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  • CLASSES

    Small Molecule Antineoplastic B-Cell Lymphoma-2 (BCL-2) Inhibitors

    DEA CLASS

    Rx

    DESCRIPTION

    B-cell lymphoma-2 (BCL-2) protein inhibitor
    Used as a single agent or in combination with obinutuzumab or rituximab in adults with CLL or SLL and in combination with azacitidine, decitabine, or low-dose cytarabine in adults with newly-diagnosed AML who are ineligible for intensive induction chemotherapy
    Prophylactic hydration and antihyperuricemic agents are recommended due to the risk for tumor lysis syndrome

    COMMON BRAND NAMES

    Venclexta

    HOW SUPPLIED

    Venclexta Oral Tab: 10mg, 50mg, 100mg, 10-50-100mg

    DOSAGE & INDICATIONS

    For the treatment of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).
    NOTE: The FDA has designated venetoclax as an orphan drug for the treatment of CLL.
    For the treatment of CLL or SLL, as a single agent.
    Oral dosage
    Adults

    initial, 20 mg orally once daily for 7 days. The venetoclax dose is increased once weekly over 5 weeks as follows: week 2, 50 mg/day; week 3, 100 mg/day; week 4, 200 mg/day; and week 5 and beyond, 400 mg/day. Continue therapy until disease progression. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. A dose reduction and/or therapy interruption may be necessary in patients who develop toxicity. Assess a patient's risk factors for developing tumor lysis syndrome (TLS) prior to starting therapy and after a dosage interruption. All patients must have prophylactic hydration and anti-hyperuricemics prior to first venetoclax dose and during the ramp-up phase to reduce the risk of TLS. The overall response rate (ORR) was 79% in patients with relapsed or refractory CLL (n = 102) or SLL (n = 14) who received venetoclax in a multicenter, dose-escalation trial; 20% of patients had a complete response (CR). Additionally, the median progression-free survival (PFS) time was 22 months and the 2-year overall survival (OS) rate was 84%. In CLL patients with a chromosome 17p deletion (n = 31), the ORR was 71% (CR, 16%) and the median PFS time was 15 months. The ORR was 79.4% in relapsed or refractory CLL patients who had a 17p deletion in a multinational, phase II trial (M13-982 trial; n = 107); 8% of patients had a CR or a CR with incomplete recovery of blood counts (CRi). At a median follow-up of 12.1 months, the estimated 12-month PFS and OS rates were 72% and 86.7%, respectively. In an interim analysis of a nonrandomized, phase 2 trial, the ORR was 65% following treatment with venetoclax in 91 patients with relapsed or refractory CLL who had received prior therapy with ibrutinib; 9% of patients achieved a CR or CRi. Response rates were similar in patients with and without high-risk chromosomal abnormalities (e.g., chromosome 17p deletion, TP53 mutations). At a median follow-up time of 14 months, the median PFS time was 24.7 months and the median OS time had not been reached; estimated 12-month PFS and OS rates were 75% and 91%, respectively.

    For the treatment of CLL or SLL, in combination with rituximab.
    Oral dosage
    Adults

    initial, 20 mg orally once daily for 7 days. The venetoclax dose is increased once weekly over 5 weeks as follows: week 2, 50 mg/day; week 3, 100 mg/day; week 4, 200 mg/day; and week 5 and beyond, 400 mg/day. Following the venetoclax titration period and 7 days of the 400 mg/day dosage, start rituximab 375 mg/m2 IV on day 1 of cycle 1 followed by 500 mg/m2 IV on day 1 of cycles 2 to 6 repeated every 28 days. Continue venetoclax therapy for 24 months after starting rituximab. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. A dose reduction and/or therapy interruption may be necessary in patients who develop toxicity. Assess a patient's risk factors for developing tumor lysis syndrome (TLS) prior to starting therapy and after a dosage interruption. All patients must have prophylactic hydration and anti-hyperuricemics prior to first venetoclax dose and during the ramp-up phase to reduce the risk of TLS.

    For the treatment of CLL or SLL, in combination with obinutuzumab.
    Oral dosage
    Adults

    Obinutuzumab is started on day 1 of cycle 1 (without venetoclax). On day 22 of cycle 1, start venetoclax using a 5-week ramp-up schedule as follows: week 1, 20 mg orally once daily for 7 days; week 2, 50 mg/day; week 3, 100 mg/day; week 4, 200 mg/day; and week 5 and beyond, 400 mg/day. After completing the 5-week ramp up schedule (on day 28 of cycle 2), continue venetoclax 400 mg/day from cycle 3 day 1 until the last day of cycle 12. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. A dose reduction and/or therapy interruption may be necessary in patients who develop toxicity. Assess a patient's risk factors for developing tumor lysis syndrome (TLS) prior to starting therapy and after a dosage interruption. All patients must have prophylactic hydration and anti-hyperuricemics prior to first venetoclax dose and during the ramp-up phase to reduce the risk of TLS. Obinutuzumab is administered as follows: cycle 1, 100 mg IV on day 1, 900 mg IV on day 2, then 1,000 mg IV on days 8 and 15; begin the next cycle of therapy on day 29. For cycles 2 to 6, give obinutuzumab 1,000 mg IV on day 1 repeated every 28 days.[60706] At a median follow-up of 39.6 months, the progression-free survival time (assessed by an independent review committee) was significantly improved with venetoclax plus obinutuzumab compared with obinutuzumab plus chlorambucil therapy (median time not reached vs. 35.6 months; hazard ratio (HR) = 0.31; 95% CI, 0.22 to 0.44; p less than 0.0001) in patients with previously untreated CLL in a randomized, open-label, phase 3 trial (the CLL14 trial; n = 432). Patients (median age, 72 years) in this study had coexisting medical conditions (defined as a total Cumulative Illness Rating Scale (CIRS) score of greater than 6 or a creatinine clearance of less than 70 mL/min). Additionally, undetectable minimal residual disease (MRD) rates were significantly improved in the peripheral blood (76% vs. 35%; p less than 0.0001) in patients who received venetoclax plus obinutuzumab therapy. At the time of analysis, the median overall survival time was not reached in either treatment arm (HR = 1.03; 95% CI, 0.6 to 1.75).

    For the treatment of acute myelogenous leukemia (AML).
    NOTE: Venetoclax has been designated an orphan drug by the FDA for the treatment of AML.
    For the treatment of newly-diagnosed AML in adults who are 75 years or older or who have comorbidities that make them ineligible for intensive induction chemotherapy, in combination with azacitidine.
    Oral dosage
    Adults

    The oral venetoclax dose is increased during a ramp-up phase as follows: 100 mg on day 1; 200 mg on day 2; 400 mg on day 3; and 400 mg once daily on day 4 and beyond. Give in combination with azacitidine (75 mg/m2 IV or subcutaneously daily on days 1 to 7 repeated every 28 days) starting on day 1 of cycle 1. Continue treatment until disease progression. Verify patients have a white blood cell count less than 25 X 109 cells/L prior to therapy; cytoreduction may be required. All patients must have prophylactic hydration and anti-hyperuricemics prior to first venetoclax dose and during the ramp-up phase to reduce the risk of tumor lysis syndrome. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. A dose reduction and/or therapy interruption may be necessary in patients who develop toxicity. At a median follow-up time of 20.5 months (range, less than 0.1 to 30.7 months), the median overall survival (OS) time was significantly longer in patients with previously untreated acute myelogenous leukemia who received azacitidine plus venetoclax compared with azacitidine plus placebo (14.7 months vs. 9.6 months; hazard ratio (HR) = 0.66; 95% CI, 0.52 to 0.85; p less than 0.001) in a prespecified interim analysis of a randomized (2:1), double-blind, phase 3 trial (n = 431; the VIALE-A trial). The complete remission plus complete remission with partial hematologic recovery was significantly higher in the azacitidine plus venetoclax arm compared with azacitidine plus placebo arm (64.7% vs. 22.8%; p less than 0.001). In a subgroup of patients with IDH1 or IDH2 mutations at baseline (n = 89), the 12-month OS rate was higher with azacitidine plus venetoclax compared with azacitidine plus placebo (66.8% vs. 35.7%; HR = 0.35; 95% CI, 0.2 to 0.6; p less than 0.001). Eligible patients (median age, 76 years; range, 49 to 91 years) in this trial were aged 75 years or older (approximately 60%) and/or had coexisting conditions that prevented the use of intensive chemotherapy (i.e., standard induction therapy).

    For the treatment of newly-diagnosed AML in adults who are 75 years or older or who have comorbidities that make them ineligible for intensive induction chemotherapy, in combination with low-dose cytarabine.
    Oral dosage
    Adults

    The oral venetoclax dose is increased during a ramp-up phase as follows: 100 mg on day 1; 200 mg on day 2; 400 mg on day 3; and 600 mg once daily on day 4 and beyond. Give in combination with low-dose cytarabine (20 mg/m2 subcutaneously once daily on days 1 to 10 repeated every 28 days) starting on day 1 of cycle 1. Continue treatment until disease progression. Verify patients have a white blood cell count less than 25 X 109 cells/L prior to therapy; cytoreduction may be required. All patients must have prophylactic hydration and anti-hyperuricemics prior to first venetoclax dose and during the ramp-up phase to reduce the risk of tumor lysis syndrome. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. A dose reduction and/or therapy interruption may be necessary in patients who develop toxicity.  At a median follow-up time of 12 months, the median overall survival (OS) time was nonsignificantly longer in patients with previously untreated acute myelogenous leukemia who received venetoclax plus low-dose cytarabine compared with placebo plus low-dose cytarabine (7.2 months vs. 4.1 months; hazard ratio (HR) = 0.75; 95% CI, 0.52 to 1.07; p = 0.11) in a multinational, randomized (2:1), double-blind, phase 3 trial (n = 211; the VIALE-C trial). However, the median OS time was significantly improved with venetoclax plus low-dose cytarabine following an additional 6 months of follow-up (8.4 months vs. 4.1 months; hazard ratio (HR) = 0.7; 95% CI, 0.5 to 0.99; p = 0.04). The complete remission (CR) (27% vs. 7%; p less than 0.001) and CR plus CR with partial hematologic recovery (CRh) by cycle 2 (48% vs. 13%; p less than 0.001) rates were significantly higher in the venetoclax plus low-dose cytarabine arm compared with the placebo plus low-dose cytarabine arm. Eligible patients (median age, 76 years; range, 36 to 93 years) in this trial were aged 75 years or older (approximately 58%) and/or had coexisting conditions that prevented the use of intensive chemotherapy (i.e., standard induction therapy). The CR and CRh rates were each 21% in a subgroup of 61 patients with newly diagnosed AML who were 75 years of age or older or had comorbidities who received venetoclax plus low-dose cytarabine in a nonrandomized trial.[60706]

    For the treatment of newly-diagnosed AML in adults who are 75 years or older or who have comorbidities that make them ineligible for intensive induction chemotherapy, in combination with decitabine.
    Oral dosage
    Adults

    The oral venetoclax dose is increased during a ramp-up phase as follows: 100 mg on day 1; 200 mg on day 2; 400 mg on day 3; and 400 mg once daily on day 4 and beyond. Give in combination with decitabine (20 mg/m2 IV daily on days 1, 2, 3, 4, and 5 repeated every 28 days) starting on day 1 of cycle 1. Continue treatment until disease progression. Verify patients have a white blood cell count less than 25 X 109 cells/L prior to therapy; cytoreduction may be required. All patients must have prophylactic hydration and anti-hyperuricemics prior to first venetoclax dose and during the ramp-up phase to reduce the risk of tumor lysis syndrome. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. A dose reduction and/or therapy interruption may be necessary in patients who develop toxicity. Treatment with venetoclax plus a hypomethylating agent was evaluated in patients with newly diagnosed AML who were 75 years of age or older or had comorbidities in a nonrandomized trial. The complete remission (CR) and CR with partial hematological recovery (CRh) rates were 54% and 7.7%, respectively, in 13 patients who received venetoclax plus decitabine; the median time to first CR or CRh was 1.9 months (range, 0.8 to 4.2 months). At a median follow-up was 11 months (range, 0.7 to 38.8 months), the median duration of CR was 12.7 months in patients who received venetoclax plus decitabine. In this study, the median patient age was 75 years (range, 68 to 86 years) in patients who received venetoclax plus decitabine. Patient comorbidities included severe cardiac disease (7.7%) or a creatinine clearance of less than 45 mL/min (7.7%).

    MAXIMUM DOSAGE

    Adults

    CLL/SLL: 400 mg/day PO; AML: 400 mg/day PO with azacitidine or decitabine or 600 mg/day PO with low-dose cytarabine.

