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  • CLASSES

    Small Molecule Antineoplastic Janus Associated Kinase (JAKs) Inhibitors

    DEA CLASS

    Rx

    DESCRIPTION

    JAK1 and JAK2 kinase inhibitor
    Used in adults with myelofibrosis or polycythemia vera and in patients 12 years and older with steroid-refractory acute graft-versus-host disease
    Hematologic toxicity and infection have been reported

    COMMON BRAND NAMES

    Jakafi

    HOW SUPPLIED

    Jakafi Oral Tab: 5mg, 10mg, 15mg, 20mg, 25mg

    DOSAGE & INDICATIONS

    For the treatment of polycythemia vera.
    The FDA has designated ruxolitinib as an orphan drug for the treatment of polycythemia vera.
    For the treatment of polycythemia vera in patients who have had an inadequate response to or are intolerant of hydroxyurea.
    Oral dosage
    Adults

    Initially, 10 mg orally twice daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Titrate the ruxolitinib dosage based on response and toxicity. After the first 4 weeks of therapy, and no more frequently than every 2 weeks, the dosage may be increased in 5 mg twice daily increments. Maximum dosage: 25 mg orally twice daily if the patient meets all of the following criteria: an inadequate response defined as the continued need for phlebotomy, WBC count greater than the upper limit of normal (ULN), platelet count greater than the ULN, and/or a palpable spleen that is reduced by less than 25% from baseline; a platelet count 140 x 109 cells/L or more; hemoglobin 12 grams/dL or more; and ANC 1.5 x 109 cells/L or more. A significantly higher response rate at week 32 was achieved with ruxolitinib compared with investigator selected best available therapy (20.9% vs. 0.9%; p less than 0.001) in patients with polycythemia vera who had an inadequate response to or unacceptable side effects from hydroxyurea in a multinational, randomized, phase 3 trial (n = 222; the RESPONSE trial); additionally, this response was maintained at week 48 (19.1% vs. 0.9%; p less than 0.001). Eligible patients had a spleen volume of 450 cm3 or more and phlebotomy dependence, defined as 2 or more phlebotomies within 24 weeks before screening and at least 1 phlebotomy within 16 weeks before screening. Best available therapy consisted of single-agent anagrelide (7.1%), low-dose hydroxyurea (58.9%), immunomodulators such as lenalidomide or thalidomide (4.5%), interferon or pegylated interferon (11.6%), pipobroman (1.8%), or no medication (15.2%). All patients received low-dose aspirin unless it was contraindicated. The primary endpoint of response at 32 weeks was defined as a reduction in spleen volume of 35% or more from baseline and hematocrit control (eligible for no more than 1 phlebotomy between randomization and study week 8 and not eligible for a phlebotomy during study weeks 8 to 32). The complete hematologic remission (CHR) rate (defined as hematocrit control, a platelet count of 400 x 109 cells/L or less, and a white blood cell count of 10 x 109 cells/L or less) at week 32 was significantly higher with ruxolitinib compared with best standard therapy (23.6% vs. 8.9%, p = 0.003). Crossover to the ruxolitinib arm occurred in 85.7% of patients in the best standard therapy arm at or after week 32. In an extended analysis at week 80, 76% of patients who achieved a response at 32 weeks maintained a response, and 58% of patients who achieved a CHR at 32 weeks maintained this response.

    For the treatment of intermediate or high-risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis.
    NOTE: Patients experiencing significant decreases in platelet counts may be candidates for abrupt dose reductions and/or treatment interruptions. Consider risk to benefits ratio in patients maintained on 5 mg PO twice daily (minimum dose) as long-term use at this dose has failed to produce clinical response.
    Oral dosage
    Adults with initial platelet count more than 200 x 10(9) cells/L

    20 mg PO twice daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. After the first 4 weeks of therapy, and no more frequently than every 2 weeks, the dose may be increased in 5 mg twice daily increments to a maximum dose of 25 mg PO twice daily if the patient meets all of the following criteria: 1) failure to achieve a reduction from baseline palpable spleen length of 50% or a 35% reduction in spleen volume as measured by CT or MRI; 2) platelet count more than 125 x 109 cells/L at treatment week 4 and platelet counts never less than 100 x 109 cells/L; 3) absolute neutrophil count (ANC) more than 0.75 x 109 cells/L. Discontinue ruxolitinib if spleen size reduction or symptom improvement is not observed after 6 months of therapy. When discontinuing therapy for any reason other than thrombocytopenia, consider gradually tapering dose by 5 mg twice daily each week.

    Adults with initial platelet count of 100 to 200 x 10(9) cells/L

    15 mg PO twice daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. After the first 4 weeks of therapy, and no more frequently than every 2 weeks, the dose may be increased in 5 mg twice daily increments to a maximum dose of 25 mg PO twice daily if the patient meets all of the following criteria: 1) failure to achieve a reduction from baseline palpable spleen length of 50% or a 35% reduction in spleen volume as measured by CT or MRI; 2) platelet count more than 125 x 109 cells/L at treatment week 4 and platelet counts never less than 100 x 109 cells/L; 3) absolute neutrophil count (ANC) more than 0.75 x 109 cells/L. Discontinue ruxolitinib if spleen size reduction or symptom improvement is not observed after 6 months of therapy. When discontinuing therapy for any reason other than thrombocytopenia, consider gradually tapering dose by 5 mg twice daily each week.

