepsin. Use caution when concomitant administration of these agents is necessary.
    Cabotegravir; Rilpivirine: (Moderate) Consider monitoring electrolytes and ECGs at baseline and periodically during treatment if romidepsin is administered with rilpivirine as concurrent use may increase the risk of QT prolongation. Romidepsin has been reported to prolong the QT interval. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Cabozantinib: (Minor) Monitor for an increase in romidepsin-related adverse reactions if coadministration with cabozantinib is necessary; a dose adjustment of romidepsin may be necessary. Romidepsin 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.
    Carbamazepine: (Major) The concomitant use of romidepsin, a CYP3A4 substrate, and carbamazepine, a strong CYP3A4 inducer, may result in significantly altered romidepsin plasma exposure. Therefore, avoid using romidepsin with potent CYP3A4 inducers if possible.
    Ceritinib: (Major) Avoid coadministration of ceritinib with romidepsin if possible due to the risk of QT prolongation; plasma concentrations of romidepsin may also increase. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Monitor for romidepsin-related adverse reactions and follow dose modifications for toxicity during initial administration. Romidepsin is a CYP3A4 substrate that has been reported to prolong the QT interval. Ceritinib is a strong CYP3A4 inhibitor that has been associated with concentration-dependent QT prolongation. In a pharmacokinetic drug interaction trial a strong CYP3A4 inhibitor increased romidepsin AUC by approximately 25%.
    Chloramphenicol: (Moderate) Romidepsin is a substrate for CYP3A4. Chloramphenicol is an inhibitor of CYP3A4. Concurrent administration of romidepsin with an inhibitor of CYP3A4 may cause an increase in systemic romidepsin concentrations. Use caution when concomitant administration of these agents is necessary.
    Chloroquine: (Major) Avoid coadministration of chloroquine with romidepsin due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Chloroquine is associated with an increased risk of QT prolongation and torsade de pointes (TdP); the risk of QT prolongation is increased with higher chloroquine doses. Romidepsin has been reported to prolong the QT interval.
    Chlorpromazine: (Major) Romidepsin has been reported to prolong the QT interval. If romidepsin must be coadministered with another drug that prolongs the QT interval, such as chlorpromazine, appropriate cardiovascular monitoring precautions should be considered, such as the monitoring of electrolytes and ECGs at baseline and periodically during treatment. Phenothiazines have been associated with a risk of QT prolongation and/or torsade de pointes (TdP). This risk is generally higher at elevated drugs concentrations of phenothiazines. Chlorpromazine is specifically associated with an established risk of QT prolongation and TdP; case reports have included patients receiving therapeutic doses of chlorpromazine.
    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: (Moderate) Romidepsin is a substrate for CYP3A4. Cimetidine is a mild inhibitor of CYP3A4. Concurrent administration of romidepsin with a mild CYP3A4 inhibitor may cause an increase in systemic romidepsin concentrations. Use caution when concomitant administration of these agents is necessary.
    Ciprofloxacin: (Moderate) Consider monitoring electrolytes and ECGs at baseline and periodically during treatment if romidepsin is administered with ciprofloxacin. Romidepsin has been reported to prolong the QT interval. Rare cases of QT prolongation and torsade de pointes (TdP) have been reported with ciprofloxacin during postmarketing surveillance.
    Cisapride: (Contraindicated) Romidepsin has been reported to prolong the QT interval. Because of the potential for torsade de pointes (TdP), use of cisapride with romidepsin is contraindicated.
    Citalopram: (Major) Citalopram causes dose-dependent QT interval prolongation. Romidepsin has been reported to prolong the QT interval. According to the manufacturer of citalopram, concurrent use of citalopram with other drugs that prolong the QT interval is not recommended. If concurrent therapy is considered essential, ECG monitoring is recommended.
    Clarithromycin: (Major) The concomitant use of romidepsin, a CYP3A4 substrate and a P-glycoprotein (P-gp) substrate, and clarithromycin, a strong CYP3A4 inhibitor and a P-gp inhibitor, may increase romidepsin plasma exposure. If these agents are used together, monitor patients for signs and symptoms of romidepsin toxicity including hematologic toxicity, infection, and electrocardiogram (ECG) changes; therapy interruption or discontinuation or a dosage reduction may be required if toxicity develops. In addition, romidepsin has been reported to prolong the QT interval. Clarithromycin may also prolong the QT interval. If romidepsin and the clarithromycin must be continued, appropriate cardiovascular monitoring precautions should be considered, such as the monitoring of electrolytes and ECGs at baseline and periodically during treatment.
    Clofazimine: (Major) Monitor ECG and electrolytes if clofazimine is coadministered with romidepsin due to the potential for additive QT prolongation. QT prolongation and torsade de pointes have been reported in patients receiving clofazimine in combination with QT prolonging medications. Romidepsin has been reported to prolong the QT interval.
    Clozapine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist. Additionally, treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Antineoplastic agents with a possible risk of QT prolongation and TdP (torsade de pointes) include romidepsin. In theory, coadministration could produce clinically significant prolongation of the QTc interval.
    Cobicistat: (Moderate) Monitor for toxicity related to increased romidepsin exposure and follow the dose modifications for toxicity during initial administration of romidepsin with cobicistat. Romidepsin is a CYP3A4 and P-gp substrate; cobicistat is a P-gp inhibitor and strong CYP3A4 inhibitor. In a pharmacokinetic drug interaction trial a strong CYP3A4 inhibitor increased romidepsin AUC by approximately 25%.
    Codeine; Phenylephrine; Promethazine: (Moderate) Consider monitoring electrolytes and ECGs at baseline and periodically during treatment if romidepsin is administered with promethazine as concurrent use may increase the risk of QT prolongation. Romidepsin has been reported to prolong the QT interval. Promethazine carries a possible risk of QT prolongation.
    Codeine; Promethazine: (Moderate) Consider monitoring electrolytes and ECGs at baseline and periodically during treatment if romidepsin is administered with promethazine as concurrent use may increase the risk of QT prolongation. Romidepsin has been reported to prolong the QT interval. Promethazine carries a possible risk of QT prolongation.
    Crizotinib: (Moderate) Avoid coadministration of crizotinib with romidepsin due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Romidepsin has also been reported to prolong the QT interval.
    Cyclosporine: (Moderate) Romidepsin is a substrate for P-glycoprotein (P-gp). Cyclosporine is an inhibitor of P-gp. Concurrent administration of romidepsin with an inhibitor of P-gp may cause an increase in systemic romidepsin concentrations. Use caution when concomitant administration of these agents is necessary.
    Daclatasvir: (Moderate) Systemic exposure of romidepsin, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a P-gp inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of romidepsin; monitor patients for potential adverse effects.
    Danazol: (Moderate) Romidepsin is a substrate for CYP3A4. Danazol is an inhibitor of CYP3A4. Concurrent administration of romidepsin with an inhibitor of CYP3A4 may cause an increase in systemic romidepsin concentrations. Use caution when concomitant administration of these agents is necessary.
    Darunavir: (Moderate) Concurrent administration of romidepsin and darunavir may cause an increase in systemic romidepsin concentrations. Use caution when concomitant administration of these agents is necessary. Romidepsin is a substrate for CYP3A4. Darunavir is an inhibitor of CYP3A4.
    Darunavir; Cobicistat: (Moderate) Concurrent administration of romidepsin and darunavir may cause an increase in systemic romidepsin concentrations. Use caution when concomitant administration of these agents is necessary. Romidepsin is a substrate for CYP3A4. Darunavir is an inhibitor of CYP3A4. (Moderate) Monitor for toxicity related to increased romidepsin exposure and follow the dose modifications for toxicity during initial administration of romidepsin with cobicistat. Romidepsin is a CYP3A4 and P-gp substrate; cobicistat is a P-gp inhibitor and strong CYP3A4 inhibitor. In a pharmacokinetic drug interaction trial a strong CYP3A4 inhibitor increased romidepsin AUC by approximately 25%.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Concurrent administration of romidepsin and darunavir may cause an increase in systemic romidepsin concentrations. Use caution when concomitant administration of these agents is necessary. Romidepsin is a substrate for CYP3A4. Darunavir is an inhibitor of CYP3A4. (Moderate) Monitor for toxicity related to increased romidepsin exposure and follow the dose modifications for toxicity during initial administration of romidepsin with cobicistat. Romidepsin is a CYP3A4 and P-gp substrate; cobicistat is a P-gp inhibitor and strong CYP3A4 inhibitor. In a pharmacokinetic drug interaction trial a strong CYP3A4 inhibitor increased romidepsin AUC by approximately 25%.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir with romidepsin may increase romidepsin concentrations and the risk for QT prolongation and torsade de pointes (TdP). Romidepsin is known to increase the QT interval. While dasabuvir; ombitasvir; paritaprevir; ritonavir did not prolong the QT interval to a clinically relevant extent in healthy subjects, ritonavir has been associated with dose-related QT prolongation in other trials. In addition, romidepsin is a CYP3A4 substrate and a P-glycoprotein (P-gp) substrate, while ritonavir is a strong inhibitor of CYP3A4 and P-gp. Paritaprevir is also a P-gp inhibitor. Therefore, coadministration may increase romidepsin plasma concentrations and further increase the risk of QT prolongation and romidepsin toxicity; dosage adjustments may be necessary. Caution and close monitoring is advised if these drugs are administered together. (Moderate) Monitor for toxicity related to increased romidepsin exposure and follow the dose modifications for toxicity during initial administration of romidepsin with ritonavir. Romidepsin is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. In a pharmacokinetic drug interaction trial a strong CYP3A4 inhibitor increased romidepsin AUC by approximately 25%.
    Dasatinib: (Moderate) Monitoring of electrolytes and ECGs at baseline and periodically during treatment is recommended if dasatinib and romidepsin are coadministered. Romidepsin has been reported to prolong the QT interval. In vitro studies have shown that dasatinib has the potential to prolong the QT interval.
    Degarelix: (Moderate) Consider monitoring electrolytes and ECGs at baseline and periodically during treatment if romidepsin is administered with degarelix as concurrent use may increase the risk of QT prolongation. Androgen deprivation therapy (i.e., degarelix) may prolong the QT/QTc interval. Romidepsin has been reported to prolong the QT interval.
    Delavirdine: (Moderate) The concomitant use of romidepsin, a CYP3A4 substrate, and delavirdine, a strong CYP3A4 inhibitor, may increase romidepsin plasma exposure. If these agents are used together, monitor patients for signs and symptoms of romidepsin toxicity including hematologic toxicity, infection, and electrocardiogram changes; therapy interruption or discontinuation or a dosage reduction may be required if toxicity develops.
    Desogestrel; Ethinyl Estradiol: (Major) The concomitant use of romidepsin and ethinyl estradiol may reduce the efficacy of ethinyl estradiol. Because romidepsin can cause fetal harm if administered to a pregnant woman, females of reproductive potential should use an alternative effective contraception method (e.g., condoms or intrauterine devices) during treatment with romidepsin and for at least 1 month after the final dose. Romidepsin showed high affinity for binding to estrogen receptors in pharmacology studies.
    Deutetrabenazine: (Moderate) Consider monitoring electrolytes and ECGs at baseline and periodically during treatment if romidepsin is administered with deutetrabenazine. Romidepsin has been reported to prolong the QT interval. Deutetrabenazine may prolong the QT interval, but the degree of QT prolongation is not clinically significant when deutetrabenazine is administered within the recommended dosage range.
    Dexamethasone: (Major) The concomitant use of romidepsin, a CYP3A4 substrate, and dexamethasone, a strong CYP3A4 inducer, may result in significantly altered romidepsin plasma exposure. Therefore, avoid using romidepsin with potent CYP3A4 inducers if possible.
    Dextromethorphan; Quinidine: (Major) Romidepsin is a substrate for P-glycoprotein (P-gp). Quinidine is an inhibitor of P-gp. Concurrent administration of romidepsin with an inhibitor of P-gp may cause an increase in systemic romidepsin concentrations. Use caution when concomitant administration of these agents is necessary. In addition, romidepsin has been reported to prolong the QT interval. Quinidine also prolongs the QT interval. If romidepsin and quinidine must be coadministered, appropriate cardiovascular monitoring precautions should be considered, such as the monitoring of electrolytes and ECGs at baseline and periodically during treatment.