    Geriatric

    CLL/SLL: 400 mg/day PO; AML: 400 mg/day PO with azacitidine or decitabine or 600 mg/day PO with low-dose cytarabine.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Mild and moderate hepatic impairment (Child-Pugh A and B): No venetoclax dosage adjustment is necessary.
    Severe hepatic impairment (Child-Pugh C): Reduce the venetoclax once-daily dose by 50%; monitor these patients frequently for signs of adverse reactions.[60706]

    Renal Impairment

    No venetoclax dosage adjustment is necessary in patients with mild, moderate, or severe renal impairment (creatinine clearance 15 mL/min or higher).

    ADMINISTRATION

    Oral Administration
    Oral Solid Formulations

    Take venetoclax with a meal and water at the same time each day.
    Swallow tablets whole; do not chew, crush, or break tablets.
    Patients should drink 6 to 8 glasses (about 56 ounces total) of water each day at 2 days before the first dose, on the day of the first dose, and each time the dose is increased.
    For patients with CLL/SLL, keep venetoclax in the original packaging during the first 4 weeks of treatment; do not transfer the tablets to a different container.
    If a dose is missed, take within 8 hours of missing the dose. If more than 8 hours have passed, skip the dose that day and take the dose the next day at the scheduled time.
    If vomiting occurs after a dose, do not take another dose that day; resume dosing the next day at the usual time.

    STORAGE

    Venclexta:
    - Store at room temperature not exceeding 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Electrolyte imbalance, renal failure, tumor lysis syndrome (TLS)

    Tumor lysis syndrome (TLS) may occur at initiation and during the ramp-up phase in all patients who receive venetoclax; patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) are also at risk for TLS during re-initiation after a dosage interruption. Fatal events and renal failure requiring dialysis have been reported as a result of TLS. In patients with CLL/SLL, the concomitant use of venetoclax with a strong CYP3A inhibitor is contraindicated during the initial and dose titration dosing phase. Assess patient-specific factors for level of TLS risk (e.g., tumor burden using radiographic evaluation, blood chemistries, comorbidities). All patients require hydration and anti-hyperuricemic agents prior to starting therapy and during the ramp-up phase to reduce the risk of TLS; more intensive measures (e.g., IV hydration, increased monitoring, hospitalization) may be necessary as the overall risk increases. Prior to starting venetoclax, evaluate serum electrolytes (e.g., potassium, phosphorus, calcium), uric acid level, and serum creatinine concentration; correct any electrolyte imbalance. In patients with acute myelogenous leukemia (AML), monitor for signs of TLS prior to therapy, at 6 to 8 hours after each new dose during the ramp-up phase, and at 24 hours after reaching the final dose. For patients with risk factors for TLS (e.g., circulating blasts, high burden of leukemia involvement in bone marrow, elevated pretreatment lactate dehydrogenase levels, or reduced renal function), consider additional measures such as increased laboratory monitoring and a reduced venetoclax starting dose. Patients with CLL or SLL who have reduced renal function (creatinine clearance less than 80 mL/min), a high tumor burden, or splenomegaly may be at increased risk of developing TLS. Monitor for laboratory signs of TLS at 6 to 8 hours after the first dose of 20 mg/day and 50 mg/day and then prior to subsequent dose titrations in patients with low or medium tumor burden. Consider hospitalization during the first dose of 20 mg/day and 50 mg/day in patients with a medium tumor burden who have a creatinine clearance less than 80 mL/min; monitor for signs of TLS at 6 to 8 hours and 24 hours after the subsequent dose titrations in these patients. In patients with a high tumor burden, administer the first dose of 20 mg/day and 50 mg/day in the hospital and monitor for laboratory signs of TLS at 4, 8, 12, and 24 hours. Monitor for signs of TLS at 6 to 8 hours and 24 hours after subsequent dose titrations in these patients in the outpatient setting. A dose reduction and/or therapy interruption may be necessary in patients who develop TLS.[60706]

    Anemia, infection, neutropenia, thrombocytopenia

    Hematologic toxicity (e.g., neutropenia, thrombocytopenia, and anemia) and fatal and serious infections (e.g., pneumonia and sepsis) have been reported with venetoclax therapy. Monitor patients for fever or other signs or symptoms of infection; obtain complete blood counts periodically during treatment in patients with chronic lymphocytic leukemia or small lymphocytic lymphoma and frequently through the resolution of cytopenias in patients with acute myelogenous leukemia. A dose reduction and/or therapy interruption may be necessary in patients who develop severe hematologic toxicities. Treat infection promptly; hold venetoclax in patients who develop a grade 3 or 4 infection until resolution. Consider the use of antimicrobial agents and granulocyte-colony stimulating factors as indicated.[60706]

    Vaccination

    Avoid vaccination with live attenuated vaccines prior to, during, and after venetoclax treatment because the antibody response may be suboptimal. Live vaccines may be administered after B-cell recovery.

    Renal disease, renal impairment

    Patients with renal disease or renal impairment (CrCl less than 80 mL/min) may be at increased risk of developing tumor lysis syndrome (TLS) with venetoclax therapy; increased monitoring and more intensive TLS prophylaxis may be necessary.[60706]

    Hepatic disease

    Use venetoclax with caution in patients with severe hepatic disease/impairment (Child-Pugh C); these patients require a 50% dose reduction and frequent monitoring for adverse events.

    Multiple myeloma, treatment outside of a clinical trial

    Venetoclax, in combination with bortezomib plus dexamethasone, is not recommended in patients with multiple myeloma for treatment outside of a clinical trial. Interim results of a randomized, double-blind, phase 3 clinical trial (the BELLINI trial) demonstrated an increased risk of death for patients with relapsed or refractory multiple myeloma treated with venetoclax plus bortezomib and dexamethasone compared to the control group (HR 2.03; 95% CI, 1.04 to 3.94). The FDA suspended enrollment in ongoing multiple myeloma clinical trials of venetoclax, including the BELLINI trial; patients receiving clinical benefit can continue treatment after reconsent. Any adverse events related to venetoclax should be reported to the FDA's MedWatch program.[64023] [60706]

    Pregnancy

    Venetoclax may cause fetal harm if administered during pregnancy based on its mechanism of action and data from animal studies. Females of reproductive potential should be advised to avoid becoming pregnant while receiving venetoclax. If a woman becomes pregnant while taking this drug, she should be apprised of the potential hazard to the fetus. In an embryo-fetal study in pregnant mice, post-implantation loss and decreased fetal weight were observed following venetoclax doses that resulted in drug exposures 1.2-times those reported at clinical human doses of 400 mg/day (based on AUC). No teratogenicity occurred in mice or rabbits.

    Contraception requirements, infertility, pregnancy testing, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during venetoclax treatment. Pregnancy testing should be performed prior to starting venetoclax in female patients of reproductive potential. These patients should use effective contraception and avoid pregnancy during and for 30 days after venetoclax therapy. Women who become pregnant while receiving venetoclax should be apprised of the potential hazard to the fetus. Venetoclax may cause infertility in male patients based on animal findings; these patients should consider sperm banking.

    Breast-feeding

    Women should avoid breast-feeding during venetoclax therapy and for 1 week after the last dose due to the potential for serious adverse reactions in breastfed infants. No information is available regarding the presence of venetoclax in human milk, the effects on the breastfed infant, or the effects on milk production.

    ADVERSE REACTIONS

    Severe

    neutropenia / Delayed / 0-98.0
    thrombocytopenia / Delayed / 0-95.0
    lymphopenia / Delayed / 7.0-71.0
    anemia / Delayed / 12.0-69.0
    infection / Delayed / 0-46.0
    leukopenia / Delayed / 0-46.0
    hyperuricemia / Delayed / 0-38.0
    hypokalemia / Delayed / 0-16.0
    hyponatremia / Delayed / 0-14.0
    hypophosphatemia / Delayed / 0-13.0
    hyperglycemia / Delayed / 0-13.0
    hypocalcemia / Delayed / 0-12.0
    bleeding / Early / 0-8.0
    hyperbilirubinemia / Delayed / 0-7.0
    fatigue / Early / 0-6.0
    hypoalbuminemia / Delayed / 0-6.0
    elevated hepatic enzymes / Delayed / 0-6.0
    nephrotoxicity / Delayed / 0-6.0
    tumor lysis syndrome (TLS) / Delayed / 0-5.6
    hyperkalemia / Delayed / 0-5.0
    diarrhea / Early / 0-5.0
    hypotension / Rapid / 0-5.0
    anorexia / Delayed / 0-4.0
    dyspnea / Early / 0-4.0
    cholecystitis / Delayed / 0-4.0
    hypercalcemia / Delayed / 0-3.0
    abdominal pain / Early / 0-3.0
    musculoskeletal pain / Early / 0-3.0
    hyperphosphatemia / Delayed / 0-2.0
    nausea / Early / 0-2.0
    edema / Delayed / 0-2.0
    hypoglycemia / Early / 0-2.0
    constipation / Delayed / 0-1.0
    stomatitis / Delayed / 0-1.0
    vomiting / Early / 0-1.0
    arthralgia / Delayed / 0-1.0
    dizziness / Early / 0-1.0
    headache / Early / 0-1.0
    fever / Early / 0-1.0
    rash / Early / 0-1.0
    metabolic acidosis / Delayed / 0-1.0
    renal failure (unspecified) / Delayed / Incidence not known
    hematemesis / Delayed / Incidence not known
    hemolytic anemia / Delayed / Incidence not known
    exfoliative dermatitis / Delayed / Incidence not known
    retinal hemorrhage / Delayed / Incidence not known
    GI bleeding / Delayed / Incidence not known
    ocular hemorrhage / Delayed / Incidence not known
    stroke / Early / Incidence not known
    intracranial bleeding / Delayed / Incidence not known
    vasculitis / Delayed / Incidence not known

    Moderate

    cholelithiasis / Delayed / 0-4.0
    glossitis / Early / Incidence not known
    bone pain / Delayed / Incidence not known
    erythema / Early / Incidence not known
    vaginal bleeding / Delayed / Incidence not known
    hemoptysis / Delayed / Incidence not known
    hematuria / Delayed / Incidence not known
    orthostatic hypotension / Delayed / Incidence not known

    Mild

    back pain / Delayed / 0-31.0
    cough / Delayed / 0-22.0
    weight loss / Delayed / 0-13.0
    cheilitis / Delayed / Incidence not known
    asthenia / Delayed / Incidence not known
    myalgia / Early / Incidence not known
    vertigo / Early / Incidence not known
    maculopapular rash / Early / Incidence not known
    acneiform rash / Delayed / Incidence not known
    pruritus / Rapid / Incidence not known
    epistaxis / Delayed / Incidence not known

    DRUG INTERACTIONS

    Afatinib: (Moderate) If the concomitant use of venetoclax and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of venetoclax. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day but does not address a minimum dose otherwise. Afatinib is a P-glycoprotein (P-gp) substrate and venetoclax is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
    Amiodarone: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with amiodarone due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of amiodarone. Venetoclax is a CYP3A4 and P-glycoprotein (P-gp) substrate; amiodarone is a CYP3A4 (moderate) and P-gp inhibitor. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Coadministration of clarithromycin with venetoclax is contraindicated during the initiation and ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL); consider an alternative medication or adjust the venetoclax dose with close monitoring for toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) in patients receiving a steady daily dose of venetoclax if concurrent use is necessary. In patients with acute myeloid leukemia (AML), reduce the venetoclax dose and monitor for toxicity during concurrent use. Resume the original venetoclax dose 2 to 3 days after discontinuation of clarithromycin. Specific venetoclax dosage adjustments are as follows: CLL/SLL patients at steady daily dose: 100 mg/day. AML patients: 10 mg on day 1, 20 mg on day 2, 50 mg on day 3, then 100 mg/day starting on day 4. Venetoclax is a CYP3A4 and P-glycoprotein (P-gp) substrate; clarithromycin is a CYP3A4 (strong) and P-gp inhibitor Coadministration of strong CYP3A4 inhibitors increased the venetoclax AUC by 90% to 690% in drug interaction studies, while coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
    Apalutamide: (Major) Avoid coadministration of venetoclax with apalutamide due to decreased plasma concentrations of venetoclax. Venetoclax is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased venetoclax exposure by 71%.
    Aprepitant, Fosaprepitant: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with a multi-day oral aprepitant, fosaprepitant regimen due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of aprepitant, fosaprepitant. Venetoclax is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor. When administered as a single oral or single intravenous dose, the inhibitory effect of aprepitant on CYP3A4 is weak and did not result in a clinically significant increase in the AUC of a sensitive substrate.
    Atazanavir: (Major) Coadministration of atazanavir with venetoclax is contraindicated during the initiation and ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL); consider an alternative medication or adjust the venetoclax dose with close monitoring for toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) in patients receiving a steady daily dose of venetoclax if concurrent use is necessary. In patients with acute myeloid leukemia (AML), reduce the venetoclax dose and monitor for toxicity during concurrent use. Resume the original venetoclax dose 2 to 3 days after discontinuation of atazanavir. Specific venetoclax dosage adjustments are as follows: CLL/SLL patients at steady daily dose: 100 mg/day. AML patients: 10 mg on day 1, 20 mg on day 2, 50 mg on day 3, then 100 mg/day starting on day 4. Venetoclax is a CYP3A4 substrate; atazanavir is a strong CYP3A4 inhibitor. Coadministration of strong CYP3A4 inhibitors increased the venetoclax AUC by 90% to 690% in drug interaction studies.
    Atazanavir; Cobicistat: (Major) Coadministration of atazanavir with venetoclax is contraindicated during the initiation and ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL); consider an alternative medication or adjust the venetoclax dose with close monitoring for toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) in patients receiving a steady daily dose of venetoclax if concurrent use is necessary. In patients with acute myeloid leukemia (AML), reduce the venetoclax dose and monitor for toxicity during concurrent use. Resume the original venetoclax dose 2 to 3 days after discontinuation of atazanavir. Specific venetoclax dosage adjustments are as follows: CLL/SLL patients at steady daily dose: 100 mg/day. AML patients: 10 mg on day 1, 20 mg on day 2, 50 mg on day 3, then 100 mg/day starting on day 4. Venetoclax is a CYP3A4 substrate; atazanavir is a strong CYP3A4 inhibitor. Coadministration of strong CYP3A4 inhibitors increased the venetoclax AUC by 90% to 690% in drug interaction studies. (Major) Coadministration of cobicistat with venetoclax is contraindicated during the initiation and ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL); consider an alternative medication or adjust the venetoclax dose with close monitoring for toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) in patients receiving a steady daily dose of venetoclax if concurrent use is necessary. In patients with acute myeloid leukemia (AML), reduce the venetoclax dose and monitor for toxicity during concurrent use. Resume the original venetoclax dose 2 to 3 days after discontinuation of cobicistat. Specific venetoclax dosage adjustments are as follows: CLL/SLL patients at steady daily dose: 100 mg/day. AML patients: 10 mg on day 1, 20 mg on day 2, 50 mg on day 3, then 100 mg/day starting on day 4. Venetoclax is a CYP3A4 and P-glycoprotein (P-gp) substrate; cobicistat is a CYP3A4 (strong) and P-gp inhibitor Coadministration of strong CYP3A4 inhibitors increased the venetoclax AUC by 90% to 690% in drug interaction studies, while coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Avoid the concomitant use of venetoclax and phenobarbital; venetoclax levels may be significantly decreased and its efficacy reduced. Venetoclax is a CYP3A4 and P-glycoprotein (P-gp) substrate and phenobarbital is a strong CYP3A4 inducer and a P-gp inducer. Consider alternative agents. In a drug interaction study in healthy subjects (n = 10), the venetoclax Cmax and AUC values were decreased by 42% and 71%, respectively, following the co-administration of multiple doses of a strong CYP3A4 inducer.
    Berotralstat: (Major) Reduce the berotralstat dose to 110 mg PO once daily in patients taking venetoclax. Concurrent use may increase berotralstat exposure and the risk of adverse effects. Additionally, reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of berotralstat. Berotralstat is a P-gp substrate and Pgp and moderate CYP3A4 inhibitor; venetoclax is a CYP3A4 and P-gp substrate and P-gp inhibitor. Coadministration with another P-gp inhibitor increased berotralstat exposure by 69% and venetoclax exposure by 78%.
    Betrixaban: (Major) Avoid betrixaban use in patients with severe renal impairment receiving venetoclax. Reduce betrixaban dosage to 80 mg PO once followed by 40 mg PO once daily in all other patients receiving venetoclax. Bleeding risk may be increased; monitor patients closely for signs and symptoms of bleeding. Betrixaban is a substrate of P-gp; venetoclax inhibits P-gp.
    Bexarotene: (Major) Avoid the concomitant use of venetoclax and bexarotene; venetoclax levels may be decreased and its efficacy reduced. Venetoclax is a CYP3A4 substrate and bexarotene is a moderate CYP3A4 inducer. Consider alternative agents. In a drug interaction study (n = 11), the venetoclax Cmax and AUC values were decreased by 42% and 71%, respectively, following the co-administration of multiple doses of a strong CYP3A4 inducer. Use of venetoclax with a moderate CYP3A4 inducer has not been evaluated.
    Boceprevir: (Contraindicated) Boceprevir is contraindicated for use with medications that are highly dependent on CYP3A4 for clearance and are associated with serious and/or life-threatening events, such as venetoclax. Significantly increased venetoclax levels may occur. Venetoclax is a sensitive CYP3A4 substrate; boceprevir is a strong CYP3A inhibitor. When venetoclax was administered with multiple doses of other strong CYP3A4 inhibitors, the Cmax and AUC values of venetoclax were increased significantly.
    Bosentan: (Major) Avoid the concomitant use of venetoclax and bosentan; venetoclax levels may be decreased and its efficacy reduced. Venetoclax is a CYP3A4 substrate and bosentan is a moderate CYP3A4 inducer. Consider alternative agents. In a drug interaction study (n = 11), the venetoclax Cmax and AUC values were decreased by 42% and 71%, respectively, following the co-administration of multiple doses of a strong CYP3A4 inducer. Use of venetoclax with a moderate CYP3A4 inducer has not been evaluated.
    Brigatinib: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with brigatinib due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of brigatinib. Brigatinib is a P-gp inhibitor; venetoclax is a P-gp substrate. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
    Cabozantinib: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with cabozantinib due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of cabozantinib. Venetoclax is a P-glycoprotein (P-gp) substrate; cabozantinib is a P-gp inhibitor. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
    Cannabidiol: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with cannabidiol due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of cannabidiol. Venetoclax is a P-gp substrate; cannabidiol is a P-gp inhibitor. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
    Capmatinib: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with capmatinib due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of capmatinib. Capmatinib is a P-glycoprotein (P-gp) inhibitor; venetoclax is a P-gp substrate. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
    Carbamazepine: (Major) Avoid the concomitant use of venetoclax and carbamazepine; venetoclax levels may be significantly decreased and its efficacy reduced. Venetoclax is a CYP3A4 substrate and carbamazepine is a strong CYP3A4 inducer. Consider alternative agents. In a drug interaction study in healthy subjects (n = 10), the venetoclax Cmax and AUC values were decreased by 42% and 71%, respectively, following the co-administration of multiple doses of a strong CYP3A4 inducer.
    Carvedilol: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with carvedilol due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of carvedilol. Venetoclax is a P-glycoprotein (P-gp) substrate; carvedilol is a P-gp inhibitor. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
    Cenobamate: (Major) Avoid coadministration of venetoclax with cenobamate as concurrent use may decrease venetoclax exposure and lead to reduced efficacy. Venetoclax is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. Coadministration with a strong CYP3A4 inducer decreased venetoclax exposure by 71%.
    Ceritinib: (Contraindicated) Coadministration of ceritinib with venetoclax is contraindicated during the initiation and ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL); consider an alternative medication or adjust the venetoclax dose with close monitoring for toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) in patients receiving a steady daily dose of venetoclax if concurrent use is necessary. In patients with acute myeloid leukemia (AML), reduce the venetoclax dose and monitor for toxicity during concurrent use. Resume the original venetoclax dose 2 to 3 days after discontinuation of ceritinib. Specific venetoclax dosage adjustments are as follows: CLL/SLL patients at steady daily dose: 100 mg/day. AML patients: 10 mg on day 1, 20 mg on day 2, 50 mg on day 3, then 100 mg/day starting on day 4. Venetoclax is a CYP3A4 substrate; ceritinib is a strong CYP3A4 inhibitor. Coadministration of strong CYP3A4 inhibitors increased the venetoclax AUC by 90% to 690% in drug interaction studies.
    Chloramphenicol: (Major) Coadministration of chloramphenicol with venetoclax is contraindicated during the initiation and ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL); consider an alternative medication or adjust the venetoclax dose with close monitoring for toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) in patients receiving a steady daily dose of venetoclax if concurrent use is necessary. In patients with acute myeloid leukemia (AML), reduce the venetoclax dose and monitor for toxicity during concurrent use. Resume the original venetoclax dose 2 to 3 days after discontinuation of chloramphenicol. Specific venetoclax dosage adjustments are as follows: CLL/SLL patients at steady daily dose: 100 mg/day. AML patients: 10 mg on day 1, 20 mg on day 2, 50 mg on day 3, then 100 mg/day starting on day 4. Venetoclax is a CYP3A4 substrate; chloramphenicol is a strong CYP3A4 inhibitor. Coadministration of strong CYP3A4 inhibitors increased the venetoclax AUC by 90% to 690% in drug interaction studies.
    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.
    Ciprofloxacin: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with ciprofloxacin due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of ciprofloxacin. Venetoclax is a CYP3A4 substrate; ciprofloxacin is a moderate CYP3A4 inhibitor.
    Clarithromycin: (Major) Coadministration of clarithromycin with venetoclax is contraindicated during the initiation and ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL); consider an alternative medication or adjust the venetoclax dose with close monitoring for toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) in patients receiving a steady daily dose of venetoclax if concurrent use is necessary. In patients with acute myeloid leukemia (AML), reduce the venetoclax dose and monitor for toxicity during concurrent use. Resume the original venetoclax dose 2 to 3 days after discontinuation of clarithromycin. Specific venetoclax dosage adjustments are as follows: CLL/SLL patients at steady daily dose: 100 mg/day. AML patients: 10 mg on day 1, 20 mg on day 2, 50 mg on day 3, then 100 mg/day starting on day 4. Venetoclax is a CYP3A4 and P-glycoprotein (P-gp) substrate; clarithromycin is a CYP3A4 (strong) and P-gp inhibitor Coadministration of strong CYP3A4 inhibitors increased the venetoclax AUC by 90% to 690% in drug interaction studies, while coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
    Cobicistat: (Major) Coadministration of cobicistat with venetoclax is contraindicated during the initiation and ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL); consider an alternative medication or adjust the venetoclax dose with close monitoring for toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) in patients receiving a steady daily dose of venetoclax if concurrent use is necessary. In patients with acute myeloid leukemia (AML), reduce the venetoclax dose and monitor for toxicity during concurrent use. Resume the original venetoclax dose 2 to 3 days after discontinuation of cobicistat. Specific venetoclax dosage adjustments are as follows: CLL/SLL patients at steady daily dose: 100 mg/day. AML patients: 10 mg on day 1, 20 mg on day 2, 50 mg on day 3, then 100 mg/day starting on day 4. Venetoclax is a CYP3A4 and P-glycoprotein (P-gp) substrate; cobicistat is a CYP3A4 (strong) and P-gp inhibitor Coadministration of strong CYP3A4 inhibitors increased the venetoclax AUC by 90% to 690% in drug interaction studies, while coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
    Colchicine: (Major) Coadministration of colchicine and venetoclax should be avoided due to the potential for serious and life-threatening colchicine toxicity. Colchicine is a substrate of P-glycoprotein (P-gp) and venetoclax is an inhibitor of P-gp; increased concentrations of colchicine are expected with concurrent use. Colchicine accumulation may be greater in patients with renal or hepatic impairment; therefore, the manufacturer of Colcrys contraindicates the use of colchicine and P-gp inhibitors in this population. If coadministration in patients with normal renal and hepatic function cannot be avoided, adjust the dose of colchicine either by reducing the daily dose or reducing the dose frequency, and carefully monitor for colchicine toxicity. Specific dosage adjustment recommendations for coadministration with P-gp inhibitors are provided by the manufacturer of Colcrys.
    Conivaptan: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with conivaptan due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of conivaptan. Venetoclax is a CYP3A and P-gp substrate; conivaptan is a moderate CYP3A and P-gp inhibitor. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
    Crizotinib: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with crizotinib due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of crizotinib. Venetoclax is a CYP3A4 substrate and crizotinib is a moderate CYP3A inhibitor.
    Cyclosporine: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with cyclosporine due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of cyclosporine. Venetoclax is a CYP3A4 and P-glycoprotein (P-gp) substrate; cyclosporine is a CYP3A4 (moderate) and P-gp inhibitor. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
    Dabrafenib: (Major) Avoid the concomitant use of venetoclax and dabrafenib; venetoclax levels may be decreased and its efficacy reduced. Venetoclax is a CYP3A4 substrate and dabrafenib is a moderate CYP3A4 inducer. Consider alternative agents. In a drug interaction study (n = 11), the venetoclax Cmax and AUC values were decreased by 42% and 71%, respectively, following the co-administration of multiple doses of a strong CYP3A4 inducer. Use of venetoclax with a moderate CYP3A4 inducer has not been evaluated.
    Daclatasvir: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with daclatasvir due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of daclatasvir. Venetoclax is a substrate of P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP); daclatasvir is an inhibitor of P-gp and BCRP. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