    Dienogest; Estradiol valerate: (Major) The concomitant use of romidepsin and estradiol valerate may reduce the efficacy of estradiol valerate. Because romidepsin can cause fetal harm if administered to a pregnant woman, females of reproductive potential should use an alternative effective contraception method (e.g., condoms or intrauterine devices) during treatment with romidepsin and for at least 1 month after the final dose. Romidepsin showed high affinity for binding to estrogen receptors in pharmacology studies.
    Disopyramide: (Major) Romidepsin has been reported to prolong the QT interval. Disopyramide also prolongs the QT interval. If romidepsin and disopyramide must be continued, appropriate cardiovascular monitoring precautions should be considered, such as the monitoring of electrolytes and ECGs at baseline and periodically during treatment.
    Dofetilide: (Major) Coadministration of dofetilide and romidepsin is not recommended as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor electrolytes and ECGs at baseline and periodically during treatment. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Romidepsin has been reported to prolong the QT interval.
    Dolasetron: (Moderate) Consider monitoring electrolytes and ECGs at baseline and periodically during treatment if romidepsin is administered with dolasetron. Romidepsin has been reported to prolong the QT interval. Dolasetron has been associated with a dose-dependent prolongation in the QT, PR, and QRS intervals on an electrocardiogram.
    Dolutegravir; Rilpivirine: (Moderate) Consider monitoring electrolytes and ECGs at baseline and periodically during treatment if romidepsin is administered with rilpivirine as concurrent use may increase the risk of QT prolongation. Romidepsin has been reported to prolong the QT interval. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Donepezil: (Moderate) Consider monitoring electrolytes and ECGs at baseline and periodically during treatment if romidepsin is administered with donepezil as concurrent use may increase the risk of QT prolongation. Romidepsin has been reported to prolong the QT interval. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy.
    Donepezil; Memantine: (Moderate) Consider monitoring electrolytes and ECGs at baseline and periodically during treatment if romidepsin is administered with donepezil as concurrent use may increase the risk of QT prolongation. Romidepsin has been reported to prolong the QT interval. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy.
    Dronedarone: (Contraindicated) Concurrent use of romidepsin and dronedarone is contraindicated. Romidepsin has been reported to prolong the QT interval. Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
    Droperidol: (Major) Droperidol should be administered with extreme caution to patients receiving other agents that may prolong the QT interval. Droperidol administration is associated with an established risk for QT prolongation and torsades de pointes (TdP). Any drug known to have potential to prolong the QT interval should not be coadministered with droperidol. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with droperidol include romidepsin. If coadministration is necessary, appropriate cardiovascular monitoring precautions should be considered, such as the monitoring of electrolytes and ECGs at baseline and periodically during treatment.
    Drospirenone; Ethinyl Estradiol: (Major) The concomitant use of romidepsin and ethinyl estradiol may reduce the efficacy of ethinyl estradiol. Because romidepsin can cause fetal harm if administered to a pregnant woman, females of reproductive potential should use an alternative effective contraception method (e.g., condoms or intrauterine devices) during treatment with romidepsin and for at least 1 month after the final dose. Romidepsin showed high affinity for binding to estrogen receptors in pharmacology studies.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Major) The concomitant use of romidepsin and ethinyl estradiol may reduce the efficacy of ethinyl estradiol. Because romidepsin can cause fetal harm if administered to a pregnant woman, females of reproductive potential should use an alternative effective contraception method (e.g., condoms or intrauterine devices) during treatment with romidepsin and for at least 1 month after the final dose. Romidepsin showed high affinity for binding to estrogen receptors in pharmacology studies.
    Efavirenz: (Moderate) Consider alternatives to efavirenz and monitoring electrolytes and ECGs at baseline and periodically during treatment if administered with romidepsin as concurrent use may increase the risk of QT prolongation. Romidepsin has been reported to prolong the QT interval. QTc prolongation has been observed with the use of efavirenz.
    Efavirenz; Emtricitabine; Tenofovir: (Moderate) Consider alternatives to efavirenz and monitoring electrolytes and ECGs at baseline and periodically during treatment if administered with romidepsin as concurrent use may increase the risk of QT prolongation. Romidepsin has been reported to prolong the QT interval. QTc prolongation has been observed with the use of efavirenz.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Consider alternatives to efavirenz and monitoring electrolytes and ECGs at baseline and periodically during treatment if administered with romidepsin as concurrent use may increase the risk of QT prolongation. Romidepsin has been reported to prolong the QT interval. QTc prolongation has been observed with the use of efavirenz.
    Elbasvir; Grazoprevir: (Moderate) Administering romidepsin with elbasvir; grazoprevir may result in elevated romidepsin plasma concentrations. Romidepsin is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
    Eliglustat: (Moderate) Consider monitoring electrolytes and ECGs at baseline and periodically during treatment if romidepsin is administered with eliglustat. Romidepsin has been reported to prolong the QT interval. Eliglustat is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Monitor for toxicity related to increased romidepsin exposure and follow the dose modifications for toxicity during initial administration of romidepsin with cobicistat. Romidepsin is a CYP3A4 and P-gp substrate; cobicistat is a P-gp inhibitor and strong CYP3A4 inhibitor. In a pharmacokinetic drug interaction trial a strong CYP3A4 inhibitor increased romidepsin AUC by approximately 25%.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Monitor for toxicity related to increased romidepsin exposure and follow the dose modifications for toxicity during initial administration of romidepsin with cobicistat. Romidepsin is a CYP3A4 and P-gp substrate; cobicistat is a P-gp inhibitor and strong CYP3A4 inhibitor. In a pharmacokinetic drug interaction trial a strong CYP3A4 inhibitor increased romidepsin AUC by approximately 25%.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Consider monitoring electrolytes and ECGs at baseline and periodically during treatment if romidepsin is administered with rilpivirine as concurrent use may increase the risk of QT prolongation. Romidepsin has been reported to prolong the QT interval. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Moderate) Consider monitoring electrolytes and ECGs at baseline and periodically during treatment if romidepsin is administered with rilpivirine as concurrent use may increase the risk of QT prolongation. Romidepsin has been reported to prolong the QT interval. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Encorafenib: (Major) Avoid coadministration of encorafenib and romidepsin due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Romidepsin has been reported to prolong the QT interval.
    Entrectinib: (Major) Avoid coadministration of entrectinib with romidepsin due to the risk of QT prolongation. If coadministration is necessary, consider monitoring electrolytes and ECGs at baseline and periodically during treatment. Entrectinib has been associated with QT prolongation. Romidepsin has been reported to prolong the QT interval.
    Enzalutamide: (Major) Avoid coadministration of romidepsin with enzalutamide if possible due to decreased plasma concentrations of romidepsin. Romidepsin is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. The effect of strong CYP3A4 inducers on the exposure of romidepsin is unknown.
    Eribulin: (Major) Romidepsin has been reported to prolong the QT interval. If romidepsin must be coadministered with another drug that prolongs the QT interval, appropriate cardiovascular monitoring precautions should be considered, such as the monitoring of electrolytes and ECGs at baseline and periodically during treatment. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with romidepsin include eribulin.
    Erythromycin: (Major) Romidepsin is a substrate for CYP3A4 and P-glycoprotein (P-gp). Erythromycin is an inhibitor of CYP3A4 and P-gp. Concurrent administration of romidepsin with an inhibitor of CYP3A4 and P-gp may cause an increase in systemic romidepsin concentrations. Use caution when concomitant administration of these agents is necessary. In addition, romidepsin has been reported to prolong the QT interval. Erythromycin may also prolong the QT interval. If romidepsin and erythromycin must be continued, appropriate cardiovascular monitoring precautions should be considered, such as the monitoring of electrolytes and ECGs at baseline and periodically during treatment.
    Erythromycin; Sulfisoxazole: (Major) Romidepsin is a substrate for CYP3A4 and P-glycoprotein (P-gp). Erythromycin is an inhibitor of CYP3A4 and P-gp. Concurrent administration of romidepsin with an inhibitor of CYP3A4 and P-gp may cause an increase in systemic romidepsin concentrations. Use caution when concomitant administration of these agents is necessary. In addition, romidepsin has been reported to prolong the QT interval. Erythromycin may also prolong the QT interval. If romidepsin and erythromycin must be continued, appropriate cardiovascular monitoring precautions should be considered, such as the monitoring of electrolytes and ECGs at baseline and periodically during treatment.
    Escitalopram: (Moderate) Consider monitoring electrolytes and ECGs at baseline and periodically during treatment if romidepsin is administered with escitalopram. Romidepsin has been reported to prolong the QT interval. Escitalopram has been associated with a risk of QT prolongation and torsade de pointes (TdP).
    Estradiol Cypionate; Medroxyprogesterone: (Major) The concomitant use of romidepsin and estradiol cypionate may reduce the efficacy of estradiol cypionate. Because romidepsin can cause fetal harm if administered to a pregnant woman, females of reproductive potential should use an alternative effective contraception method (e.g., condoms or intrauterine devices) during treatment with romidepsin and for at least 1 month after the final dose. Romidepsin showed high affinity for binding to estrogen receptors in pharmacology studies.
    Estradiol: (Major) The concomitant use of romidepsin and estradiol cypionate may reduce the efficacy of estradiol cypionate. Because romidepsin can cause fetal harm if administered to a pregnant woman, females of reproductive potential should use an alternative effective contraception method (e.g., condoms or intrauterine devices) during treatment with romidepsin and for at least 1 month after the final dose. Romidepsin showed high affinity for binding to estrogen receptors in pharmacology studies. (Major) The concomitant use of romidepsin and estradiol valerate may reduce the efficacy of estradiol valerate. Because romidepsin can cause fetal harm if administered to a pregnant woman, females of reproductive potential should use an alternative effective contraception method (e.g., condoms or intrauterine devices) during treatment with romidepsin and for at least 1 month after the final dose. Romidepsin showed high affinity for binding to estrogen receptors in pharmacology studies.
    Ethinyl Estradiol: (Major) The concomitant use of romidepsin and ethinyl estradiol may reduce the efficacy of ethinyl estradiol. Because romidepsin can cause fetal harm if administered to a pregnant woman, females of reproductive potential should use an alternative effective contraception method (e.g., condoms or intrauterine devices) during treatment with romidepsin and for at least 1 month after the final dose. Romidepsin showed high affinity for binding to estrogen receptors in pharmacology studies.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Major) The concomitant use of romidepsin and ethinyl estradiol may reduce the efficacy of ethinyl estradiol. Because romidepsin can cause fetal harm if administered to a pregnant woman, females of reproductive potential should use an alternative effective contraception method (e.g., condoms or intrauterine devices) during treatment with romidepsin and for at least 1 month after the final dose. Romidepsin showed high affinity for binding to estrogen receptors in pharmacology studies.
    Ethinyl Estradiol; Norelgestromin: (Major) The concomitant use of romidepsin and ethinyl estradiol may reduce the efficacy of ethinyl estradiol. Because romidepsin can cause fetal harm if administered to a pregnant woman, females of reproductive potential should use an alternative effective contraception method (e.g., condoms or intrauterine devices) during treatment with romidepsin and for at least 1 month after the final dose. Romidepsin showed high affinity for binding to estrogen receptors in pharmacology studies.
    Ethinyl Estradiol; Norethindrone Acetate: (Major) The concomitant use of romidepsin and ethinyl estradiol may reduce the efficacy of ethinyl estradiol. Because romidepsin can cause fetal harm if administered to a pregnant woman, females of reproductive potential should use an alternative effective contraception method (e.g., condoms or intrauterine devices) during treatment with romidepsin and for at least 1 month after the final dose. Romidepsin showed high affinity for binding to estrogen receptors in pharmacology studies.
    Ethinyl Estradiol; Norgestrel: (Major) The concomitant use of romidepsin and ethinyl estradiol may reduce the efficacy of ethinyl estradiol. Because romidepsin can cause fetal harm if administered to a pregnant woman, females of reproductive potential should use an alternative effective contraception method (e.g., condoms or intrauterine devices) during treatment with romidepsin and for at least 1 month after the final dose. Romidepsin showed high affinity for binding to estrogen receptors in pharmacology studies.