    Danazol: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with danazol due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of danazol. Venetoclax is a CYP3A4 substrate; danazol is a moderate CYP3A4 inhibitor.
    Darunavir: (Major) Coadministration of darunavir with venetoclax is contraindicated during the initiation and ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL); consider an alternative medication or adjust the venetoclax dose with close monitoring for toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) in patients receiving a steady daily dose of venetoclax if concurrent use is necessary. In patients with acute myeloid leukemia (AML), reduce the venetoclax dose and monitor for toxicity during concurrent use. Resume the original venetoclax dose 2 to 3 days after discontinuation of darunavir. Specific venetoclax dosage adjustments are as follows: CLL/SLL patients at steady daily dose: 100 mg/day. AML patients: 10 mg on day 1, 20 mg on day 2, 50 mg on day 3, then 100 mg/day starting on day 4. Venetoclax is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. Coadministration of strong CYP3A4 inhibitors increased the venetoclax AUC by 90% to 690% in drug interaction studies.
    Darunavir; Cobicistat: (Major) Coadministration of cobicistat with venetoclax is contraindicated during the initiation and ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL); consider an alternative medication or adjust the venetoclax dose with close monitoring for toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) in patients receiving a steady daily dose of venetoclax if concurrent use is necessary. In patients with acute myeloid leukemia (AML), reduce the venetoclax dose and monitor for toxicity during concurrent use. Resume the original venetoclax dose 2 to 3 days after discontinuation of cobicistat. Specific venetoclax dosage adjustments are as follows: CLL/SLL patients at steady daily dose: 100 mg/day. AML patients: 10 mg on day 1, 20 mg on day 2, 50 mg on day 3, then 100 mg/day starting on day 4. Venetoclax is a CYP3A4 and P-glycoprotein (P-gp) substrate; cobicistat is a CYP3A4 (strong) and P-gp inhibitor Coadministration of strong CYP3A4 inhibitors increased the venetoclax AUC by 90% to 690% in drug interaction studies, while coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study. (Major) Coadministration of darunavir with venetoclax is contraindicated during the initiation and ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL); consider an alternative medication or adjust the venetoclax dose with close monitoring for toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) in patients receiving a steady daily dose of venetoclax if concurrent use is necessary. In patients with acute myeloid leukemia (AML), reduce the venetoclax dose and monitor for toxicity during concurrent use. Resume the original venetoclax dose 2 to 3 days after discontinuation of darunavir. Specific venetoclax dosage adjustments are as follows: CLL/SLL patients at steady daily dose: 100 mg/day. AML patients: 10 mg on day 1, 20 mg on day 2, 50 mg on day 3, then 100 mg/day starting on day 4. Venetoclax is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. Coadministration of strong CYP3A4 inhibitors increased the venetoclax AUC by 90% to 690% in drug interaction studies.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Coadministration of cobicistat with venetoclax is contraindicated during the initiation and ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL); consider an alternative medication or adjust the venetoclax dose with close monitoring for toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) in patients receiving a steady daily dose of venetoclax if concurrent use is necessary. In patients with acute myeloid leukemia (AML), reduce the venetoclax dose and monitor for toxicity during concurrent use. Resume the original venetoclax dose 2 to 3 days after discontinuation of cobicistat. Specific venetoclax dosage adjustments are as follows: CLL/SLL patients at steady daily dose: 100 mg/day. AML patients: 10 mg on day 1, 20 mg on day 2, 50 mg on day 3, then 100 mg/day starting on day 4. Venetoclax is a CYP3A4 and P-glycoprotein (P-gp) substrate; cobicistat is a CYP3A4 (strong) and P-gp inhibitor Coadministration of strong CYP3A4 inhibitors increased the venetoclax AUC by 90% to 690% in drug interaction studies, while coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study. (Major) Coadministration of darunavir with venetoclax is contraindicated during the initiation and ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL); consider an alternative medication or adjust the venetoclax dose with close monitoring for toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) in patients receiving a steady daily dose of venetoclax if concurrent use is necessary. In patients with acute myeloid leukemia (AML), reduce the venetoclax dose and monitor for toxicity during concurrent use. Resume the original venetoclax dose 2 to 3 days after discontinuation of darunavir. Specific venetoclax dosage adjustments are as follows: CLL/SLL patients at steady daily dose: 100 mg/day. AML patients: 10 mg on day 1, 20 mg on day 2, 50 mg on day 3, then 100 mg/day starting on day 4. Venetoclax is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. Coadministration of strong CYP3A4 inhibitors increased the venetoclax AUC by 90% to 690% in drug interaction studies.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Coadministration of ritonavir with venetoclax is contraindicated during the initiation and ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL); consider an alternative medication or adjust the venetoclax dose with close monitoring for toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) in patients receiving a steady daily dose of venetoclax if concurrent use is necessary. In patients with acute myeloid leukemia (AML), reduce the venetoclax dose and monitor for toxicity during concurrent use. Resume the original venetoclax dose 2 to 3 days after discontinuation of ritonavir. Specific venetoclax dosage adjustments are as follows: CLL/SLL patients at steady daily dose: 100 mg/day. AML patients: 10 mg on day 1, 20 mg on day 2, 50 mg on day 3, then 100 mg/day starting on day 4. Coadministration of ritonavir, a strong CYP3A, P-gp, and OATP1B1/B3 inhibitor increased the venetoclax AUC by 690% in a drug interaction study.
    Delavirdine: (Major) Coadministration of delavirdine with venetoclax is contraindicated during the initiation and ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL); consider an alternative medication or adjust the venetoclax dose with close monitoring for toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) in patients receiving a steady daily dose of venetoclax if concurrent use is necessary. In patients with acute myeloid leukemia (AML), reduce the venetoclax dose and monitor for toxicity during concurrent use. Resume the original venetoclax dose 2 to 3 days after discontinuation of delavirdine. Specific venetoclax dosage adjustments are as follows: CLL/SLL patients at steady daily dose: 100 mg/day. AML patients: 10 mg on day 1, 20 mg on day 2, 50 mg on day 3, then 100 mg/day starting on day 4. Venetoclax is a CYP3A4 substrate; delavirdine is a strong CYP3A4 inhibitor. Coadministration of strong CYP3A4 inhibitors increased the venetoclax AUC by 90% to 690% in drug interaction studies.
    Dexamethasone: (Major) Avoid the concomitant use of venetoclax and dexamethasone; venetoclax levels may be decreased and its efficacy reduced. Venetoclax is a CYP3A4 substrate and dexamethasone is a moderate CYP3A4 inducer. Consider alternative agents. In a drug interaction study (n = 11), the venetoclax Cmax and AUC values were decreased by 42% and 71%, respectively, following the co-administration of multiple doses of a strong CYP3A4 inducer. Use of venetoclax with a moderate CYP3A4 inducer has not been evaluated.
    Dextromethorphan; Quinidine: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with quinidine due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of quinidine. Venetoclax is a P-glycoprotein (P-gp) substrate; quinidine is a P-gp inhibitor. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
    Digoxin: (Major) Avoid the concomitant use of venetoclax and digoxin as digoxin levels may be increased. If concomitant use of these drugs is required, administer digoxin at least 6 hours before venetoclax. Monitor patients for signs and symptoms of digoxin toxicity. Venetoclax is an inhibitor of P-glycoprotein (P-gp) and digoxin is a P-gp substrate with a narrow therapeutic index. Coadministration of a single 100-mg dose of venetoclax with digoxin led to an increase in digoxin Cmax and AUC values by 35% and 9%, respectively.
    Diltiazem: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with diltiazem due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of diltiazem. Venetoclax is a CYP3A4 substrate; diltiazem is a moderate CYP3A4 inhibitor.
    Dronedarone: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with dronedarone due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of dronedarone. Venetoclax is a CYP3A4 and P-glycoprotein (P-gp) substrate; dronedarone is a CYP3A4 (moderate) and P-gp inhibitor. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
    Duvelisib: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with duvelisib due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of duvelisib. Venetoclax is a CYP3A4 substrate; duvelisib is a moderate CYP3A4 inhibitor.
    Efavirenz: (Major) Avoid the concomitant use of venetoclax and efavirenz; venetoclax levels may be decreased and its efficacy reduced. Venetoclax is a CYP3A4 substrate and efavirenz is a moderate CYP3A4 inducer. Consider alternative agents. In a drug interaction study (n = 11), the venetoclax Cmax and AUC values were decreased by 42% and 71%, respectively, following the co-administration of multiple doses of a strong CYP3A4 inducer. Use of venetoclax with a moderate CYP3A4 inducer has not been evaluated.
    Efavirenz; Emtricitabine; Tenofovir: (Major) Avoid the concomitant use of venetoclax and efavirenz; venetoclax levels may be decreased and its efficacy reduced. Venetoclax is a CYP3A4 substrate and efavirenz is a moderate CYP3A4 inducer. Consider alternative agents. In a drug interaction study (n = 11), the venetoclax Cmax and AUC values were decreased by 42% and 71%, respectively, following the co-administration of multiple doses of a strong CYP3A4 inducer. Use of venetoclax with a moderate CYP3A4 inducer has not been evaluated.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Avoid the concomitant use of venetoclax and efavirenz; venetoclax levels may be decreased and its efficacy reduced. Venetoclax is a CYP3A4 substrate and efavirenz is a moderate CYP3A4 inducer. Consider alternative agents. In a drug interaction study (n = 11), the venetoclax Cmax and AUC values were decreased by 42% and 71%, respectively, following the co-administration of multiple doses of a strong CYP3A4 inducer. Use of venetoclax with a moderate CYP3A4 inducer has not been evaluated.
    Elagolix: (Major) Avoid coadministration of venetoclax with elagolix due to decreased plasma concentrations of venetoclax. Venetoclax is a CYP3A4 substrate and elagolix is a weak to moderate CYP3A4 inducer. Coadministration with a strong CYP3A4 inducer decreased venetoclax exposure by 71%.
    Elagolix; Estradiol; Norethindrone acetate: (Major) Avoid coadministration of venetoclax with elagolix due to decreased plasma concentrations of venetoclax. Venetoclax is a CYP3A4 substrate and elagolix is a weak to moderate CYP3A4 inducer. Coadministration with a strong CYP3A4 inducer decreased venetoclax exposure by 71%.
    Elexacaftor; tezacaftor; ivacaftor: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with ivacaftor due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of ivacaftor. Venetoclax is a CYP3A4 and P-glycoprotein (P-gp) substrate; ivacaftor is a CYP3A4 (weak) and P-gp inhibitor. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
    Eliglustat: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with eliglustat due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of eliglustat. Venetoclax is a P-glycoprotein (P-gp) substrate; eliglustat is a P-gp inhibitor. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Coadministration of cobicistat with venetoclax is contraindicated during the initiation and ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL); consider an alternative medication or adjust the venetoclax dose with close monitoring for toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) in patients receiving a steady daily dose of venetoclax if concurrent use is necessary. In patients with acute myeloid leukemia (AML), reduce the venetoclax dose and monitor for toxicity during concurrent use. Resume the original venetoclax dose 2 to 3 days after discontinuation of cobicistat. Specific venetoclax dosage adjustments are as follows: CLL/SLL patients at steady daily dose: 100 mg/day. AML patients: 10 mg on day 1, 20 mg on day 2, 50 mg on day 3, then 100 mg/day starting on day 4. Venetoclax is a CYP3A4 and P-glycoprotein (P-gp) substrate; cobicistat is a CYP3A4 (strong) and P-gp inhibitor Coadministration of strong CYP3A4 inhibitors increased the venetoclax AUC by 90% to 690% in drug interaction studies, while coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Coadministration of cobicistat with venetoclax is contraindicated during the initiation and ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL); consider an alternative medication or adjust the venetoclax dose with close monitoring for toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) in patients receiving a steady daily dose of venetoclax if concurrent use is necessary. In patients with acute myeloid leukemia (AML), reduce the venetoclax dose and monitor for toxicity during concurrent use. Resume the original venetoclax dose 2 to 3 days after discontinuation of cobicistat. Specific venetoclax dosage adjustments are as follows: CLL/SLL patients at steady daily dose: 100 mg/day. AML patients: 10 mg on day 1, 20 mg on day 2, 50 mg on day 3, then 100 mg/day starting on day 4. Venetoclax is a CYP3A4 and P-glycoprotein (P-gp) substrate; cobicistat is a CYP3A4 (strong) and P-gp inhibitor Coadministration of strong CYP3A4 inhibitors increased the venetoclax AUC by 90% to 690% in drug interaction studies, while coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
    Enasidenib: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with enasidenib due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of enasidenib. Venetoclax is a P-gp substrate and enasidenib is a P-gp inhibitor. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
    Encorafenib: (Moderate) Coadministration of encorafenib with venetoclax may result in increased toxicity or decreased efficacy of venetoclax. Venetoclax is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established.
    Enzalutamide: (Major) Avoid the concomitant use of venetoclax and enzalutamide; venetoclax levels may be significantly decreased and its efficacy reduced. Venetoclax is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Consider alternative agents. In a drug interaction study in healthy subjects (n = 10), the venetoclax Cmax and AUC values were decreased by 42% and 71%, respectively, following the coadministration of multiple doses of a strong CYP3A4 inducer.
    Erythromycin: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with erythromycin due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of erythromycin. Venetoclax is a CYP3A4 and P-glycoprotein (P-gp) substrate; erythromycin is a CYP3A4 (moderate) and P-gp inhibitor. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
    Erythromycin; Sulfisoxazole: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with erythromycin due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of erythromycin. Venetoclax is a CYP3A4 and P-glycoprotein (P-gp) substrate; erythromycin is a CYP3A4 (moderate) and P-gp inhibitor. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
    Eslicarbazepine: (Major) Avoid the concomitant use of venetoclax and eslicarbazepine; venetoclax levels may be decreased and its efficacy reduced. Venetoclax is a CYP3A4 substrate and eslicarbazepine is a moderate CYP3A4 inducer. Consider alternative agents. In a drug interaction study (n = 11), the venetoclax Cmax and AUC values were decreased by 42% and 71%, respectively, following the co-administration of multiple doses of a strong CYP3A4 inducer. Use of venetoclax with a moderate CYP3A4 inducer has not been evaluated.
    Etravirine: (Major) Avoid the concomitant use of venetoclax and etravirine; venetoclax levels may be altered. Consider alternative agents. Venetoclax is a substrate of CYP3A4 and P-glycoprotein (P-gp) and etravirine is a moderate inducer of CYP3A4 and an inhibitor of P-gp. In a drug interaction study in healthy subjects (n = 10), the venetoclax Cmax and AUC values were decreased by 42% and 71%, respectively, following the co-administration of multiple doses of a strong CYP3A4 inducer. Use of venetoclax with a moderate CYP3A4 inducer has not been evaluated. In another drug interaction study (n = 11), the venetoclax Cmax and AUC values were increased by 106% and 78%, respectively, when a single dose of a P-gp inhibitor was co-administered in healthy subjects.
    Everolimus: (Moderate) If concomitant use is necessary, take everolimus at least 6 hours before venetoclax. Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions. The dose of everolimus may need to be reduced. Everolimus is a P-glycoprotein (P-gp) substrate and venetoclax is a P-gp inhibitor. Coadministration with P-gp inhibitors may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentrations.
    Fedratinib: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with fedratinib due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of fedratinib. Venetoclax is a CYP3A4 substrate; fedratinib is a moderate CYP3A4 inhibitor.
    Flibanserin: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with flibanserin due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of flibanserin. Venetoclax is a P-glycoprotein (P-gp) substrate; flibanserin is a P-gp inhibitor. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
    Fluconazole: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with fluconazole due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of fluconazole. Venetoclax is a CYP3A4 substrate; fluconazole is a moderate CYP3A4 inhibitor.
    Fluoxetine: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with fluoxetine due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of fluoxetine. Venetoclax is a CYP3A4 substrate; norfluoxetine, the active metabolite of fluoxetine, is a moderate CYP3A4 inhibitor.
    Fluvoxamine: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with fluvoxamine due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of fluvoxamine. Venetoclax is a CYP3A4 substrate; fluvoxamine is a moderate CYP3A4 inhibitor.
    Fosamprenavir: (Major) Coadministration of fosamprenavir with venetoclax is contraindicated during the initiation and ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL); consider an alternative medication or adjust the venetoclax dose with close monitoring for toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) in patients receiving a steady daily dose of venetoclax if concurrent use is necessary. In patients with acute myeloid leukemia (AML), reduce the venetoclax dose and monitor for toxicity during concurrent use. Resume the original venetoclax dose 2 to 3 days after discontinuation of fosamprenavir. Specific venetoclax dosage adjustments are as follows: CLL/SLL patients at steady daily dose: 100 mg/day. AML patients: 10 mg on day 1, 20 mg on day 2, 50 mg on day 3, then 100 mg/day starting on day 4. Venetoclax is a CYP3A4 substrate; fosamprenavir is a strong CYP3A4 inhibitor. Coadministration of strong CYP3A4 inhibitors increased the venetoclax AUC by 90% to 690% in drug interaction studies.
    Fosphenytoin: (Major) Avoid the concomitant use of venetoclax and phenytoin or fosphenytoin; venetoclax levels may be significantly decreased and its efficacy reduced. Venetoclax is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Consider alternative agents. In a drug interaction study in healthy subjects (n = 10), the venetoclax Cmax and AUC values were decreased by 42% and 71%, respectively, following the co-administration of multiple doses of a strong CYP3A4 inducer.
    Fostamatinib: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with fostamatinib due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of fostamatinib. Venetoclax is a CYP3A4 and P-glycoprotein (P-gp) substrate; fostamatinib is a CYP3A4 (weak) and P-gp inhibitor. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
    Glecaprevir; Pibrentasvir: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with glecaprevir due to the potential for increased venetoclax exposure. Additionally, glecaprevir exposure may be increased. Resume the original venetoclax dose 2 to 3 days after discontinuation of glecaprevir. Both venetoclax and glecaprevir are P-glycoprotein (P-gp) substrates and inhibitors. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study. (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with pibrentasvir due to the potential for increased venetoclax exposure. Additionally, pibrentasvir exposure may be increased. Resume the original venetoclax dose 2 to 3 days after discontinuation of pibrentasvir. Both venetoclax and pibrentasvir are P-glycoprotein (P-gp) substrates and inhibitors. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
    Grapefruit juice: (Major) Advise patients to avoid concomitant use of venetoclax with grapefruit juice, Seville oranges, and starfruit due to increased venetoclax exposure. Venetoclax is a CYP3A4 and P-glycoprotein (P-gp) substrate and these food items are CYP3A4 and P-gp inhibitors.
    Idelalisib: (Major) Coadministration of idelalisib with venetoclax is contraindicated during the initiation and ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL); consider an alternative medication or adjust the venetoclax dose with close monitoring for toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) in patients receiving a steady daily dose of venetoclax if concurrent use is necessary. In patients with acute myeloid leukemia (AML), reduce the venetoclax dose and monitor for toxicity during concurrent use. Resume the original venetoclax dose 2 to 3 days after discontinuation of idelalisib. Specific venetoclax dosage adjustments are as follows: CLL/SLL patients at steady daily dose: 100 mg/day. AML patients: 10 mg on day 1, 20 mg on day 2, 50 mg on day 3, then 100 mg/day starting on day 4. Venetoclax is a CYP3A4 substrate; idelalisib is a strong CYP3A4 inhibitor. Coadministration of strong CYP3A4 inhibitors increased the venetoclax AUC by 90% to 690% in drug interaction studies.
    Imatinib: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with imatinib due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of imatinib. Venetoclax is a CYP3A4 substrate; imatinib is a moderate CYP3A4 inhibitor.
    Indinavir: (Major) Coadministration of indinavir with venetoclax is contraindicated during the initiation and ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL); consider an alternative medication or adjust the venetoclax dose with close monitoring for toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) in patients receiving a steady daily dose of venetoclax if concurrent use is necessary. In patients with acute myeloid leukemia (AML), reduce the venetoclax dose and monitor for toxicity during concurrent use. Resume the original venetoclax dose 2 to 3 days after discontinuation of indinavir. Specific venetoclax dosage adjustments are as follows: CLL/SLL patients at steady daily dose: 100 mg/day. AML patients: 10 mg on day 1, 20 mg on day 2, 50 mg on day 3, then 100 mg/day starting on day 4. Venetoclax is a CYP3A4 substrate; indinavir is a strong CYP3A4 inhibitor. Coadministration of strong CYP3A4 inhibitors increased the venetoclax AUC by 90% to 690% in drug interaction studies.
    Isavuconazonium: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with isavuconazonium due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of isavuconazonium. Venetoclax is a CYP3A4 and P-glycoprotein (P-gp) substrate; isavuconazonium is a CYP3A4 (moderate) and P-gp inhibitor. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid the concomitant use of venetoclax and rifampin due to the potential for decreased venetoclax exposure and efficacy. Consider alternative agents. Venetoclax is a substrate of CYP3A4 and P-glycoprotein (P-gp) and rifampin is a strong inducer of CYP3A4 and an inducer of P-gp. Coadministration of rifampin decreased the venetoclax Cmax and AUC values by 42% and 71%, respectively.
    Isoniazid, INH; Rifampin: (Major) Avoid the concomitant use of venetoclax and rifampin due to the potential for decreased venetoclax exposure and efficacy. Consider alternative agents. Venetoclax is a substrate of CYP3A4 and P-glycoprotein (P-gp) and rifampin is a strong inducer of CYP3A4 and an inducer of P-gp. Coadministration of rifampin decreased the venetoclax Cmax and AUC values by 42% and 71%, respectively.
    Istradefylline: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with istradefylline due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of istradefylline. Istradefylline is a P-gp inhibitor; venetoclax is a P-gp substrate. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
    Itraconazole: (Major) Coadministration of itraconazole with venetoclax is contraindicated during the initiation and ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL); consider an alternative medication or adjust the venetoclax dose with close monitoring for toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) in patients receiving a steady daily dose of venetoclax if concurrent use is necessary. In patients with acute myeloid leukemia (AML), reduce the venetoclax dose and monitor for toxicity during concurrent use. Resume the original venetoclax dose 2 to 3 days after discontinuation of itraconazole. Specific venetoclax dosage adjustments are as follows: CLL/SLL patients at steady daily dose: 100 mg/day. AML patients: 10 mg on day 1, 20 mg on day 2, 50 mg on day 3, then 100 mg/day starting on day 4. Venetoclax is a CYP3A4 and P-glycoprotein (P-gp) substrate; itraconazole is a CYP3A4 (strong) and P-gp inhibitor Coadministration of strong CYP3A4 inhibitors increased the venetoclax AUC by 90% to 690% in drug interaction studies, while coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
    Ivacaftor: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with ivacaftor due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of ivacaftor. Venetoclax is a CYP3A4 and P-glycoprotein (P-gp) substrate; ivacaftor is a CYP3A4 (weak) and P-gp inhibitor. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
    Ketoconazole: (Major) Coadministration of ketoconazole with venetoclax is contraindicated during the initiation and ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL); consider an alternative medication or adjust the venetoclax dose with close monitoring for toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) in patients receiving a steady daily dose of venetoclax if concurrent use is necessary. In patients with acute myeloid leukemia (AML), reduce the venetoclax dose and monitor for toxicity during concurrent use. Resume the original venetoclax dose 2 to 3 days after discontinuation of ketoconazole. Specific venetoclax dosage adjustments are as follows: CLL/SLL patients at steady daily dose: 100 mg/day. AML patients: 10 mg on day 1, 20 mg on day 2, 50 mg on day 3, then 100 mg/day starting on day 4. Coadministration of ketoconazole, a strong CYP3A, P-gp, and BCRP inhibitor increased the venetoclax AUC by 540% in a drug interaction study.
    Lansoprazole; Amoxicillin; Clarithromycin: (Major) Coadministration of clarithromycin with venetoclax is contraindicated during the initiation and ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL); consider an alternative medication or adjust the venetoclax dose with close monitoring for toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) in patients receiving a steady daily dose of venetoclax if concurrent use is necessary. In patients with acute myeloid leukemia (AML), reduce the venetoclax dose and monitor for toxicity during concurrent use. Resume the original venetoclax dose 2 to 3 days after discontinuation of clarithromycin. Specific venetoclax dosage adjustments are as follows: CLL/SLL patients at steady daily dose: 100 mg/day. AML patients: 10 mg on day 1, 20 mg on day 2, 50 mg on day 3, then 100 mg/day starting on day 4. Venetoclax is a CYP3A4 and P-glycoprotein (P-gp) substrate; clarithromycin is a CYP3A4 (strong) and P-gp inhibitor Coadministration of strong CYP3A4 inhibitors increased the venetoclax AUC by 90% to 690% in drug interaction studies, while coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
    Lapatinib: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministration with lapatinib is necessary; lapatinib exposure may also be increased. Resume the original venetoclax dose 2 to 3 days after discontinuation of lapatinib. Both venetoclax and lapatinib are P-glycoprotein (P-gp) substrates and inhibitors. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study. Increased plasma concentrations of lapatinib are likely when administered with P-gp inhibitors.
    Ledipasvir; Sofosbuvir: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with ledipasvir due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of ledipasvir. Venetoclax is a substrate of P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP); ledipasvir is an inhibitor of P-gp and BCRP. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
    Lefamulin: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with oral lefamulin due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of oral lefamulin. Venetoclax is a CYP3A4 substrate; oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin.
    Letermovir: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with letermovir due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of letermovir. If the patient is also receiving cyclosporine, concurrent use is contraindicated during the initiation and ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL); consider an alternative medication or adjust the venetoclax dose with close monitoring for toxicity in patients receiving a steady daily dose of venetoclax if concurrent use with both letermovir and cyclosporine is necessary. In patients with acute myeloid leukemia (AML), reduce the venetoclax dose and monitor for toxicity during concurrent use of all 3 drugs. Resume the original dose of venetoclax 2 to 3 days after letermovir or letermovir and cyclosporine is discontinued. Specific venetoclax dosage adjustments are as follows: CLL/SLL patients at steady daily dose: 100 mg/day. AML patients: 10 mg on day 1, 20 mg on day 2, 50 mg on day 3, then 100 mg/day starting on day 4. Venetoclax 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. Coadministration of strong CYP3A4 inhibitors increased the venetoclax AUC by 90% to 690% in drug interaction studies.
    Levoketoconazole: (Major) Coadministration of ketoconazole with venetoclax is contraindicated during the initiation and ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL); consider an alternative medication or adjust the venetoclax dose with close monitoring for toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) in patients receiving a steady daily dose of venetoclax if concurrent use is necessary. In patients with acute myeloid leukemia (AML), reduce the venetoclax dose and monitor for toxicity during concurrent use. Resume the original venetoclax dose 2 to 3 days after discontinuation of ketoconazole. Specific venetoclax dosage adjustments are as follows: CLL/SLL patients at steady daily dose: 100 mg/day. AML patients: 10 mg on day 1, 20 mg on day 2, 50 mg on day 3, then 100 mg/day starting on day 4. Coadministration of ketoconazole, a strong CYP3A, P-gp, and BCRP inhibitor increased the venetoclax AUC by 540% in a drug interaction study.
    Live Vaccines: (Major) Avoid live vaccines to venetoclax recipients; no data are available regarding the risk of secondary transmission of infection by live vaccines in patients receiving venetoclax. Before initiation of venetoclax therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. Venetoclax recipients may receive inactivated vaccines, but the immune response to vaccines or toxoids may be decreased.
    Lomitapide: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with lomitapide due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of lomitapide. Venetoclax is a P-glycoprotein (P-gp) substrate; lomitapide is a P-gp inhibitor. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
    Lonafarnib: (Major) Coadministration of lonafarnib with venetoclax is contraindicated during the initiation and ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL); consider an alternative medication or adjust the venetoclax dose with close monitoring for toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) in patients receiving a steady daily dose of venetoclax if concurrent use is necessary. In patients with acute myeloid leukemia (AML), reduce the venetoclax dose and monitor for toxicity during concurrent use. Resume the original venetoclax dose two to three days after discontinuation of lonafarnib. Specific venetoclax dosage adjustments are as follows: CLL/SLL patients at steady daily dose: 100 mg/day. AML patients: 10 mg on day one, 20 mg on day two, 50 mg on day three, then 100 mg/day starting on day four. Venetoclax is a P-gp and CYP3A4 substrate; lonafarnib is a P-gp and strong CYP3A4 inhibitor. Coadministration of strong CYP3A4 inhibitors increased the venetoclax AUC by 90% to 690% in drug interaction studies while coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78%.
    Lopinavir; Ritonavir: (Major) Coadministration of ritonavir with venetoclax is contraindicated during the initiation and ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL); consider an alternative medication or adjust the venetoclax dose with close monitoring for toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) in patients receiving a steady daily dose of venetoclax if concurrent use is necessary. In patients with acute myeloid leukemia (AML), reduce the venetoclax dose and monitor for toxicity during concurrent use. Resume the original venetoclax dose 2 to 3 days after discontinuation of ritonavir. Specific venetoclax dosage adjustments are as follows: CLL/SLL patients at steady daily dose: 100 mg/day. AML patients: 10 mg on day 1, 20 mg on day 2, 50 mg on day 3, then 100 mg/day starting on day 4. Coadministration of ritonavir, a strong CYP3A, P-gp, and OATP1B1/B3 inhibitor increased the venetoclax AUC by 690% in a drug interaction study.