    Ethynodiol Diacetate; Ethinyl Estradiol: (Major) The concomitant use of romidepsin and ethinyl estradiol may reduce the efficacy of ethinyl estradiol. Because romidepsin can cause fetal harm if administered to a pregnant woman, females of reproductive potential should use an alternative effective contraception method (e.g., condoms or intrauterine devices) during treatment with romidepsin and for at least 1 month after the final dose. Romidepsin showed high affinity for binding to estrogen receptors in pharmacology studies.
    Etonogestrel; Ethinyl Estradiol: (Major) The concomitant use of romidepsin and ethinyl estradiol may reduce the efficacy of ethinyl estradiol. Because romidepsin can cause fetal harm if administered to a pregnant woman, females of reproductive potential should use an alternative effective contraception method (e.g., condoms or intrauterine devices) during treatment with romidepsin and for at least 1 month after the final dose. Romidepsin showed high affinity for binding to estrogen receptors in pharmacology studies.
    Etravirine: (Moderate) Romidepsin is a substrate for CYP3A4 and P-glycoprotein (P-gp). Coadministration of a CYP3A4 inducer, like etravirine, may decrease systemic concentrations of romidepsin. Alternately, etravirine is an inhibitor of P-gp and may increase systemic concentrations of romidepsin. Use caution when concomitant administration of these agents is necessary.
    Ezogabine: (Moderate) Consider monitoring electrolytes and ECGs at baseline and periodically during treatment if romidepsin is administered with ezogabine as concurrent use may increase the risk of QT prolongation. Both romidepsin and ezogabine have been reported to prolong the QT interval.
    Fingolimod: (Moderate) Consider monitoring electrolytes and ECGs at baseline and periodically during treatment if romidepsin is administered with romidepsin as concurrent use may increase the risk of QT prolongation. Romidepsin has been reported to prolong the QT interval. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
    Flecainide: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering romidepsin with flecainide. If these drugs must be administered together, appropriate cardiovascular monitoring precautions should be considered, such as the monitoring of electrolytes and ECGs at baseline and periodically during treatment. Romidepsin has been reported to prolong the QT interval. Flecainide, a Class IC antiarrhythmic, is also associated with a possible risk for QT prolongation and/or TdP; flecainide increases the QT interval, but largely due to prolongation of the QRS interval. Although causality for TdP has not been established for flecainide, patients receiving concurrent drugs which have the potential for QT prolongation may have an increased risk of developing proarrhythmias.
    Fluconazole: (Contraindicated) Concurrent use of fluconazole and romidepsin is contraindicated due to the risk of life threatening arrhythmias such as torsade de pointes (TdP). Fluconazole inhibits CYP3A4, an isoenzyme responsible for the metabolism of romidepsin. These drugs used in combination may result in elevated romidepsin plasma concentrations, causing an increased risk for romidepsin-related adverse events, such as QT prolongation. Additionally, fluconazole has been associated with prolongation of the QT interval as well as rare cases of TdP.
    Fluoxetine: (Moderate) Consider monitoring electrolytes and ECGs at baseline and periodically during treatment if romidepsin is administered with fluoxetine. QT prolongation and TdP have been reported in patients treated with fluoxetine. Romidepsin has also been reported to prolong the QT interval.
    Fluphenazine: (Minor) Consider monitoring electrolytes and ECGs at baseline and periodically during treatment if romidepsin is administered with fluphenazine. Romidepsin has been reported to prolong the QT interval. Fluphenazine is associated with a possible risk for QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
    Flutamide: (Moderate) Romidepsin is a substrate for CYP3A4. Coadministration of a CYP3A4 inducer, like flutamide, may decrease systemic concentrations of romidepsin. Use caution when concomitant administration of these agents is necessary.
    Fluvoxamine: (Major) There may be an increased risk for QT prolongation, torsade de pointes (TdP), and elevated romidepsin concentrations during concurrent use of fluvoxamine and romidepsin. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. Romidepsin has been reported to prolong the QT interval. If romidepsin must be coadministered with another drug that prolongs the QT interval, consider cardiac monitoring, such as monitoring electrolytes and ECGs at baseline and periodically during treatment. In addition, romidepsin is a substrate for CYP3A4 and fluvoxamine is a moderate inhibitor of CYP3A4. Concurrent administration may cause an increase in systemic romidepsin concentrations. Monitor for romidepsin-related adverse effects.
    Fosamprenavir: (Moderate) Concomitant use of romidepsin and fosamprenavir may result in altered romidepsin plasma concentrations. Romidepsin is a substrate of the hepatic isoenzyme CYP3A4 and drug transporter P-glycoprotein (P-gp). Amprenavir, the active metabolite of fosamprenavir, is an inducer of P-gp and a potent inhibitor and moderate inducer of CYP3A4. If these agents are used together, monitor patients for signs and symptoms of romidepsin toxicity including hematologic toxicity, infection, and electrocardiogram changes; therapy interruption or discontinuation or a dosage reduction may be required if toxicity develops.
    Foscarnet: (Major) When possible, avoid concurrent use of foscarnet with other drugs known to prolong the QT interval, such as romidepsin. Foscarnet has been associated with postmarketing reports of both QT prolongation and torsade de pointes (TdP). Romidepsin has been reported to prolong the QT interval. If these drugs must be coadministered, appropriate cardiovascular monitoring precautions should be considered, such as the monitoring of electrolytes and ECGs at baseline and periodically during treatment.
    Fosphenytoin: (Major) The concomitant use of romidepsin, a CYP3A4 substrate, and phenytoin or fosphenytoin, a strong CYP3A4 inducer, may result in significantly altered romidepsin plasma exposure. Therefore, avoid using romidepsin with potent CYP3A4 inducers if possible.
    Fostamatinib: (Moderate) Monitor for romidepsin toxicities that may require romidepsin dose reduction if given concurrently with fostamatinib. Concomitant use of fostamatinib with a P-gp substrate may increase the concentration of the P-gp substrate. Fostamatinib is a P-gp inhibitor; romidepsin is a substrate for P-gp. Coadministration of fostamatinib with another P-gp substrate increased the P-gp substrate AUC by 37% and Cmax by 70%.
    Fostemsavir: (Moderate) Consider monitoring electrolytes and ECGs at baseline and periodically during treatment if romidepsin is administered with fostemsavir. Romidepsin has been reported to prolong the QT interval. Supratherapeutic doses of fostemsavir (2,400 mg twice daily, four times the recommended daily dose) have been shown to cause QT prolongation. Fostemsavir causes dose-dependent QT prolongation.
    Gemifloxacin: (Moderate) Consider monitoring electrolytes and ECGs at baseline and periodically during treatment if romidepsin is administered with gemifloxacin as concurrent use may increase the risk of QT prolongation. Romidepsin has been reported to prolong the QT interval. Gemifloxacin may prolong the QT interval in some patients. The maximal change in QTc interval occurs approximately 5 to 10 hours following oral administration of gemifloxacin. The likelihood of QTc prolongation may increase with increasing dose of the drug; therefore, the recommended dose should not be exceeded especially in patients with renal or hepatic impairment where the Cmax and AUC are slightly higher.
    Gemtuzumab Ozogamicin: (Moderate) Use gemtuzumab ozogamicin and romidepsin together with caution due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If these agents are used together, obtain an ECG and serum electrolytes prior to the start of gemtuzumab and as needed during treatment. Although QT interval prolongation has not been reported with gemtuzumab, it has been reported with other drugs that contain calicheamicin. Romidepsin has also been reported to prolong the QT interval.
    Gilteritinib: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and romidepsin is necessary. Consider monitoring of electrolytes and ECGs at baseline and periodically during treatment. Both drugs have been associated with QT prolongation.
    Glasdegib: (Major) Avoid coadministration of glasdegib with romidepsin due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with electrolyte monitoring and increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Romidepsin has also been reported to prolong the QT interval.
    Glecaprevir; Pibrentasvir: (Moderate) Caution is advised with the coadministration of glecaprevir and romidepsin as coadministration may increase serum concentrations of romidepsin and increase the risk of adverse effects. Romidepsin is a substrate of P-glycoprotein (P-gp); glecaprevir is a P-gp inhibitor. (Moderate) Caution is advised with the coadministration of pibrentasvir and romidepsin as coadministration may increase serum concentrations of romidepsin and increase the risk of adverse effects. Romidepsin is a substrate of P-glycoprotein (P-gp); pibrentasvir is an inhibitor of P-gp.
    Goserelin: (Moderate) Monitor ECGs for QT prolongation and monitor electrolytes at baseline and periodically during treatment if coadministration of romidepsin with goserelin is necessary. Romidepsin has been reported to prolong the QT interval. Androgen deprivation therapy (i.e., goserelin) may also prolong the QT/QTc interval.
    Granisetron: (Moderate) Consider monitoring electrolytes and ECGs at baseline and periodically during treatment if romidepsin is administered with granisetron. Romidepsin has been reported to prolong the QT interval. Granisetron has been associated with QT prolongation.
    Grapefruit juice: (Moderate) The concomitant use of romidepsin, a CYP3A4 substrate, and grapefruit juice, a CYP3A4 inhibitor, may increase romidepsin plasma exposure.
    Halogenated Anesthetics: (Major) Romidepsin has been reported to prolong the QT interval. Halogenated anesthetics can prolong the QT interval. If romidepsin must be coadministered with a halogenated anesthetic, appropriate cardiovascular monitoring precautions should be considered, such as the monitoring of electrolytes and ECGs at baseline and periodically during treatment.
    Haloperidol: (Moderate) Consider monitoring electrolytes and ECGs at baseline and periodically during treatment if romidepsin is administered with haloperidol. Romidepsin has been reported to prolong the QT interval. QT prolongation and torsade de pointes (TdP) have been observed during haloperidol treatment. Excessive doses (particularly in the overdose setting) or IV administration of haloperidol may be associated with a higher risk of QT prolongation.
    Histrelin: (Moderate) Monitor ECGs for QT prolongation and monitor electrolytes at baseline and periodically during treatment if coadministration of romidepsin with histrelin is necessary. Romidepsin has been reported to prolong the QT interval. Androgen deprivation therapy (i.e., histrelin) may also prolong the QT/QTc interval.
    Hydroxychloroquine: (Major) Avoid coadministration of romidepsin and hydroxychloroquine due to an increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Hydroxychloroquine prolongs the QT interval. Romidepsin has been reported to prolong the QT interval.
    Hydroxyzine: (Moderate) Consider monitoring electrolytes and ECGs at baseline and periodically during treatment if romidepsin is administered with hydroxyzine. Romidepsin has been reported to prolong the QT interval. Postmarketing data indicate that hydroxyzine causes QT prolongation and torsade de pointes.
    Ibutilide: (Major) Romidepsin has been reported to prolong the QT interval. Ibutilide administration can cause QT prolongation and torsades de pointes (TdP); proarrhythmic events should be anticipated. The potential for proarrhythmic events with ibutilide increases with the coadministration of other drugs that prolong the QT interval. If romidepsin and ibutilide must be continued, appropriate cardiovascular monitoring precautions should be considered, such as the monitoring of electrolytes and ECGs at baseline and periodically during treatment.
    Iloperidone: (Major) Iloperidone has been associated with QT prolongation; however, torsade de pointes (TdP) has not been reported. According to the manufacturer, since iloperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect, such as romidepsin. If coadministration is necessary, appropriate cardiovascular monitoring precautions should be considered, such as the monitoring of electrolytes and ECGs at baseline and periodically during treatment.
    Imatinib: (Moderate) Romidepsin is a substrate for CYP3A4. Imatinib, STI-571 is an inhibitor of CYP3A4. Concurrent administration of romidepsin with an inhibitor of CYP3A4 may cause an increase in systemic romidepsin concentrations. Use caution when concomitant administration of these agents is necessary.