    Lorlatinib: (Major) Avoid coadministration of venetoclax with lorlatinib as concurrent use may decrease venetoclax exposure and lead to reduced efficacy. Venetoclax is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Coadministration with a strong CYP3A4 inducer decreased venetoclax exposure by 71%.
    Lumacaftor; Ivacaftor: (Major) Avoid the concomitant use of venetoclax and lumacaftor; ivacaftor. Venetoclax levels may be significantly decreased and its efficacy reduced. Venetoclax is a CYP3A4 substrate and lumacaftor is a strong CYP3A4 inducer. Consider alternative agents. In a drug interaction study in healthy subjects (n = 10), the venetoclax Cmax and AUC values were decreased by 42% and 71%, respectively, following the co-administration of multiple doses of a strong CYP3A4 inducer. (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with ivacaftor due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of ivacaftor. Venetoclax is a CYP3A4 and P-glycoprotein (P-gp) substrate; ivacaftor is a CYP3A4 (weak) and P-gp inhibitor. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
    Lumacaftor; Ivacaftor: (Major) Avoid the concomitant use of venetoclax and lumacaftor; ivacaftor. Venetoclax levels may be significantly decreased and its efficacy reduced. Venetoclax is a CYP3A4 substrate and lumacaftor is a strong CYP3A4 inducer. Consider alternative agents. In a drug interaction study in healthy subjects (n = 10), the venetoclax Cmax and AUC values were decreased by 42% and 71%, respectively, following the co-administration of multiple doses of a strong CYP3A4 inducer.
    Maribavir: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with maribavir due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of maribavir. Venetoclax is a P-gp substrate; maribavir is a P-gp inhibitor. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
    Mefloquine: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with mefloquine due to the potential for increased venetoclax exposure. Additionally, mefloquine exposure may be increased. Resume the original venetoclax dose 2 to 3 days after discontinuation of mefloquine. Both venetoclax and mefloquine are P-glycoprotein (P-gp) substrates and inhibitors. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
    Mifepristone: (Major) Coadministration of mifepristone with venetoclax is contraindicated during the initiation and ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL); consider an alternative medication or adjust the venetoclax dose with close monitoring for toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) in patients receiving a steady daily dose of venetoclax if concurrent use is necessary. In patients with acute myeloid leukemia (AML), reduce the venetoclax dose and monitor for toxicity during concurrent use. Resume the original venetoclax dose 2 to 3 days after discontinuation of mifepristone. Specific venetoclax dosage adjustments are as follows: CLL/SLL patients at steady daily dose: 100 mg/day. AML patients: 10 mg on day 1, 20 mg on day 2, 50 mg on day 3, then 100 mg/day starting on day 4. Venetoclax is a CYP3A4 and P-glycoprotein (P-gp) substrate; mifepristone is a CYP3A4 (strong) and P-gp inhibitor Coadministration of strong CYP3A4 inhibitors increased the venetoclax AUC by 90% to 690% in drug interaction studies, while coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study. The clinical significance of this interaction with the short-term use of mifepristone for termination of pregnancy is unknown.
    Mitotane: (Major) Avoid the concomitant use of venetoclax and mitotane; venetoclax levels may be significantly decreased and its efficacy reduced. Venetoclax is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Consider alternative agents. In a drug interaction study in healthy subjects (n = 10), the venetoclax Cmax and AUC values were decreased by 42% and 71%, respectively, following the co-administration of multiple doses of a strong CYP3A4 inducer.
    Modafinil: (Major) Avoid the concomitant use of venetoclax and modafinil; venetoclax levels may be decreased and its efficacy reduced. Venetoclax is a CYP3A4 substrate and modafinil is a moderate CYP3A4 inducer. Consider alternative agents. In a drug interaction study (n = 11), the venetoclax Cmax and AUC values were decreased by 42% and 71%, respectively, following the co-administration of multiple doses of a strong CYP3A4 inducer. Use of venetoclax with a moderate CYP3A4 inducer has not been evaluated.
    Nafcillin: (Major) Avoid the concomitant use of venetoclax and nafcillin; venetoclax levels may be decreased and its efficacy reduced. Venetoclax is a CYP3A4 substrate and nafcillin is a moderate CYP3A4 inducer. Consider alternative agents. In a drug interaction study (n = 11), the venetoclax Cmax and AUC values were decreased by 42% and 71%, respectively, following the co-administration of multiple doses of a strong CYP3A4 inducer. Use of venetoclax with a moderate CYP3A4 inducer has not been evaluated.
    Nanoparticle Albumin-Bound Sirolimus: (Major) Avoid coadministration of sirolimus with venetoclax as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a P-gp substrate and venetoclax is a P-gp inhibitor.
    Nefazodone: (Major) Coadministration of nefazodone with venetoclax is contraindicated during the initiation and ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL); consider an alternative medication or adjust the venetoclax dose with close monitoring for toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) in patients receiving a steady daily dose of venetoclax if concurrent use is necessary. In patients with acute myeloid leukemia (AML), reduce the venetoclax dose and monitor for toxicity during concurrent use. Resume the original venetoclax dose 2 to 3 days after discontinuation of nefazodone. Specific venetoclax dosage adjustments are as follows: CLL/SLL patients at steady daily dose: 100 mg/day. AML patients: 10 mg on day 1, 20 mg on day 2, 50 mg on day 3, then 100 mg/day starting on day 4. Venetoclax is a CYP3A4 substrate; nefazodone is a strong CYP3A4 inhibitor. Coadministration of strong CYP3A4 inhibitors increased the venetoclax AUC by 90% to 690% in drug interaction studies.
    Nelfinavir: (Major) Coadministration of nelfinavir with venetoclax is contraindicated during the initiation and ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL); consider an alternative medication or adjust the venetoclax dose with close monitoring for toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) in patients receiving a steady daily dose of venetoclax if concurrent use is necessary. In patients with acute myeloid leukemia (AML), reduce the venetoclax dose and monitor for toxicity during concurrent use. Resume the original venetoclax dose 2 to 3 days after discontinuation of nelfinavir. Specific venetoclax dosage adjustments are as follows: CLL/SLL patients at steady daily dose: 100 mg/day. AML patients: 10 mg on day 1, 20 mg on day 2, 50 mg on day 3, then 100 mg/day starting on day 4. Venetoclax is a CYP3A4 and P-glycoprotein (P-gp) substrate; nelfinavir is a CYP3A4 (strong) and P-gp inhibitor Coadministration of strong CYP3A4 inhibitors increased the venetoclax AUC by 90% to 690% in drug interaction studies, while coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
    Neratinib: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with neratinib due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of neratinib. Venetoclax is a P-glycoprotein (P-gp) substrate; neratinib is a P-gp inhibitor. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
    Netupitant, Fosnetupitant; Palonosetron: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with netupitant; palonosetron due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of netupitant; palonosetron. Venetoclax is a CYP3A4 substrate; netupitant is a moderate CYP3A4 inhibitor.
    Nevirapine: (Major) Avoid the concomitant use of venetoclax and nevirapine; venetoclax levels may be decreased and its efficacy reduced. Venetoclax is a CYP3A4 substrate and nevirapine is a moderate CYP3A4 inducer. Consider alternative agents. In a drug interaction study (n = 11), the venetoclax Cmax and AUC values were decreased by 42% and 71%, respectively, following the co-administration of multiple doses of a strong CYP3A4 inducer. Use of venetoclax with a moderate CYP3A4 inducer has not been evaluated.
    Nilotinib: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with nilotinib due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of nilotinib. Venetoclax is a CYP3A4 substrate; nilotinib is a moderate CYP3A4 inhibitor.
    Nirmatrelvir; Ritonavir: (Major) Coadministration of ritonavir with venetoclax is contraindicated during the initiation and ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL); consider an alternative medication or adjust the venetoclax dose with close monitoring for toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) in patients receiving a steady daily dose of venetoclax if concurrent use is necessary. In patients with acute myeloid leukemia (AML), reduce the venetoclax dose and monitor for toxicity during concurrent use. Resume the original venetoclax dose 2 to 3 days after discontinuation of ritonavir. Specific venetoclax dosage adjustments are as follows: CLL/SLL patients at steady daily dose: 100 mg/day. AML patients: 10 mg on day 1, 20 mg on day 2, 50 mg on day 3, then 100 mg/day starting on day 4. Coadministration of ritonavir, a strong CYP3A, P-gp, and OATP1B1/B3 inhibitor increased the venetoclax AUC by 690% in a drug interaction study.
    Olanzapine; Fluoxetine: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with fluoxetine due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of fluoxetine. Venetoclax is a CYP3A4 substrate; norfluoxetine, the active metabolite of fluoxetine, is a moderate CYP3A4 inhibitor.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Coadministration of ritonavir with venetoclax is contraindicated during the initiation and ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL); consider an alternative medication or adjust the venetoclax dose with close monitoring for toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) in patients receiving a steady daily dose of venetoclax if concurrent use is necessary. In patients with acute myeloid leukemia (AML), reduce the venetoclax dose and monitor for toxicity during concurrent use. Resume the original venetoclax dose 2 to 3 days after discontinuation of ritonavir. Specific venetoclax dosage adjustments are as follows: CLL/SLL patients at steady daily dose: 100 mg/day. AML patients: 10 mg on day 1, 20 mg on day 2, 50 mg on day 3, then 100 mg/day starting on day 4. Coadministration of ritonavir, a strong CYP3A, P-gp, and OATP1B1/B3 inhibitor increased the venetoclax AUC by 690% in a drug interaction study.
    Omeprazole; Amoxicillin; Rifabutin: (Major) Avoid coadministration of venetoclax with rifabutin as concurrent use may decrease venetoclax exposure and lead to reduced efficacy. Venetoclax is a CYP3A4 substrate and rifabutin is a moderate CYP3A4 inducer.
    Osimertinib: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with osimertinib due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of osimertinib. Venetoclax is a P-glycoprotein (P-gp) substrate; osimertinib is a P-gp inhibitor. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
    Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Pexidartinib: (Major) Avoid coadministration of venetoclax with pexidartinib as concurrent use may decrease venetoclax exposure and lead to reduced efficacy. Venetoclax is a CYP3A4 substrate and pexidartinib is a moderate CYP3A4 inducer. Coadministration with a strong CYP3A4 inducer decreased venetoclax exposure by 71%.
    Phenobarbital: (Major) Avoid the concomitant use of venetoclax and phenobarbital; venetoclax levels may be significantly decreased and its efficacy reduced. Venetoclax is a CYP3A4 and P-glycoprotein (P-gp) substrate and phenobarbital is a strong CYP3A4 inducer and a P-gp inducer. Consider alternative agents. In a drug interaction study in healthy subjects (n = 10), the venetoclax Cmax and AUC values were decreased by 42% and 71%, respectively, following the co-administration of multiple doses of a strong CYP3A4 inducer.
    Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Avoid the concomitant use of venetoclax and phenobarbital; venetoclax levels may be significantly decreased and its efficacy reduced. Venetoclax is a CYP3A4 and P-glycoprotein (P-gp) substrate and phenobarbital is a strong CYP3A4 inducer and a P-gp inducer. Consider alternative agents. In a drug interaction study in healthy subjects (n = 10), the venetoclax Cmax and AUC values were decreased by 42% and 71%, respectively, following the co-administration of multiple doses of a strong CYP3A4 inducer.
    Phenytoin: (Major) Avoid the concomitant use of venetoclax and phenytoin or fosphenytoin; venetoclax levels may be significantly decreased and its efficacy reduced. Venetoclax is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Consider alternative agents. In a drug interaction study in healthy subjects (n = 10), the venetoclax Cmax and AUC values were decreased by 42% and 71%, respectively, following the co-administration of multiple doses of a strong CYP3A4 inducer.
    Posaconazole: (Major) Coadministration of posaconazole with venetoclax is contraindicated during the initiation and ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL); consider an alternative medication or adjust the venetoclax dose with close monitoring for toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) in patients receiving a steady daily dose of venetoclax if concurrent use is necessary. In patients with acute myeloid leukemia (AML), reduce the venetoclax dose and monitor for toxicity during concurrent use. Resume the original venetoclax dose 2 to 3 days after discontinuation of posaconazole. Specific venetoclax dosage adjustments are as follows: CLL/SLL patients at steady daily dose: 70 mg/day. AML patients: 10 mg on day 1, 20 mg on day 2, 50 mg on day 3, then 70 mg/day starting on day 4. Coadministration of posaconazole, a strong CYP3A4 and P-gp inhibitor, increased the venetoclax AUC by 90% to 144% in a drug interaction study.
    Primidone: (Major) Avoid the concomitant use of venetoclax and primidone; venetoclax levels may be significantly decreased and its efficacy reduced. Venetoclax is a CYP3A4 and P-glycoprotein (P-gp) substrate and primidone is a strong CYP3A4 inducer and a P-gp inducer. Consider alternative agents. In a drug interaction study in healthy subjects (n = 10), the venetoclax Cmax and AUC values were decreased by 42% and 71%, respectively, following the co-administration of multiple doses of a strong CYP3A4 inducer.
    Probenecid; Colchicine: (Major) Coadministration of colchicine and venetoclax should be avoided due to the potential for serious and life-threatening colchicine toxicity. Colchicine is a substrate of P-glycoprotein (P-gp) and venetoclax is an inhibitor of P-gp; increased concentrations of colchicine are expected with concurrent use. Colchicine accumulation may be greater in patients with renal or hepatic impairment; therefore, the manufacturer of Colcrys contraindicates the use of colchicine and P-gp inhibitors in this population. If coadministration in patients with normal renal and hepatic function cannot be avoided, adjust the dose of colchicine either by reducing the daily dose or reducing the dose frequency, and carefully monitor for colchicine toxicity. Specific dosage adjustment recommendations for coadministration with P-gp inhibitors are provided by the manufacturer of Colcrys.
    Propafenone: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with propafenone due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of propafenone. Venetoclax is a P-glycoprotein (P-gp) substrate; propafenone is a P-gp inhibitor. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
    Quinidine: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with quinidine due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of quinidine. Venetoclax is a P-glycoprotein (P-gp) substrate; quinidine is a P-gp inhibitor. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
    Quinine: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with quinine due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of quinine. Venetoclax is a CYP3A4 and P-glycoprotein (P-gp) substrate; quinine is a CYP3A4 (moderate) and P-gp inhibitor. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
    Ranolazine: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with ranolazine due to the potential for increased venetoclax exposure. Additionally, ranolazine exposure may be increased. Resume the original venetoclax dose 2 to 3 days after discontinuation of ranolazine. Both venetoclax and ranolazine are P-glycoprotein (P-gp) substrates and inhibitors. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
    Relugolix: (Major) Avoid concomitant use of relugolix and oral venetoclax. Concomitant use may increase relugolix exposure and the risk of relugolix-related adverse effects. If concomitant use is unavoidable, administer venetoclax at least 6 hours after relugolix and monitor for adverse reactions. Relugolix is a P-glycoprotein (P-gp) substrate and venetoclax is a P-gp inhibitor.
    Relugolix; Estradiol; Norethindrone acetate: (Major) Avoid concomitant use of relugolix and oral venetoclax. Concomitant use may increase relugolix exposure and the risk of relugolix-related adverse effects. If concomitant use is unavoidable, administer venetoclax at least 6 hours after relugolix and monitor for adverse reactions. Relugolix is a P-glycoprotein (P-gp) substrate and venetoclax is a P-gp inhibitor.
    Ribociclib: (Major) Coadministration of ribociclib with venetoclax is contraindicated during the initiation and ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL); consider an alternative medication or adjust the venetoclax dose with close monitoring for toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) in patients receiving a steady daily dose of venetoclax if concurrent use is necessary. In patients with acute myeloid leukemia (AML), reduce the venetoclax dose and monitor for toxicity during concurrent use. Resume the original venetoclax dose 2 to 3 days after discontinuation of ribociclib. Specific venetoclax dosage adjustments are as follows: CLL/SLL patients at steady daily dose: 100 mg/day. AML patients: 10 mg on day 1, 20 mg on day 2, 50 mg on day 3, then 100 mg/day starting on day 4. Venetoclax is a CYP3A4 substrate; ribociclib is a strong CYP3A4 inhibitor. Coadministration of strong CYP3A4 inhibitors increased the venetoclax AUC by 90% to 690% in drug interaction studies.
    Ribociclib; Letrozole: (Major) Coadministration of ribociclib with venetoclax is contraindicated during the initiation and ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL); consider an alternative medication or adjust the venetoclax dose with close monitoring for toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) in patients receiving a steady daily dose of venetoclax if concurrent use is necessary. In patients with acute myeloid leukemia (AML), reduce the venetoclax dose and monitor for toxicity during concurrent use. Resume the original venetoclax dose 2 to 3 days after discontinuation of ribociclib. Specific venetoclax dosage adjustments are as follows: CLL/SLL patients at steady daily dose: 100 mg/day. AML patients: 10 mg on day 1, 20 mg on day 2, 50 mg on day 3, then 100 mg/day starting on day 4. Venetoclax is a CYP3A4 substrate; ribociclib is a strong CYP3A4 inhibitor. Coadministration of strong CYP3A4 inhibitors increased the venetoclax AUC by 90% to 690% in drug interaction studies.
    Rifabutin: (Major) Avoid coadministration of venetoclax with rifabutin as concurrent use may decrease venetoclax exposure and lead to reduced efficacy. Venetoclax is a CYP3A4 substrate and rifabutin is a moderate CYP3A4 inducer.
    Rifampin: (Major) Avoid the concomitant use of venetoclax and rifampin due to the potential for decreased venetoclax exposure and efficacy. Consider alternative agents. Venetoclax is a substrate of CYP3A4 and P-glycoprotein (P-gp) and rifampin is a strong inducer of CYP3A4 and an inducer of P-gp. Coadministration of rifampin decreased the venetoclax Cmax and AUC values by 42% and 71%, respectively.
    Rifapentine: (Major) Avoid coadministration of venetoclax with rifapentine as concurrent use may decrease venetoclax exposure and lead to reduced efficacy. Venetoclax is a CYP3A4 substrate and rifapentine is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased venetoclax exposure by 71%.
    Rimegepant: (Major) Avoid a second dose of rimegepant within 48 hours if coadministered with venetoclax; concurrent use may increase rimegepant exposure. Rimegepant is a P-gp substrate and venetoclax is a P-gp inhibitor.
    Ritonavir: (Major) Coadministration of ritonavir with venetoclax is contraindicated during the initiation and ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL); consider an alternative medication or adjust the venetoclax dose with close monitoring for toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) in patients receiving a steady daily dose of venetoclax if concurrent use is necessary. In patients with acute myeloid leukemia (AML), reduce the venetoclax dose and monitor for toxicity during concurrent use. Resume the original venetoclax dose 2 to 3 days after discontinuation of ritonavir. Specific venetoclax dosage adjustments are as follows: CLL/SLL patients at steady daily dose: 100 mg/day. AML patients: 10 mg on day 1, 20 mg on day 2, 50 mg on day 3, then 100 mg/day starting on day 4. Coadministration of ritonavir, a strong CYP3A, P-gp, and OATP1B1/B3 inhibitor increased the venetoclax AUC by 690% in a drug interaction study.
    Rolapitant: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with rolapitant due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of rolapitant. Venetoclax is a substrate of P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP); rolapitant is an inhibitor of P-gp and BCRP. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
    Saquinavir: (Major) Coadministration of saquinavir with venetoclax is contraindicated during the initiation and ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL); consider an alternative medication or adjust the venetoclax dose with close monitoring for toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) in patients receiving a steady daily dose of venetoclax if concurrent use is necessary. In patients with acute myeloid leukemia (AML), reduce the venetoclax dose and monitor for toxicity during concurrent use. Resume the original venetoclax dose 2 to 3 days after discontinuation of saquinavir. Specific venetoclax dosage adjustments are as follows: CLL/SLL patients at steady daily dose: 100 mg/day. AML patients: 10 mg on day 1, 20 mg on day 2, 50 mg on day 3, then 100 mg/day starting on day 4. Venetoclax is a CYP3A4 and P-glycoprotein (P-gp) substrate; saquinavir is a CYP3A4 (strong) and P-gp inhibitor Coadministration of strong CYP3A4 inhibitors increased the venetoclax AUC by 90% to 690% in drug interaction studies, while coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
    Sarecycline: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with sarecycline due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of sarecycline. Venetoclax is a P-glycoprotein (P-gp) substrate; sarecycline is a P-gp inhibitor. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
    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.
    Simeprevir: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with simeprevir due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of simeprevir. Venetoclax is a CYP3A4 and P-glycoprotein (P-gp) substrate; simeprevir is a CYP3A4 (weak) and P-gp inhibitor. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
    Sirolimus: (Major) Avoid coadministration of sirolimus with venetoclax as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a P-gp substrate and venetoclax is a P-gp inhibitor.
    Sofosbuvir; Velpatasvir: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with velpatasvir due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of velpatasvir. Venetoclax is a P-glycoprotein (P-gp) substrate; velpatasvir is a P-gp inhibitor. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with velpatasvir due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of velpatasvir. Venetoclax is a P-glycoprotein (P-gp) substrate; velpatasvir is a P-gp inhibitor. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study. (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with voxilaprevir due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of voxilaprevir. Venetoclax is a P-glycoprotein (P-gp) substrate; voxilaprevir is a P-gp inhibitor. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
    Sorafenib: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with sorafenib due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of sorafenib. Sorafenib is a P-gp inhibitor in vitro; venetoclax is a P-gp substrate. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
    Sotorasib: (Major) Avoid concurrent use of sotorasib and venetoclax due to unpredictable effects. Coadministration may alter the exposure of venetoclax resulting in decreased efficacy or increased toxicity. Venetoclax is a CYP3A and P-gp substrate; sotorasib is a moderate CYP3A inducer and P-gp inhibitor.
    St. John's Wort, Hypericum perforatum: (Major) Avoid the concomitant use of venetoclax and St. John's wort; venetoclax levels may be significantly decreased and its efficacy reduced. Venetoclax is a CYP3A4 substrate and St. John's wort is a strong CYP3A4 inducer. Consider alternative agents. In a drug interaction study in healthy subjects (n = 10), the venetoclax Cmax and AUC values were decreased by 42% and 71%, respectively, following the co-administration of multiple doses of a strong CYP3A4 inducer.
    Talazoparib: (Moderate) Monitor for an increase in talazoparib-related adverse reactions if coadministration with venetoclax is necessary. Talazoparib is a P-glycoprotein (P-gp) substrate and venetoclax is a P-gp inhibitor. Coadministration with other P-gp inhibitors increased talazoparib exposure by 8% to 45%.
    Telaprevir: (Major) Avoid the concomitant use of venetoclax and telaprevir; venetoclax is a substrate of CYP3A4 and P-glycoprotein (P-gp) and telaprevir is a strong CYP3A4 and a P-gp inhibitor. The concomitant use of these agents together is contraindicated during the initial and dose titration phase of venetoclax. If concomitant use of these drugs is required when the patient is on a steady venetoclax dose (after the titration phase), reduce the venetoclax dosage by at least 75% (maximum dose of 100 mg/day). If telaprevir is discontinued, wait 2 to 3 days and then resume the recommended venetoclax dosage (or prior dosage if less). Monitor patients for signs and symptoms of venetoclax toxicity such as hematologic toxicity, GI toxicity, and tumor lysis syndrome. When venetoclax was administered with multiple doses of other strong CYP3A4 inhibitors, the Cmax and AUC values of venetoclax were increased significantly.
    Telithromycin: (Major) Coadministration of telithromycin with venetoclax is contraindicated during the initiation and ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL); consider an alternative medication or adjust the venetoclax dose with close monitoring for toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) in patients receiving a steady daily dose of venetoclax if concurrent use is necessary. In patients with acute myeloid leukemia (AML), reduce the venetoclax dose and monitor for toxicity during concurrent use. Resume the original venetoclax dose 2 to 3 days after discontinuation of telithromycin. Specific venetoclax dosage adjustments are as follows: CLL/SLL patients at steady daily dose: 100 mg/day. AML patients: 10 mg on day 1, 20 mg on day 2, 50 mg on day 3, then 100 mg/day starting on day 4. Venetoclax is a CYP3A4 and P-glycoprotein (P-gp) substrate; telithromycin is a CYP3A4 (strong) and P-gp inhibitor Coadministration of strong CYP3A4 inhibitors increased the venetoclax AUC by 90% to 690% in drug interaction studies, while coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
    Temsirolimus: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with temsirolimus due to the potential for increased venetoclax exposure. Additionally, temsirolimus exposure may be increased. Resume the original venetoclax dose 2 to 3 days after discontinuation of temsirolimus. Both venetoclax and temsirolimus are P-glycoprotein (P-gp) substrates and inhibitors. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
    Tepotinib: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with tepotinib due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of tepotinib. Venetoclax is a P-gp substrate; tepotinib is a P-gp inhibitor. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
    Tezacaftor; Ivacaftor: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with ivacaftor due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of ivacaftor. Venetoclax is a CYP3A4 and P-glycoprotein (P-gp) substrate; ivacaftor is a CYP3A4 (weak) and P-gp inhibitor. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
    Ticagrelor: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with ticagrelor due to the potential for increased venetoclax exposure. Additionally, ticagrelor exposure may be increased. Resume the original venetoclax dose 2 to 3 days after discontinuation of ticagrelor. Venetoclax is a CYP3A4 and P-glycoprotein (P-gp) substrate and P-gp inhibitor; ticagrelor is a CYP3A4 (weak) and P-gp inhibitor and P-gp substrate. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
    Tipranavir: (Major) Coadministration of tipranavir with venetoclax is contraindicated during the initiation and ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL); consider an alternative medication or adjust the venetoclax dose with close monitoring for toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) in patients receiving a steady daily dose of venetoclax if concurrent use is necessary. In patients with acute myeloid leukemia (AML), reduce the venetoclax dose and monitor for toxicity during concurrent use. Resume the original venetoclax dose 2 to 3 days after discontinuation of tipranavir. Specific venetoclax dosage adjustments are as follows: CLL/SLL patients at steady daily dose: 100 mg/day. AML patients: 10 mg on day 1, 20 mg on day 2, 50 mg on day 3, then 100 mg/day starting on day 4. Venetoclax is a CYP3A4 substrate; tipranavir is a strong CYP3A4 inhibitor. Coadministration of strong CYP3A4 inhibitors increased the venetoclax AUC by 90% to 690% in drug interaction studies.
    Topotecan: (Major) Avoid coadministration of venetoclax with oral topotecan due to increased topotecan exposure; venetoclax may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and venetoclax is a P-gp inhibitor. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
    Trandolapril; Verapamil: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with verapamil due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of verapamil. Venetoclax is a CYP3A4 and P-glycoprotein (P-gp) substrate; verapamil is a CYP3A4 (moderate) and P-gp inhibitor. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
    Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
    Tucatinib: (Major) Coadministration of tucatinib with venetoclax is contraindicated during the initiation and ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL); consider an alternative medication or adjust the venetoclax dose with close monitoring for toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) in patients receiving a steady daily dose of venetoclax if concurrent use is necessary. In patients with acute myeloid leukemia (AML), reduce the venetoclax dose and monitor for toxicity during concurrent use. Resume the original venetoclax dose 2 to 3 days after discontinuation of tucatinib. Specific venetoclax dosage adjustments are as follows: CLL/SLL patients at steady daily dose: 100 mg/day. AML patients: 10 mg on day 1, 20 mg on day 2, 50 mg on day 3, then 100 mg/day starting on day 4. Venetoclax is a CYP3A4 and P-glycoprotein (P-gp) substrate; tucatinib is a strong CYP3A4 inhibitor and P-gp inhibitor. Coadministration of strong CYP3A4 inhibitors increased the venetoclax AUC by 90% to 690% in drug interaction studies.
    Ubrogepant: (Major) Limit the initial and second dose of ubrogepant to 50 mg if coadministered with venetoclax. Concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a substrate of the P-gp drug transporter; venetoclax is a P-gp inhibitor.
    Vemurafenib: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with vemurafenib due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of vemurafenib. Venetoclax is a P-glycoprotein (P-gp) substrate; vemurafenib is a P-gp inhibitor. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
    Verapamil: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with verapamil due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of verapamil. Venetoclax is a CYP3A4 and P-glycoprotein (P-gp) substrate; verapamil is a CYP3A4 (moderate) and P-gp inhibitor. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
    Voclosporin: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with voclosporin due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of voclosporin. Venetoclax is a P-gp substrate; voclosporin is a P-gp inhibitor. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
    Voriconazole: (Major) Coadministration of voriconazole with venetoclax is contraindicated during the initiation and ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL); consider an alternative medication or adjust the venetoclax dose with close monitoring for toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) in patients receiving a steady daily dose of venetoclax if concurrent use is necessary. In patients with acute myeloid leukemia (AML), reduce the venetoclax dose and monitor for toxicity during concurrent use. Resume the original venetoclax dose 2 to 3 days after discontinuation of voriconazole. Specific venetoclax dosage adjustments are as follows: CLL/SLL patients at steady daily dose: 100 mg/day. AML patients: 10 mg on day 1, 20 mg on day 2, 50 mg on day 3, then 100 mg/day starting on day 4. Venetoclax is a CYP3A4 substrate; voriconazole is a strong CYP3A4 inhibitor. Coadministration of strong CYP3A4 inhibitors increased the venetoclax AUC by 90% to 690% in drug interaction studies.
    Warfarin: (Major) The concomitant use of venetoclax and warfarin may increase the concentration and exposure of warfarin and increase the risk of bleeding. If these agents are used together, monitor the international normalized ratio (INR) more frequently and adjust the dosage of warfarin as necessary. In a drug-drug interaction study, the R- and S-warfarin Cmax and AUC values increased by 18% to 28% when a single 400-mg dose of venetoclax was co-administered with a single 5-mg dose of warfarin.
    Zonisamide: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with zonisamide due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of zonisamide. Venetoclax is a P-glycoprotein (P-gp) substrate; zonisamide is a P-gp inhibitor. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.