    Indinavir: (Moderate) The concomitant use of romidepsin, a CYP3A4 substrate, and indinavir, a strong CYP3A4 inhibitor, may increase romidepsin plasma exposure. If these agents are used together, monitor patients for signs and symptoms of romidepsin toxicity including hematologic toxicity, infection, and electrocardiogram changes; therapy interruption or discontinuation or a dosage reduction may be required if toxicity develops.
    Inotuzumab Ozogamicin: (Major) Avoid coadministration of inotuzumab ozogamicin with romidepsin due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Romidepsin has also been reported to prolong the QT interval.
    Isavuconazonium: (Moderate) Caution is warranted when isavuconazonium is administered with romidepsin as there is a potential for elevated romidepsin concentrations. Clinical monitoring for adverse effects is recommended during coadministration. Romidepsin 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.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) The concomitant use of romidepsin, a CYP3A4 substrate and a P-glycoprotein (P-gp) substrate, and rifampin, a strong CYP3A4 inducer and a P-gp inhibitor and substrate, increased the romidepsin plasma exposure in a drug interaction trial in patients with advanced cancer. Avoid using romidepsin with potent CYP3A4 inducers if possible. Following a 4-hour infusion of romidepsin 14mg/m2 IV administered with multiple oral doses of rifampin, the AUC and Cmax values of romidepsin were increased by 80% and 60%, respectively, compared with romidepsin alone; these increases were statistically significant. Co-administration of rifampin decreased the romidepsin clearance and volume of distribution by 44% and 52%, respectively. Typically, administering a CYP3A4 substrate with a strong CYP3A4 inducer would decrease the substrate exposure; this interaction may be due to the P-gp inhibitor effect of rifampin or because of another undetermined hepatic uptake process that rifampin inhibits. If these agents are used together, monitor patients for signs and symptoms of romidepsin toxicity including hematologic toxicity, infection, and electrocardiogram changes; therapy interruption or discontinuation or a dosage reduction may be required if toxicity develops.
    Isoniazid, INH; Rifampin: (Major) The concomitant use of romidepsin, a CYP3A4 substrate and a P-glycoprotein (P-gp) substrate, and rifampin, a strong CYP3A4 inducer and a P-gp inhibitor and substrate, increased the romidepsin plasma exposure in a drug interaction trial in patients with advanced cancer. Avoid using romidepsin with potent CYP3A4 inducers if possible. Following a 4-hour infusion of romidepsin 14mg/m2 IV administered with multiple oral doses of rifampin, the AUC and Cmax values of romidepsin were increased by 80% and 60%, respectively, compared with romidepsin alone; these increases were statistically significant. Co-administration of rifampin decreased the romidepsin clearance and volume of distribution by 44% and 52%, respectively. Typically, administering a CYP3A4 substrate with a strong CYP3A4 inducer would decrease the substrate exposure; this interaction may be due to the P-gp inhibitor effect of rifampin or because of another undetermined hepatic uptake process that rifampin inhibits. If these agents are used together, monitor patients for signs and symptoms of romidepsin toxicity including hematologic toxicity, infection, and electrocardiogram changes; therapy interruption or discontinuation or a dosage reduction may be required if toxicity develops.
    Itraconazole: (Major) The concomitant use of romidepsin, a CYP3A4 substrate, and itraconazole, a strong CYP3A4 inhibitor, may increase romidepsin plasma exposure. If these agents are used together, monitor patients for signs and symptoms of romidepsin toxicity including hematologic toxicity, infection, and electrocardiogram (ECG) changes; therapy interruption or discontinuation or a dosage reduction may be required if toxicity develops. Additionally, itraconazole has been associated with QT prolongation and rare cases of torsade de pointes and changes in ECGs (including T-wave and ST-segment changes) have been reported with romidepsin use. If romidepsin is administered with agents that may cause significant QT prolongation, such as itraconazole, appropriate cardiovascular monitoring precautions should be considered, such as the monitoring of electrolytes and electrocardiograms at baseline and periodically during treatment. If itraconazole therapy is stopped, it may be prudent to continue close monitoring for up to 2 weeks after discontinuing itraconazole. Once discontinued, the plasma concentration of itraconazole decreases to almost undetectable concentrations within 7 to 14 days. The decline in plasma concentrations may be even more gradual in patients with hepatic cirrhosis or who are receiving concurrent CYP3A4 inhibitors.
    Ivosidenib: (Major) Avoid coadministration of ivosidenib with romidepsin due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Romidepsin has been reported to prolong the QT interval.
    Ketoconazole: (Major) The concomitant use of romidepsin, a CYP3A4 substrate, and ketoconazole, a strong CYP3A4 inhibitor, may increase romidepsin plasma exposure. If these agents are used together, monitor patients for signs and symptoms of romidepsin toxicity including hematologic toxicity, infection, and electrocardiogram (ECG) changes; therapy interruption or discontinuation or a dosage reduction may be required if toxicity develops. Additionally, ketoconazole has been associated with QT prolongation and rare cases of torsade de pointes and changes in ECGs (including T-wave and ST-segment changes) have been reported with romidepsin use. If romidepsin is administered with agents that may cause significant QT prolongation, such as ketoconazole, appropriate cardiovascular monitoring precautions should be considered, such as the monitoring of electrolytes and electrocardiograms at baseline and periodically during treatment. Following a 4-hour infusion of romidepsin 8 mg/m2 IV administered with multiple oral doses of ketoconazole, the AUC and Cmax values of romidepsin were increased by 25% and 10%, respectively, compared with romidepsin alone; the increase was statistically significant for AUC.
    Lansoprazole; Amoxicillin; Clarithromycin: (Major) The concomitant use of romidepsin, a CYP3A4 substrate and a P-glycoprotein (P-gp) substrate, and clarithromycin, a strong CYP3A4 inhibitor and a P-gp inhibitor, may increase romidepsin plasma exposure. If these agents are used together, monitor patients for signs and symptoms of romidepsin toxicity including hematologic toxicity, infection, and electrocardiogram (ECG) changes; therapy interruption or discontinuation or a dosage reduction may be required if toxicity develops. In addition, romidepsin has been reported to prolong the QT interval. Clarithromycin may also prolong the QT interval. If romidepsin and the clarithromycin must be continued, appropriate cardiovascular monitoring precautions should be considered, such as the monitoring of electrolytes and ECGs at baseline and periodically during treatment.
    Lapatinib: (Major) Monitor for an increase in treatment-related adverse reactions if coadministration with romidepsin is necessary. Lapatinib is a P-glycoprotein (P-gp) substrate/inhibitor that has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have also been reported in postmarketing experience. Romidepsin is also a P-gp substrate/inhibitor that has been reported to prolong the QT interval. Increased plasma concentrations of both drugs are likely when administered with P-gp inhibitors.
    Lefamulin: (Major) Avoid coadministration of lefamulin with romidepsin as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECGs and electrolytes at baseline and periodically during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Romidepsin has been reported to prolong the QT interval.
    Lenvatinib: (Major) Avoid coadministration of lenvatinib with romidepsin due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Romidepsin has also been reported to prolong the QT interval.
    Letermovir: (Moderate) A clinically relevant increase in the plasma concentration of romidepsin may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Romidepsin is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. In a drug interaction study, administration of romidepsin with another strong CYP3A4 inhibitor increased romidepsin concentration by approximately 25%.
    Leuprolide: (Moderate) Monitor ECGs and monitor electrolytes at baseline and periodically during treatment if coadministration of romidepsin with leuprolide is necessary as concurrent use may increase the risk of QT prolongation. Romidepsin has been reported to prolong the QT interval. Androgen deprivation therapy (i.e., leuprolide) may also prolong the QT/QTc interval.
    Leuprolide; Norethindrone: (Moderate) Monitor ECGs and monitor electrolytes at baseline and periodically during treatment if coadministration of romidepsin with leuprolide is necessary as concurrent use may increase the risk of QT prolongation. Romidepsin has been reported to prolong the QT interval. Androgen deprivation therapy (i.e., leuprolide) may also prolong the QT/QTc interval.
    Levofloxacin: (Moderate) Consider monitoring electrolytes and ECGs at baseline and periodically during treatment if romidepsin is administered with levofloxacin. Romidepsin has been reported to prolong the QT interval. Levofloxacin has been associated with a risk of QT prolongation and torsade de pointes (TdP). Although extremely rare, TdP has been reported during postmarketing surveillance of levofloxacin.
    Levoketoconazole: (Major) The concomitant use of romidepsin, a CYP3A4 substrate, and ketoconazole, a strong CYP3A4 inhibitor, may increase romidepsin plasma exposure. If these agents are used together, monitor patients for signs and symptoms of romidepsin toxicity including hematologic toxicity, infection, and electrocardiogram (ECG) changes; therapy interruption or discontinuation or a dosage reduction may be required if toxicity develops. Additionally, ketoconazole has been associated with QT prolongation and rare cases of torsade de pointes and changes in ECGs (including T-wave and ST-segment changes) have been reported with romidepsin use. If romidepsin is administered with agents that may cause significant QT prolongation, such as ketoconazole, appropriate cardiovascular monitoring precautions should be considered, such as the monitoring of electrolytes and electrocardiograms at baseline and periodically during treatment. Following a 4-hour infusion of romidepsin 8 mg/m2 IV administered with multiple oral doses of ketoconazole, the AUC and Cmax values of romidepsin were increased by 25% and 10%, respectively, compared with romidepsin alone; the increase was statistically significant for AUC.
    Levonorgestrel; Ethinyl Estradiol: (Major) The concomitant use of romidepsin and ethinyl estradiol may reduce the efficacy of ethinyl estradiol. Because romidepsin can cause fetal harm if administered to a pregnant woman, females of reproductive potential should use an alternative effective contraception method (e.g., condoms or intrauterine devices) during treatment with romidepsin and for at least 1 month after the final dose. Romidepsin showed high affinity for binding to estrogen receptors in pharmacology studies.
    Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Major) The concomitant use of romidepsin and ethinyl estradiol may reduce the efficacy of ethinyl estradiol. Because romidepsin can cause fetal harm if administered to a pregnant woman, females of reproductive potential should use an alternative effective contraception method (e.g., condoms or intrauterine devices) during treatment with romidepsin and for at least 1 month after the final dose. Romidepsin showed high affinity for binding to estrogen receptors in pharmacology studies.
    Lithium: (Moderate) Consider monitoring electrolytes and ECGs at baseline and periodically during treatment if romidepsin is administered with lithium as concurrent use may increase the risk of QT prolongation. Romidepsin has been reported to prolong the QT interval. Lithium has been associated with QT prolongation.
    Lofexidine: (Major) Monitor ECG and electrolytes if lofexidine is coadministered with romidepsin due to the potential for additive QT prolongation. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes. Romidepsin has been reported to prolong the QT interval.
    Lonafarnib: (Moderate) Monitor for toxicity related to increased romidepsin exposure and follow the dose modifications for toxicity during initial administration of romidepsin with lonafarnib. Romidepsin is a CYP3A4 substrate; lonafarnib is a strong CYP3A4 inhibitor. In a pharmacokinetic drug interaction trial, a strong CYP3A4 inhibitor increased romidepsin AUC by approximately 25%.
    Loperamide: (Moderate) Consider monitoring electrolytes and ECGs at baseline and periodically during treatment if romidepsin is administered with loperamide as concurrent use may increase the risk of QT prolongation. Romidepsin has been reported to prolong the QT interval. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest.
    Loperamide; Simethicone: (Moderate) Consider monitoring electrolytes and ECGs at baseline and periodically during treatment if romidepsin is administered with loperamide as concurrent use may increase the risk of QT prolongation. Romidepsin has been reported to prolong the QT interval. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest.
    Lopinavir; Ritonavir: (Major) Avoid coadministration of lopinavir with romidepsin due to the potential for additive QT prolongation. If use together is necessary, obtain a baseline ECG to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Lopinavir is associated with QT prolongation. Romidepsin has also been reported to prolong the QT interval. (Moderate) Monitor for toxicity related to increased romidepsin exposure and follow the dose modifications for toxicity during initial administration of romidepsin with ritonavir. Romidepsin is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. In a pharmacokinetic drug interaction trial a strong CYP3A4 inhibitor increased romidepsin AUC by approximately 25%.