    PREGNANCY AND LACTATION

    Pregnancy

    Venetoclax may cause fetal harm if administered during pregnancy based on its mechanism of action and data from animal studies. Females of reproductive potential should be advised to avoid becoming pregnant while receiving venetoclax. If a woman becomes pregnant while taking this drug, she should be apprised of the potential hazard to the fetus. In an embryo-fetal study in pregnant mice, post-implantation loss and decreased fetal weight were observed following venetoclax doses that resulted in drug exposures 1.2-times those reported at clinical human doses of 400 mg/day (based on AUC). No teratogenicity occurred in mice or rabbits.

    Counsel patients about the reproductive risk and contraception requirements during venetoclax treatment. Pregnancy testing should be performed prior to starting venetoclax in female patients of reproductive potential. These patients should use effective contraception and avoid pregnancy during and for 30 days after venetoclax therapy. Women who become pregnant while receiving venetoclax should be apprised of the potential hazard to the fetus. Venetoclax may cause infertility in male patients based on animal findings; these patients should consider sperm banking.

    MECHANISM OF ACTION

    Venetoclax (ABT-199) is a selective inhibitor of B-cell lymphoma-2 (BCL-2) protein, an antiapoptotic protein that prevents chronic lymphocytic leukemia (CLL) cell death and is associated with chemotherapy resistance. Venetoclax mimics the BH3 domain on BCL-2 family proteins and binds with high affinity; this action antagonizes pro-apoptotic proteins like BIM and causes mitochondrial outer membrane permeabilization and the activation of caspases that kill cells.

    PHARMACOKINETICS

    Venetoclax is administered orally. It is highly bound to plasma proteins (greater than 99%) and has a mean blood-to-plasma ratio of 0.57. The apparent volume of distribution ranges from 256 to 321 liters and the terminal elimination half-life is about 26 hours. Venetoclax was metabolized via CYP3A to form the major metabolite, M27. This metabolite has activity that is at least 58-times lower than that of venetoclax in vitro; its AUC represents 80% of the parent AUC. Venetoclax is eliminated primarily via feces; clearance from the systemic circulation is from hepatic elimination. In healthy subjects, greater than 99.9% and less than 0.1% of the radioactivity was excreted in the feces and urine, respectively, within 9 days of a radiolabeled [14C]-venetoclax 200-mg dose. Unchanged venetoclax accounted for 21% of the radiolabeled excretion product in feces.[60706]
    Affected cytochrome P450 isoenzymes or transporters: CYP3A4/5 and P-gp
    Venetoclax is a substrate of CYP3A and P-glycoprotein (P-gp). Concomitant use with strong or moderate CYP3A inhibitors or P-gp inhibitors increase the Cmax and AUC values of venetoclax; coadministration with a strong CYP3A inhibitor at initiation or during the dose titration phase is contraindicated in patients with CLL or SLL. Concomitant use with strong or moderate CYP3A inducers decrease the Cmax and AUC values of venetoclax; therefore, avoid the use of these agents together. Concomitant use with P-gp substrates may increase the Cmax and AUC values of the P-gp substrate; avoid using these agents together if possible or give the P-gp drug at least 6 hours before venetoclax. In vitro, venetoclax is a weak inhibitor of CYP2C8, CYP2C9, and UGT1A1; an inhibitor and substrate of P-gp and Breast Cancer Resistance Protein; and a weak inhibitor of OATP1B1.[60706]

    Oral Route

    The maximum plasma concentration (Cmax) was achieved at a Tmax of 5 to 8 hours following multiple venetoclax doses administered with food. The steady-state AUC value increased proportionally over the dose range of 150 mg to 800 mg. When venetoclax 400 mg/day was given with a low-fat meal, the mean steady state Cmax was 2.1 +/- 1.1 microgram (mcg)/mL and the mean AUC(0-24) was 32.8 +/- 16.9 mcg/mL X hour.
    Effect of food: When venetoclax was administered with a low-fat and a high-fat meal, the AUC values were increased by 3.4-fold and 5.1 to 5.3-fold, respectively, compared with the AUC value achieved under fasting conditions. Administer venetoclax with a meal.