    Lumacaftor; Ivacaftor: (Major) Lumacaftor; ivacaftor is expected to alter the systemic exposure of romidepsin; avoid concomitant use if possible. Romidepsin is extensively metabolized by CYP3A4, and lumacaftor is a strong CYP3A inducer. Typically, coadministration of CYP3A inducers (e.g., lumacaftor; ivacaftor) decreases the plasma concentrations of CYP3A substrates (e.g., romidepsin). However, coadministration of romidepsin with rifampin, another strong CYP3A inducer, resulted in an approximate 80% and 60% increase in romidepsin AUC and Cmax, respectively. This increase in exposure is likely due to rifampin's inhibition of an undetermined hepatic uptake process that is predominantly responsible for the disposition of romidepsin; it is not known whether lumacaftor; ivacaftor would have similar effects.
    Lumacaftor; Ivacaftor: (Major) Lumacaftor; ivacaftor is expected to alter the systemic exposure of romidepsin; avoid concomitant use if possible. Romidepsin is extensively metabolized by CYP3A4, and lumacaftor is a strong CYP3A inducer. Typically, coadministration of CYP3A inducers (e.g., lumacaftor; ivacaftor) decreases the plasma concentrations of CYP3A substrates (e.g., romidepsin). However, coadministration of romidepsin with rifampin, another strong CYP3A inducer, resulted in an approximate 80% and 60% increase in romidepsin AUC and Cmax, respectively. This increase in exposure is likely due to rifampin's inhibition of an undetermined hepatic uptake process that is predominantly responsible for the disposition of romidepsin; it is not known whether lumacaftor; ivacaftor would have similar effects.
    Macimorelin: (Major) Avoid concurrent administration of macimorelin with drugs that prolong the QT interval, such as romidepsin. Use of these drugs together may increase the risk of developing torsade de pointes-type ventricular tachycardia. Sufficient washout time of drugs that are known to prolong the QT interval prior to administration of macimorelin is recommended. Treatment with macimorelin has been associated with an increase in the corrected QT (QTc) interval. Romidepsin has also been reported to prolong the QT interval.
    Maprotiline: (Moderate) Consider monitoring electrolytes and ECGs at baseline and periodically during treatment if romidepsin is administered with maprotiline as concurrent use may increase the risk of QT prolongation. Romidepsin has been reported to prolong the QT interval. Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs.
    Mefloquine: (Moderate) Consider monitoring electrolytes and ECGs at baseline and periodically during treatment if romidepsin is administered with mefloquine as concurrent use may increase the risk of QT prolongation. Romidepsin has been reported to prolong the QT interval. There is evidence that the use of halofantrine after mefloquine causes a significant lengthening of the QTc interval. Mefloquine alone has not been reported to cause QT prolongation.
    Meperidine; Promethazine: (Moderate) Consider monitoring electrolytes and ECGs at baseline and periodically during treatment if romidepsin is administered with promethazine as concurrent use may increase the risk of QT prolongation. Romidepsin has been reported to prolong the QT interval. Promethazine carries a possible risk of QT prolongation.
    Mephobarbital: (Moderate) Romidepsin is a substrate for CYP3A4. Coadministration of CYP3A4 inducers, like barbiturates, may decrease systemic concentrations of romidepsin. Use caution when concomitant administration of these agents is necessary.
    Mestranol; Norethindrone: (Major) The concomitant use of romidepsin and mestranol may reduce the efficacy of mestranol. Because romidepsin can cause fetal harm if administered to a pregnant woman, females of reproductive potential should use an alternative effective contraception method (e.g., condoms or intrauterine devices) during treatment with romidepsin and for at least 1 month after the final dose. Romidepsin showed high affinity for binding to estrogen receptors in pharmacology studies
    Methadone: (Major) Romidepsin has been reported to prolong the QT interval. The need to coadminister methadone with drugs known to prolong the QT interval should be done with extreme caution and a careful assessment of treatment risks versus benefits. Methadone is considered to be associated with an increased risk for QT prolongation and torsades de pointes (TdP), especially at higher doses (> 200 mg/day but averaging approximately 400 mg/day in adult patients). Laboratory studies, both in vivo and in vitro, have demonstrated that methadone inhibits cardiac potassium channels and prolongs the QT interval. Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction. If romidepsin and methadone must be coadministered, appropriate cardiovascular monitoring precautions should be considered, such as the monitoring of electrolytes and ECGs at baseline and periodically during treatment.
    Methohexital: (Moderate) Romidepsin is a substrate for CYP3A4. Coadministration of CYP3A4 inducers, like barbiturates, may decrease systemic concentrations of romidepsin. Use caution when concomitant administration of these agents is necessary.
    Metronidazole: (Moderate) Concomitant use of metronidazole and romidepsin may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
    Midostaurin: (Major) The concomitant use of midostaurin and romidepsin may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring at baseline and periodically during treatment. Correct electrolyte abnormalities, particularly potassium and magnesium levels, prior to starting romidepsin. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin and in patients who received romidepsin.
    Mifepristone: (Major) Avoid use together if possible. Both romidepsin and mifepristone have been reported to prolong the QT interval. If romidepsin must be coadministered with another drug that prolongs the QT interval, appropriate cardiovascular monitoring precautions should be considered, such as the monitoring of electrolytes and ECGs at baseline and periodically during treatment. To minimize the risk of QT prolongation, the lowest effect dose of mifepristone should always be used when it is given chronically for hormonal conditions, such as Cushing's syndrome. In addition, romidepsin is a substrate for CYP3A4 and P-glycoprotein (P-gp). Mifepristone is a CYP3A4 inhibitor and may inhibit P-gp. Concurrent administration of romidepsin with an inhibitor of CYP3A4 and P-gp may cause an increase in systemic romidepsin concentrations. Monitor for toxicity related to increased romidepsin exposure, including hematologic and non-hematologic toxicity and follow the romidepsin dose modifications for toxicity as clinically indicated.
    Mirtazapine: (Moderate) Consider monitoring electrolytes and ECGs at baseline and periodically during treatment if romidepsin is administered with mirtazapine as concurrent use may increase the risk of QT prolongation. Romidepsin has been reported to prolong the QT interval. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported postmarketing, primarily in overdose or in patients with other risk factors for QT prolongation.
    Mitotane: (Major) Avoid the concomitant use of mitotane with romidepsin due to possible decreases in exposure and efficacy. Mitotane is a strong CYP3A4 inducer and romidepsin is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of romidepsin. Formal drug interaction studies have not been completed for romidepsin.
    Mobocertinib: (Major) Concomitant use of mobocertinib and romidepsin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Modafinil: (Moderate) Romidepsin is a substrate for CYP3A4. Coadministration of a CYP3A4 inducer, like modafinil, may decrease systemic concentrations of romidepsin. Use caution when concomitant administration of these agents is necessary.
    Moxifloxacin: (Major) Concurrent use of romidepsin and moxifloxacin should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). If these drugs must be coadministered, appropriate cardiovascular monitoring precautions should be considered, such as the monitoring of electrolytes and ECGs at baseline and periodically during treatment. Romidepsin has been reported to prolong the QT interval. Moxifloxacin has also been associated with prolongation of the QT interval. Additionally, post-marketing surveillance has identified very rare cases of ventricular arrhythmias including TdP, usually in patients with severe underlying proarrhythmic conditions. The likelihood of QT prolongation may increase with increasing concentrations of moxifloxacin, therefore the recommended dose or infusion rate should not be exceeded.
    Nafcillin: (Moderate) Romidepsin is a substrate for CYP3A4. Coadministration of a CYP3A4 inducer, like nafcillin, may decrease systemic concentrations of romidepsin. Use caution when concomitant administration of these agents is necessary.
    Nefazodone: (Moderate) The concomitant use of romidepsin, a CYP3A4 substrate, and nefazodone, a strong CYP3A4 inhibitor, may increase romidepsin plasma exposure. If these agents are used together, monitor patients for signs and symptoms of romidepsin toxicity including hematologic toxicity, infection, and electrocardiogram changes; therapy interruption or discontinuation or a dosage reduction may be required if toxicity develops.
    Nelfinavir: (Moderate) The concomitant use of romidepsin, a CYP3A4 substrate and a P-glycoprotein (P-gp) substrate, and nelfinavir, a strong CYP3A4 inhibitor and a P-gp substrate and inhibitor, may increase romidepsin plasma exposure. If these agents are used together, monitor patients for signs and symptoms of romidepsin toxicity including hematologic toxicity, infection, and electrocardiogram changes; therapy interruption or discontinuation or a dosage reduction may be required if toxicity develops.
    Nevirapine: (Moderate) Romidepsin is a substrate for CYP3A4. Coadministration of a CYP3A4 inducer, like nevirapine, may decrease systemic concentrations of romidepsin. Use caution when concomitant administration of these agents is necessary.
    Nilotinib: (Major) Avoid the concomitant use of nilotinib with other agents that prolong the QT interval, such as romidepsin. Nilotinib is a moderate inhibitor of CYP3A4 and romidepsin is a substrate of CYP3A4; administering these drugs together may result in increased romidepsin levels. If the use of romidepsin is necessary, hold nilotinib therapy. If these drugs are used together, consider a romidepsin dose reduction and monitor patients for toxicity (e.g., QT interval prolongation).
    Nirmatrelvir; Ritonavir: (Moderate) Monitor for toxicity related to increased romidepsin exposure and follow the dose modifications for toxicity during initial administration of romidepsin with ritonavir. Romidepsin is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. In a pharmacokinetic drug interaction trial a strong CYP3A4 inhibitor increased romidepsin AUC by approximately 25%.
    Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Major) The concomitant use of romidepsin and ethinyl estradiol may reduce the efficacy of ethinyl estradiol. Because romidepsin can cause fetal harm if administered to a pregnant woman, females of reproductive potential should use an alternative effective contraception method (e.g., condoms or intrauterine devices) during treatment with romidepsin and for at least 1 month after the final dose. Romidepsin showed high affinity for binding to estrogen receptors in pharmacology studies.
    Norethindrone; Ethinyl Estradiol: (Major) The concomitant use of romidepsin and ethinyl estradiol may reduce the efficacy of ethinyl estradiol. Because romidepsin can cause fetal harm if administered to a pregnant woman, females of reproductive potential should use an alternative effective contraception method (e.g., condoms or intrauterine devices) during treatment with romidepsin and for at least 1 month after the final dose. Romidepsin showed high affinity for binding to estrogen receptors in pharmacology studies.
    Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Major) The concomitant use of romidepsin and ethinyl estradiol may reduce the efficacy of ethinyl estradiol. Because romidepsin can cause fetal harm if administered to a pregnant woman, females of reproductive potential should use an alternative effective contraception method (e.g., condoms or intrauterine devices) during treatment with romidepsin and for at least 1 month after the final dose. Romidepsin showed high affinity for binding to estrogen receptors in pharmacology studies.
    Norfloxacin: (Major) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering romidepsin with norfloxacin. If coadministered is required, appropriate cardiovascular monitoring precautions should be considered, such as the monitoring of electrolytes and ECGs at baseline and periodically during treatment. Romidepsin has been reported to prolong the QT interval. Quinolones have also been associated with QT prolongation and TdP. For norfloxacin specifically, extremely rare cases of TdP were reported during post-marketing surveillance. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
    Norgestimate; Ethinyl Estradiol: (Major) The concomitant use of romidepsin and ethinyl estradiol may reduce the efficacy of ethinyl estradiol. Because romidepsin can cause fetal harm if administered to a pregnant woman, females of reproductive potential should use an alternative effective contraception method (e.g., condoms or intrauterine devices) during treatment with romidepsin and for at least 1 month after the final dose. Romidepsin showed high affinity for binding to estrogen receptors in pharmacology studies.
    Octreotide: (Moderate) Consider monitoring electrolytes and ECGs at baseline and periodically during treatment if romidepsin is administered with octreotide as concurrent use may increase the risk of QT prolongation. Romidepsin has been reported to prolong the QT interval. Arrhythmias, sinus bradycardia, and conduction disturbances have occurred during octreotide therapy warranting more cautious monitoring during octreotide administration in higher risk patients with cardiac disease. Since bradycardia is a risk factor for development of TdP, the potential occurrence of bradycardia during octreotide administration could theoretically increase the risk of TdP in patients receiving drugs that prolong the QT interval.
    Ofloxacin: (Moderate) Consider monitoring electrolytes and ECGs at baseline and periodically during treatment if romidepsin is administered with ofloxacin as concurrent use may increase the risk of QT prolongation. Romidepsin has been reported to prolong the QT interval. Quinolones have been associated with a risk of QT prolongation and torsade de pointes (TdP). Although extremely rare, TdP has been reported during postmarketing surveillance of ofloxacin. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
    Olanzapine: (Moderate) Consider monitoring electrolytes and ECGs at baseline and periodically during treatment if romidepsin is administered with olanzapine as concurrent use may increase the risk of QT prolongation. Romidepsin has been reported to prolong the QT interval. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
    Olanzapine; Fluoxetine: (Moderate) Consider monitoring electrolytes and ECGs at baseline and periodically during treatment if romidepsin is administered with fluoxetine. QT prolongation and TdP have been reported in patients treated with fluoxetine. Romidepsin has also been reported to prolong the QT interval. (Moderate) Consider monitoring electrolytes and ECGs at baseline and periodically during treatment if romidepsin is administered with olanzapine as concurrent use may increase the risk of QT prolongation. Romidepsin has been reported to prolong the QT interval. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
    Olanzapine; Samidorphan: (Moderate) Consider monitoring electrolytes and ECGs at baseline and periodically during treatment if romidepsin is administered with olanzapine as concurrent use may increase the risk of QT prolongation. Romidepsin has been reported to prolong the QT interval. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir with romidepsin may increase romidepsin concentrations and the risk for QT prolongation and torsade de pointes (TdP). Romidepsin is known to increase the QT interval. While dasabuvir; ombitasvir; paritaprevir; ritonavir did not prolong the QT interval to a clinically relevant extent in healthy subjects, ritonavir has been associated with dose-related QT prolongation in other trials. In addition, romidepsin is a CYP3A4 substrate and a P-glycoprotein (P-gp) substrate, while ritonavir is a strong inhibitor of CYP3A4 and P-gp. Paritaprevir is also a P-gp inhibitor. Therefore, coadministration may increase romidepsin plasma concentrations and further increase the risk of QT prolongation and romidepsin toxicity; dosage adjustments may be necessary. Caution and close monitoring is advised if these drugs are administered together. (Moderate) Monitor for toxicity related to increased romidepsin exposure and follow the dose modifications for toxicity during initial administration of romidepsin with ritonavir. Romidepsin is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. In a pharmacokinetic drug interaction trial a strong CYP3A4 inhibitor increased romidepsin AUC by approximately 25%.
    Ondansetron: (Major) If ondansetron and romidepsin must be coadministered, appropriate cardiovascular monitoring precautions should be considered, such as the monitoring of electrolytes and ECGs at baseline and periodically during treatment. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP). Romidepsin has been reported to prolong the QT interval.
    Osilodrostat: (Moderate) Monitor ECG and electrolytes if triclabendazole is coadministered with romidepsin due to the potential for additive QT prolongation as concurrent use may increase the risk of QT prolongation. Romidepsin has been reported to prolong the QT interval. Osilodrostat is associated with dose-dependent QT prolongation.
    Osimertinib: (Major) Avoid coadministration of romidepsin with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, monitor for an increase in romidepsin-related adverse reactions, monitor electrolytes, and monitor ECGs for QT prolongation at baseline and periodically during treatment; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Romidepsin is a P-glycoprotein (P-gp) substrate that has been reported to prolong the QT interval. Concentration-dependent QTc prolongation also occurred during clinical trials of osimertinib, which is a P-gp inhibitor.
    Oxaliplatin: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of romidepsin with oxaliplatin is necessary; correct electrolyte abnormalities prior to administration of oxaliplatin. Romidepsin has been reported to prolong the QT interval. QT prolongation and ventricular arrhythmias including fatal torsade de pointes have also been reported with oxaliplatin use in postmarketing experience.
    Ozanimod: (Major) In general, do not initiate ozanimod in patients taking romidepsin due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). If concomitant use is necessary, consider monitoring electrolytes and ECGs at baseline and periodically during treatment. Ozanimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ozanimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia. Romidepsin has been reported to prolong the QT interval.
    Pacritinib: (Major) Concomitant use of pacritinib and romidepsin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
    Paliperidone: (Major) Per the manufacturer, since paliperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect. Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. Romidepsin has been reported to prolong the QT interval. If romidepsin must be coadministered with another drug that prolongs the QT interval, appropriate cardiovascular monitoring precautions should be considered, such as the monitoring of electrolytes and ECGs at baseline and periodically during treatment. Closely monitor patients with risk factors for cardiac disease or arrhythmias.
    Panobinostat: (Major) QT prolongation has been reported with panobinostat therapy in patients with multiple myeloma in a clinical trial; use of panobinostat with other agents that prolong the QT interval is not recommended. Obtain an electrocardiogram at baseline and periodically during treatment. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve. Drugs with a possible risk for QT prolongation and torsade de pointes that should be used cautiously and with close monitoring with panobinostat include romidepsin.
    Pasireotide: (Moderate) Consider monitoring electrolytes and ECGs at baseline and periodically during treatment if romidepsin is administered with pasireotide as concurrent use may increase the risk of QT prolongation. Romidepsin has been reported to prolong the QT interval. QT prolongation has occurred with pasireotide at therapeutic and supra-therapeutic doses.
    Pazopanib: (Major) Coadministration of pazopanib and other drugs that prolong the QT interval is not advised; pazopanib and romidepsin have been reported to prolong the QT interval. If pazopanib and romidepsin must be continued, appropriate cardiovascular monitoring precautions should be considered, such as the monitoring of electrolytes and ECGs at baseline and periodically during treatment. In addition, pazopanib is a weak inhibitor of CYP3A4. Coadministration of pazopanib and romidepsin, a CYP3A4 substrate, may cause an increase in systemic concentrations of romidepsin. Use caution when concurrent administration is necessary.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Pentamidine: (Major) Romidepsin has been reported to prolong the QT interval. Pentamidine has been associated with QT prolongation. If romidepsin must be coadministered with another drug that prolongs the QT interval, appropriate cardiovascular monitoring precautions should be considered, such as the monitoring of electrolytes and ECGs at baseline and periodically during treatment.
    Pentobarbital: (Moderate) Romidepsin is a substrate for CYP3A4. Coadministration of CYP3A4 inducers, like barbiturates, may decrease systemic concentrations of romidepsin. Use caution when concomitant administration of these agents is necessary.
    Perphenazine: (Minor) Consider monitoring electrolytes and ECGs at baseline and periodically during treatment if romidepsin is administered with perphenazine as concurrent use may increase the risk of QT prolongation. Romidepsin has been reported to prolong the QT interval. Perphenazine is associated with a possible risk for QT prolongation. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
    Perphenazine; Amitriptyline: (Minor) Consider monitoring electrolytes and ECGs at baseline and periodically during treatment if romidepsin is administered with perphenazine as concurrent use may increase the risk of QT prolongation. Romidepsin has been reported to prolong the QT interval. Perphenazine is associated with a possible risk for QT prolongation. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
    Phenobarbital: (Major) The concomitant use of romidepsin, a CYP3A4 substrate, and phenobarbital, a strong CYP3A4 inducer, may result in significantly altered romidepsin plasma exposure. Therefore, avoid using romidepsin with potent CYP3A4 inducers if possible.
    Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) The concomitant use of romidepsin, a CYP3A4 substrate, and phenobarbital, a strong CYP3A4 inducer, may result in significantly altered romidepsin plasma exposure. Therefore, avoid using romidepsin with potent CYP3A4 inducers if possible.
    Phentermine; Topiramate: (Moderate) Romidepsin is a substrate for CYP3A4. Coadministration of a CYP3A4 inducer, like topiramate, may decrease systemic concentrations of romidepsin. Use caution when concomitant administration of these agents is necessary.
    Phenytoin: (Major) The concomitant use of romidepsin, a CYP3A4 substrate, and phenytoin, a strong CYP3A4 inducer, may result in significantly altered romidepsin plasma exposure. Therefore, avoid using romidepsin with potent CYP3A4 inducers if possible.
    Pimavanserin: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as romidepsin. Romidepsin has been reported to prolong the QT interval. Coadministration may increase the risk for QT prolongation. If romidepsin must be coadministered with another drug that prolongs the QT interval, the manufacturer recommends appropriate cardiovascular monitoring precautions, such as the monitoring of electrolytes and ECGs at baseline and periodically during treatment.
    Pimozide: (Contraindicated) Pimozide is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Because of the potential for TdP, use of romidepsin with pimozide is contraindicated.
    Pitolisant: (Major) Avoid coadministration of pitolisant with romidepsin as concurrent use may increase the risk of QT prolongation. If concomitant use is necessary, consider monitoring electrolytes and ECGs at baseline and periodically during treatment. Pitolisant prolongs the QT interval. Romidepsin has been reported to prolong the QT interval.
    Ponesimod: (Major) In general, do not initiate ponesimod in patients taking romidepsin due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP); additive immunosuppression may also occur which may extend the duration or severity of immune suppression. If concomitant use is unavoidable, monitor ECGs, electrolytes, and for signs and symptoms of infection. Ponesimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ponesimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia. Romidepsin has been reported to prolong the QT interval.
    Posaconazole: (Contraindicated) The concurrent use of romidepsin and posaconazole is contraindicated due to the risk of life threatening arrhythmias such as torsade de pointes (TdP). Romidepsin is a substrate for CYP3A4 and P-glycoprotein (P-gp). Posaconazole is an inhibitor of CYP3A4 and P-gp. Concurrent administration may cause an increase in systemic romidepsin concentrations, causing an increased risk for romidepsin-related adverse events, such as QT prolongation.
    Primaquine: (Moderate) Consider monitoring electrolytes and ECGs at baseline and periodically during treatment if romidepsin is administered with primaquine as concurrent use may increase the risk of QT prolongation. Romidepsin has been reported to prolong the QT interval. Primaquine is associated with QT prolongation.
    Primidone: (Moderate) Romidepsin is a substrate for CYP3A4. Coadministration of CYP3A4 inducers, like barbiturates, may decrease systemic concentrations of romidepsin. Use caution when concomitant administration of these agents is necessary.
    Procainamide: (Major) Romidepsin has been reported to prolong the QT interval. Procainamide also prolongs the QT interval. If romidepsin and procainamide must be continued, appropriate cardiovascular monitoring precautions should be considered, such as the monitoring of electrolytes and ECGs at baseline and periodically during treatment.
    Prochlorperazine: (Minor) Consider monitoring electrolytes and ECGs at baseline and periodically during treatment if romidepsin is administered with prochlorperazine as concurrent use may increase the risk of QT prolongation. Romidepsin has been reported to prolong the QT interval. Prochlorperazine is associated with a possible risk for QT prolongation. Theoretically, prochlorperazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
    Promethazine: (Moderate) Consider monitoring electrolytes and ECGs at baseline and periodically during treatment if romidepsin is administered with promethazine as concurrent use may increase the risk of QT prolongation. Romidepsin has been reported to prolong the QT interval. Promethazine carries a possible risk of QT prolongation.
    Promethazine; Dextromethorphan: (Moderate) Consider monitoring electrolytes and ECGs at baseline and periodically during treatment if romidepsin is administered with promethazine as concurrent use may increase the risk of QT prolongation. Romidepsin has been reported to prolong the QT interval. Promethazine carries a possible risk of QT prolongation.
    Promethazine; Phenylephrine: (Moderate) Consider monitoring electrolytes and ECGs at baseline and periodically during treatment if romidepsin is administered with promethazine as concurrent use may increase the risk of QT prolongation. Romidepsin has been reported to prolong the QT interval. Promethazine carries a possible risk of QT prolongation.
    Propafenone: (Major) Romidepsin is a substrate for P-glycoprotein (P-gp). Propafenone is an inhibitor of P-gp. Concurrent administration of romidepsin with an inhibitor of P-gp may cause an increase in systemic romidepsin concentrations. In addition, romidepsin has been reported to prolong the QT interval. Propafenone may also prolong the QT interval. If romidepsin and propafenone must be continued, closely monitor the patient for QT interval prolongation.
    Quetiapine: (Major) Romidepsin has been reported to prolong the QT interval. Limited data, including some case reports, suggest that quetiapine may be associated with a significant prolongation of the QTc interval in rare instances. According to the manufacturer, use of quetiapine should be avoided in combination with drugs known to increase the QT interval. If romidepsin and quetiapine must be coadministered, appropriate cardiovascular monitoring precautions should be considered, such as the monitoring of electrolytes and ECGs at baseline and periodically during treatment.
    Quinidine: (Major) Romidepsin is a substrate for P-glycoprotein (P-gp). Quinidine is an inhibitor of P-gp. Concurrent administration of romidepsin with an inhibitor of P-gp may cause an increase in systemic romidepsin concentrations. Use caution when concomitant administration of these agents is necessary. In addition, romidepsin has been reported to prolong the QT interval. Quinidine also prolongs the QT interval. If romidepsin and quinidine must be coadministered, appropriate cardiovascular monitoring precautions should be considered, such as the monitoring of electrolytes and ECGs at baseline and periodically during treatment.
    Quinine: (Major) Concurrent use of quinine and romidepsin should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). If these drugs must be coadministered, appropriate cardiovascular monitoring precautions should be considered, such as the monitoring of electrolytes and ECGs at baseline and periodically during treatment. Quinine has been associated with prolongation of the QT interval and rare cases of TdP. Romidepsin has also been reported to prolong the QT interval. In addition, concentrations of romidepsin may be increased with concomitant use of quinine. Romidepsin is a CYP3A4 substrate and quinine is a CYP3A4 inhibitor.
    Ranolazine: (Moderate) Consider monitoring electrolytes and ECGs at baseline and periodically during treatment if romidepsin is administered with ranolazine as concurrent use may increase the risk of QT prolongation. Romidepsin has been reported to prolong the QT interval. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs concurrent use may result in additive QT prolongation.
    Relugolix: (Moderate) Consider monitoring electrolytes and ECGs at baseline and periodically during treatment if romidepsin is administered with relugolix. Romidepsin has been reported to prolong the QT interval. Androgen deprivation therapy (i.e., relugolix) may also prolong the QT/QTc interval.
    Relugolix; Estradiol; Norethindrone acetate: (Moderate) Consider monitoring electrolytes and ECGs at baseline and periodically during treatment if romidepsin is administered with relugolix. Romidepsin has been reported to prolong the QT interval. Androgen deprivation therapy (i.e., relugolix) may also prolong the QT/QTc interval.
    Ribociclib: (Major) Avoid coadministration of ribociclib with romidepsin due to an increased risk for QT prolongation; exposure to romidepsin may also increase. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Romidepsin is a CYP3A4 substrate that has also been associated with QT prolongation.
    Ribociclib; Letrozole: (Major) Avoid coadministration of ribociclib with romidepsin due to an increased risk for QT prolongation; exposure to romidepsin may also increase. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Romidepsin is a CYP3A4 substrate that has also been associated with QT prolongation.
    Rifampin: (Major) The concomitant use of romidepsin, a CYP3A4 substrate and a P-glycoprotein (P-gp) substrate, and rifampin, a strong CYP3A4 inducer and a P-gp inhibitor and substrate, increased the romidepsin plasma exposure in a drug interaction trial in patients with advanced cancer. Avoid using romidepsin with potent CYP3A4 inducers if possible. Following a 4-hour infusion of romidepsin 14mg/m2 IV administered with multiple oral doses of rifampin, the AUC and Cmax values of romidepsin were increased by 80% and 60%, respectively, compared with romidepsin alone; these increases were statistically significant. Co-administration of rifampin decreased the romidepsin clearance and volume of distribution by 44% and 52%, respectively. Typically, administering a CYP3A4 substrate with a strong CYP3A4 inducer would decrease the substrate exposure; this interaction may be due to the P-gp inhibitor effect of rifampin or because of another undetermined hepatic uptake process that rifampin inhibits. If these agents are used together, monitor patients for signs and symptoms of romidepsin toxicity including hematologic toxicity, infection, and electrocardiogram changes; therapy interruption or discontinuation or a dosage reduction may be required if toxicity develops.
    Rifapentine: (Major) Avoid coadministration of romidepsin with rifapentine if possible due to decreased plasma concentrations of romidepsin. Romidepsin is a CYP3A4 substrate and rifapentine is a strong CYP3A4 inducer. The effect of strong CYP3A4 inducers on the exposure of romidepsin is unknown.
    Rifaximin: (Moderate) Coadministration of romidepsin, a substrate for P-glycoprotein (P-gp) with rifaximin, a P-gp inhibitor may cause an increase in systemic romidepsin concentrations. Use caution when concomitant administration of these agents is necessary.
    Rilpivirine: (Moderate) Consider monitoring electrolytes and ECGs at baseline and periodically during treatment if romidepsin is administered with rilpivirine as concurrent use may increase the risk of QT prolongation. Romidepsin has been reported to prolong the QT interval. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Risperidone: (Moderate) Monitor ECG and electrolytes if risperidone is coadministered with romidepsin due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). Risperidone has been associated with a possible risk for QT prolongation and/or TdP, primarily in the overdose setting. Romidepsin has also been reported to prolong the QT interval.
    Ritonavir: (Moderate) Monitor for toxicity related to increased romidepsin exposure and follow the dose modifications for toxicity during initial administration of romidepsin with ritonavir. Romidepsin is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. In a pharmacokinetic drug interaction trial a strong CYP3A4 inhibitor increased romidepsin AUC by approximately 25%.
    Saquinavir: (Major) The concomitant use of romidepsin, a CYP3A4 substrate, and saquinavir, a strong CYP3A4 inhibitor, may increase romidepsin plasma exposure. If these agents are used together, monitor patients for signs and symptoms of romidepsin toxicity including hematologic toxicity, infection, and electrocardiogram (ECG) changes; therapy interruption or discontinuation or a dosage reduction may be required if toxicity develops. Additionally, saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as torsade de pointes (TdP). Avoid administering saquinavir boosted with ritonavir concurrently with other drugs that may prolong the QT interval, such as romidepsin. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations.
    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: (Moderate) Romidepsin is a substrate for CYP3A4. Coadministration of CYP3A4 inducers, like barbiturates, may decrease systemic concentrations of romidepsin. Use caution when concomitant administration of these agents is necessary.
    Segesterone Acetate; Ethinyl Estradiol: (Major) The concomitant use of romidepsin and ethinyl estradiol may reduce the efficacy of ethinyl estradiol. Because romidepsin can cause fetal harm if administered to a pregnant woman, females of reproductive potential should use an alternative effective contraception method (e.g., condoms or intrauterine devices) during treatment with romidepsin and for at least 1 month after the final dose. Romidepsin showed high affinity for binding to estrogen receptors in pharmacology studies.
    Selpercatinib: (Major) Monitor electrolytes and ECGs at baseline and frequently during treatment if romidepsin is administered with selpercatinib due to the risk of additive QT prolongation. Romidepsin has been reported to prolong the QT interval. Concentration-dependent QT prolongation has been observed with selpercatinib therapy.
    Sertraline: (Moderate) Consider monitoring electrolytes and ECGs at baseline and periodically during treatment if romidepsin is administered with sertraline. Romidepsin has been reported to prolong the QT interval. Sertraline's FDA-approved labeling recommends avoiding concomitant use with drugs known to prolong the QTc interval; however, the risk of sertraline-induced QT prolongation is generally considered to be low in clinical practice. Its effect on QTc interval is minimal (typically less than 5 msec), and the drug has been used safely in patients with cardiac disease (e.g., recent myocardial infarction, unstable angina, chronic heart failure).
    Siponimod: (Major) In general, do not initiate treatment with siponimod in patients receiving romidepsin due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Romidepsin has been reported to prolong the QT interval.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Moderate) Plasma concentrations of romidpesin, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with voxilaprevir, a P-gp inhibitor. Monitor patients for increased side effects if these drugs are administered concurrently.
    Solifenacin: (Moderate) Consider monitoring electrolytes and ECGs at baseline and periodically during treatment if romidepsin is administered with solifenacin as concurrent use may increase the risk of QT prolongation. Romidepsin has been reported to prolong the QT interval. Solifenacin has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported with postmarketing use, although causality was not determined. This should be taken into consideration when prescribing solifenacin to patients taking other drugs that are associated with QT prolongation.
    Sorafenib: (Major) Avoid coadministration of sorafenib with romidepsin due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sorafenib is associated with QTc prolongation. Romidepsin has also been reported to prolong the QT interval.
    Sotalol: (Major) Romidepsin has been reported to prolong the QT interval. Sotalol also prolongs the QT interval. If romidepsin and sotalol must be continued, appropriate cardiovascular monitoring precautions should be considered, such as the monitoring of electrolytes and ECGs at baseline and periodically during treatment.
    St. John's Wort, Hypericum perforatum: (Major) The concomitant use of romidepsin, a CYP3A4 substrate, and St. John's Wort, Hypericum perforatum a strong CYP3A4 inducer, may result in significantly altered romidepsin plasma exposure. Therefore, avoid using romidepsin with potent CYP3A4 inducers if possible.
    Sunitinib: (Moderate) Consider monitoring electrolytes and ECGs at baseline and periodically during treatment if romidepsin is administered with sunitinib. Sunitinib can prolong the QT interval. Romidepsin has been reported to prolong the QT interval.
    Tacrolimus: (Major) Romidepsin has been reported to prolong the QT interval. Tacrolimus causes QT prolongation. Reducing the tacrolimus dose, close monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation is recommended when tacrolimus is coadministered with other substrates and/or inhibitors of CYP3A4 that also have the potential to prolong the QT interval such as romidepsin. In addition, appropriate cardiovascular monitoring precautions should be considered, such as the monitoring of electrolytes and ECGs at baseline and periodically during treatment.
    Tamoxifen: (Moderate) Consider monitoring electrolytes and ECGs at baseline and periodically during treatment if romidepsin is administered with tamoxifen as concurrent use may increase the risk of QT prolongation. Romidepsin has been reported to prolong the QT interval. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses.
    Telaprevir: (Moderate) The concomitant use of romidepsin, a CYP3A4 substrate and a P-glycoprotein (P-gp) substrate, and telaprevir, a strong CYP3A4 inhibitor and a P-gp substrate and inhibitor, may increase romidepsin plasma exposure. If these agents are used together, monitor patients for signs and symptoms of romidepsin toxicity including hematologic toxicity, infection, and electrocardiogram changes; therapy interruption or discontinuation or a dosage reduction may be required if toxicity develops.
    Telavancin: (Moderate) Consider monitoring electrolytes and ECGs at baseline and periodically during treatment if romidepsin is administered with telavancin as concurrent use may increase the risk of QT prolongation. Romidepsin has been reported to prolong the QT interval. Telavancin has also been asociated with QT prolongation.
    Telithromycin: (Moderate) Monitor for toxicity related to increased romidepsin exposure and follow the dose modifications for toxicity during initial administration of romidepsin with telithromycin. Consider monitoring electrolytes and ECGs at baseline and periodically during treatment of romidepsin and telithromycin. Romidepsin is a CYP3A4 and P-gp substrate that has been reported to prolong the QT interval. Telithromycin is a P-gp and strong CYP3A4 inhibitor that is associated with QT prolongation and torsade de pointes (TdP). In a pharmacokinetic drug interaction trial a strong CYP3A4 inhibitor increased romidepsin AUC by approximately 25%.
    Temsirolimus: (Moderate) Monitor for an increase in romidepsin-related adverse reactions if coadministration with temsirolimus is necessary. Romidepsin is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of romidepsin.
    Tetrabenazine: (Major) Tetrabenazine causes a small increase in the corrected QT interval (QTc). The manufacturer recommends avoiding concurrent use of tetrabenazine with other drugs known to prolong QTc, such as romidepsin. If romidepsin and tetrabenazine must be coadministered, appropriate cardiovascular monitoring precautions should be considered, such as the monitoring of electrolytes and ECGs at baseline and periodically during treatment.
    Thiopental: (Moderate) Romidepsin is a substrate for CYP3A4. Coadministration of CYP3A4 inducers, like barbiturates, may decrease systemic concentrations of romidepsin. Use caution when concomitant administration of these agents is necessary.
    Thioridazine: (Contraindicated) Thioridazine is associated with a well-established risk of QT prolongation and torsades de pointes (TdP) and is considered contraindicated for use along with agents that, when combined with a phenothiazine, may prolong the QT interval and increase the risk of TdP, and/or cause orthostatic hypotension. Romidepsin has been reported to prolong the QT interval. Because of the potential for TdP, use of romidepsin with thioridazine is contraindicated.
    Tipranavir: (Moderate) The concomitant use of romidepsin, a CYP3A4 substrate, and tipranavir, a strong CYP3A4 inhibitor, may increase romidepsin plasma exposure. If these agents are used together, monitor patients for signs and symptoms of romidepsin toxicity including hematologic toxicity, infection, and electrocardiogram changes; therapy interruption or discontinuation or a dosage reduction may be required if toxicity develops.
    Tolterodine: (Moderate) Consider monitoring electrolytes and ECGs at baseline and periodically during treatment if romidepsin is administered with tolterodine as concurrent use may increase the risk of QT prolongation. Romidepsin has been reported to prolong the QT interval. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
    Topiramate: (Moderate) Romidepsin is a substrate for CYP3A4. Coadministration of a CYP3A4 inducer, like topiramate, may decrease systemic concentrations of romidepsin. Use caution when concomitant administration of these agents is necessary.
    Toremifene: (Major) Avoid coadministration of romidepsin with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Romidepsin has also been reported to prolong the QT interval.
    Trandolapril; Verapamil: (Moderate) Romidepsin is a substrate for CYP3A4 and P-glycoprotein (P-gp). Verapamil is an inhibitor of CYP3A4 and P-gp. Concurrent administration of romidepsin with an inhibitor of CYP3A4 and P-gp may cause an increase in systemic romidepsin concentrations. Use caution when concomitant administration of these agents is necessary.
    Trazodone: (Major) Romidepsin has been reported to prolong the QT interval and should be avoided in combination with trazodone. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval. If romidepsin must be coadministered with trazodone, appropriate cardiovascular monitoring precautions should be considered, such as the monitoring of electrolytes and ECGs at baseline and periodically during treatment.
    Triclabendazole: (Moderate) Monitor ECG and electrolytes if triclabendazole is coadministered with romidepsin due to the potential for additive QT prolongation as concurrent use may increase the risk of QT prolongation. Romidepsin has been reported to prolong the QT interval. Transient prolongation of the mean QTc interval was noted on the ECG recordings in dogs administered triclabendazole.
    Trifluoperazine: (Minor) Consider monitoring electrolytes and ECGs at baseline and periodically during treatment if romidepsin is administered with trifluoperazine as concurrent use may increase the risk of QT prolongation. Romidepsin has been reported to prolong the QT interval. Trifluoperazine is associated with a possible risk for QT prolongation. Theoretically, trifluoperazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
    Triptorelin: (Moderate) Monitor ECGs for QT prolongation and monitor electrolytes at baseline and periodically during treatment if coadministration of romidepsin with triptorelin is necessary as concurrent use may increase the risk of QT prolongation. Romidepsin has been reported to prolong the QT interval. Androgen deprivation therapy (i.e., triptorelin) may also prolong the QT/QTc interval. Androgen deprivation therapy (i.e., triptorelin) may prolong the QT/QTc interval.
    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: (Moderate) Monitor for toxicity related to increased romidepsin exposure and follow the dose modifications for toxicity during initial administration of romidepsin with tucatinib. Romidepsin is a CYP3A4 substrate; tucatinib is a strong CYP3A4 inhibitor. In a pharmacokinetic drug interaction trial a strong CYP3A4 inhibitor increased romidepsin AUC by approximately 25%.
    Vandetanib: (Major) Avoid coadministration of vandetanib with romidepsin due to an increased risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes; correct hypocalcemia, hypomagnesemia, and/or hypomagnesemia prior to vandetanib administration. An interruption of vandetanib therapy or dose reduction may be necessary for QT prolongation. Vandetanib can prolong the QT interval in a concentration-dependent manner; TdP and sudden death have been reported in patients receiving vandetanib. Romidepsin has also been reported to prolong the QT interval.
    Vardenafil: (Moderate) Consider monitoring electrolytes and ECGs at baseline and periodically during treatment if romidepsin is administered with vardenafil as concurrent use may increase the risk of QT prolongation. Romidepsin has been reported to prolong the QT interval. Vardenafil is associated with QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval.
    Vemurafenib: (Major) Vemurafenib has been associated with QT prolongation. If vemurafenib and another drug, such as romidepsin, that is associated with a possible risk for QT prolongation and torsade de pointes (TdP) must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Also, romidepsin is a CYP3A4 substrate, while vemurafenib is CYP3A4 inducer. Decreased romidepsin concentrations may occur with concomitant use.
    Venlafaxine: (Moderate) Consider monitoring electrolytes and ECGs at baseline and periodically during treatment if romidepsin is administered with venlafaxine as concurrent use may increase the risk of QT prolongation. Romidepsin has been reported to prolong the QT interval. Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has been reported with postmarketing use.
    Verapamil: (Moderate) Romidepsin is a substrate for CYP3A4 and P-glycoprotein (P-gp). Verapamil is an inhibitor of CYP3A4 and P-gp. Concurrent administration of romidepsin with an inhibitor of CYP3A4 and P-gp may cause an increase in systemic romidepsin concentrations. Use caution when concomitant administration of these agents is necessary.
    Voclosporin: (Moderate) Concomitant use of voclosporin and romidepsin may increase the risk of QT prolongation. Consider interventions to minimize the risk of progression to torsades de pointes (TdP), such as ECG monitoring and correcting electrolyte abnormalities, particularly in patients with additional risk factors for TdP. Voclosporin has been associated with QT prolongation at supratherapeutic doses. Romidepsin has been reported to prolong the QT interval.
    Voriconazole: (Major) The concomitant use of romidepsin, a CYP3A4 substrate, and voriconazole, a strong CYP3A4 inhibitor, may increase romidepsin plasma exposure. If these agents are used together, monitor patients for signs and symptoms of romidepsin toxicity including hematologic toxicity, infection, and electrocardiogram (ECG) changes; therapy interruption or discontinuation or a dosage reduction may be required if toxicity develops. Additionally, voriconazole has been associated with QT prolongation and rare cases of torsade de pointes and changes in ECGs (including T-wave and ST-segment changes) have been reported with romidepsin use. If romidepsin is administered with agents that may cause significant QT prolongation, such as voriconazole, appropriate cardiovascular monitoring precautions should be considered, such as the monitoring of electrolytes and electrocardiograms at baseline and periodically during treatment.
    Vorinostat: (Moderate) Consider monitoring electrolytes and ECGs at baseline and periodically during treatment if romidepsin is administered with vorinostat as concurrent use may increase the risk of QT prolongation. Romidepsin has been reported to prolong the QT interval. Vorinostat therapy is associated with a risk of QT prolongation.
    Warfarin: (Major) Prolongation of PT and elevation of INR have been observed in a patient receiving romidepsin and warfarin. Carefully monitor PT and INR in patients receiving romidepsin and warfarin concomitantly.
    Zafirlukast: (Moderate) Romidepsin is a substrate for CYP3A4. Zafirlukast is an inhibitor of CYP3A4. Concurrent administration of romidepsin with an inhibitor of CYP3A4 may cause an increase in systemic romidepsin concentrations. Use caution when concomitant administration of these agents is necessary.
    Ziprasidone: (Major) Concomitant use of ziprasidone and romidepsin should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Romidepsin has been reported to prolong the QT interval. If romidepsin must be coadministered with another drug that prolongs the QT interval, appropriate cardiovascular monitoring precautions should be considered, such as the monitoring of electrolytes and ECGs at baseline and periodically during treatment.
    Zonisamide: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and romidepsin 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

    Romidepsin may cause fetal harm when administered during pregnancy, based on its mechanism of action and data from animal studies. Females of reproductive potential should avoid becoming pregnant while taking romidepsin. Discuss the potential hazard to the fetus if a patient becomes pregnant while taking this drug. Although romidepsin has not been evaluated in pregnant women, fetal toxicity including reduced fetal weight, folded retina, rotated limbs, and incomplete sternal ossification occurred when pregnant rats received a romidepsin dose resulting in 0.2 times or greater the exposure that was observed in humans who received the recommended dose.[37292]

    It is not known if romidepsin or its metabolites are secreted in human milk or if it has effects on the breast-fed infant or on milk production. Because there is a potential for adverse reactions in nursing infants from romidepsin, women should be advised against breast-feeding during romidepsin therapy and for 1 week after the last dose.[37292]

    MECHANISM OF ACTION

    Romidepsin is a bicyclic depsipeptide that is an inhibitor of the histone deacetylase (HDAC) family of enzymes. Romidepsin is a potent inhibitor of class I, II, and IV HDAC. Histone deacetylases are enzymes that catalyze the removal of acetyl groups from the lysine residues of proteins, including histones and transcription factors. Overexpression of HDACs or an abnormal recruitment of HDACs to oncogenic transcription factors is present in some cancer cells. This causes hypoacetylation of core nucleosomal histones resulting in a condensed chromatin structure and repression of gene transcription. Inhibition of HDAC activity produces an accumulation of acetyl groups on the histone lysine residues resulting in an open chromatin structure and transcriptional activation. In many different malignant cell lines, HDAC inhibitors have been shown to activate differentiation, inhibit the cell cycle, and induce apoptosis. In vivo, HDAC inhibitors have exhibited stimulation of the immune system and blockage of angiogenesis. The complete mechanism of the antineoplastic effect of romidepsin observed in nonclinical and clinical studies has not been fully characterized. However, accumulation of acetylated histones, induction of cell cycle arrest and apoptosis of cancer cell lines are thought to be responsible for the activity of romidepsin.

    PHARMACOKINETICS

    Romidepsin is administered intravenously. Romidepsin is highly protein bound (92% to 94%) in plasma, primarily to alpha-1-acid glycoprotein, within the concentration range of 50 to 1,000 ng/mL. After a 4 hour infusion, romidepsin has a half-life of approximately 3 hours. No accumulation of romidepsin was observed after repeat dosing. The pharmacokinetics of romidepsin does not appear to be impacted by repeated dosing or by increasing the dose (within the dose range of 1 to 24.9 mg/m2).[37292] Preclinical studies have shown that up to 66% of romidepsin is excreted in the bile.
    Affected cytochrome P450 isoenzymes: CYP3A4 and P-gp
    Romidepsin is metabolized extensively by CYP3A4 and to a lesser extent by CYP3A5, CYP1A1, CYP2B6, and CYP2C19 in vitro. Monitor patients for signs and symptoms of romidepsin toxicity if romidepsin is given with a strong CYP3A4 inhibitor as romidepsin plasma exposure may increase; therapy interruption or discontinuation or a dosage reduction may be required if toxicity develops. Avoid concomitant use of romidepsin with strong CYP3A4 inducers as romidepsin plasma exposure may be significantly altered. Pharmacokinetic interactions are unlikely to occur due to CYP450 induction or inhibition by romidepsin when coadministered with CYP450 substrates. Romidepsin is a substrate of P-glycoprotein (P-gp) and an inhibitor of BSEP and OATP1B1 in vitro. Use caution when administering romidepsin with P-gp inhibitors as increased concentrations of romidepsin may occur.[37292]

    Intravenous Route

    In patients with CTCL who received romidepsin 14 mg/m2 IV over 4 hours, the Cmax and AUC values were 377 ng/mL and 1,549 ng x hour/mL, respectively. Romidepsin displays linear pharmacokinetics within the dose range of 1 to 24.9 mg/m2.