    Adults with initial platelet count of 50 to 99 x 10(9) cells/L

    5 mg PO twice daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. After the first 4 weeks of therapy, and no more frequently than every 2 weeks, the dose may be increased in 5 mg daily increments to a maximum dose of 10 mg PO twice daily if the patient meets all of the following criteria: 1) platelet count has remained more than 40 x 109 cells/L and has not fallen by more than 20% in prior 4 weeks; 2) absolute neutrophil count (ANC) more than 1 x 109 cells/L; 3) dose has not been reduced or interrupted for an adverse event or hematological toxicity in the prior 4 weeks. Consider risk to benefits ratio in patients continuing treatment for more than 6 months. Discontinue ruxolitinib if spleen size reduction or symptom improvement is not observed after 6 months of therapy.

    For the treatment of graft-versus-host disease (GVHD).
    NOTE: The FDA has designated ruxolitinib as an orphan drug for the treatment of GVHD.
    For the treatment of steroid-refractory acute GVHD.
    Oral dosage
    Adults

    Initially, 5 mg orally twice daily. After 3 days, consider increasing the dosage to 10 mg orally twice daily if the absolute neutrophil count and platelet counts are not decreased by at least 50%. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Therapy interruption and/or a dosage adjustment may be necessary in patients who develop toxicity. After 6 months, consider tapering therapy every 8 weeks by 1 dose level (i.e., 10 mg twice daily to 5 mg twice daily; 5mg twice daily to 5 mg once daily) in responding patients who have discontinued therapeutic doses of corticosteroids. Consider retreatment in patients who have a recurrence of acute GVHD signs or symptoms during or after the taper. The day 28 overall response rate was 57.1% in patients (median age, 57 years; range, 18 to 72 years) with grade 2, 3, or 4 steroid-refractory GVHD following an allogeneic hematopoietic stem-cell transplant in a multicenter, single-arm, phase 2 trial (n = 49; the REACH 1 trial). The median duration of response was 16 days.

    Children 12 years and Adolescents

    Initially, 5 mg orally twice daily. After 3 days, consider increasing the dosage to 10 mg orally twice daily if the absolute neutrophil count and platelet counts are not decreased by at least 50%. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Therapy interruption and/or a dosage adjustment may be necessary in patients who develop toxicity. After 6 months, consider tapering therapy every 8 weeks by 1 dose level (i.e., 10 mg twice daily to 5 mg twice daily; 5mg twice daily to 5 mg once daily) in responding patients who have discontinued therapeutic doses of corticosteroids. Consider retreatment in patients who have a recurrence of acute GVHD signs or symptoms during or after the taper. Use of ruxolitinib in pediatric patients with acute GVHD is supported by evidence from a single-arm, phase 2 trial in 49 adult patients and additional pharmacokinetic and safety data in this patient population.

    INVESTIGATIONAL USE: For adjunctive use in the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection†, the virus that causes coronavirus disease 2019 (COVID-19)†.
    Oral dosage
    Adults

    Efficacy has not been established. Due to broad immunosuppressive effects, the National Institutes of Health (NIH) COVID-19 treatment guidelines recommend against the use of JAK inhibitors outside of clinical trials.[65314] The following dosing regimens are being evaluated: 5 mg PO twice daily ; 5 mg PO twice daily for 14 to 28 days ; 5 mg PO every 12 hours for 7 days, then 10 mg PO every 12 hours for a total of 14 days ; 10 mg PO twice daily for 14 days, then 5 mg PO twice daily for 2 days, then 5 mg PO once daily for 1 day ; 10 mg PO twice daily for 14 days ; and 10 to 20 mg PO twice daily for 7 days .

    Children and Adolescents 12 years and older

    Efficacy has not been established. Due to broad immunosuppressive effects, the National Institutes of Health (NIH) COVID-19 treatment guidelines recommend against the use of JAK inhibitors outside of clinical trials.[65314] The following dosing regimens are being evaluated: 5 mg PO twice daily for 14 to 28 days ; 10 mg PO twice daily for 14 days, then 5 mg PO twice daily for 2 days, then 5 mg PO once daily for 1 day.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    Myelofibrosis or Polycythemia Vera, 25 mg PO twice daily; Graft-Versus-Host Disease, 10 mg PO twice daily.

    Geriatric

    Myelofibrosis or Polycythemia Vera, 25 mg PO twice daily; Graft-Versus-Host Disease, 10 mg PO twice daily.

    Adolescents

    Graft-Versus-Host Disease, 10 mg PO twice daily.

    Children

    12 years: Graft-Versus-Host Disease, 10 mg PO twice daily.
    11 years and younger: 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

    Myelofibrosis
    Mild, moderate, or severe (Child-Pugh class A, B, C) hepatic impairment at baseline:
    Platelet count greater than 150 X 109 cells/L: No dosage adjustment needed.
    Platelet count of 100 to 150 X 109 cells/L: Initial dosage, 10 mg PO twice daily.
    Platelet count of 50 to 99 X 109 cells/L: Initial dosage, 5 mg PO once daily.
    Platelet count less than 50 X 109 cells/L: Avoid use.
    Polycythemia Vera (any platelet count)
    Mild, moderate, or severe (Child-Pugh class A, B, C) hepatic impairment at baseline: Initial dosage, 5 mg PO twice daily.
    Graft-Versus-Host Disease (GVHD) (any platelet count)
    Mild, moderate, or severe (NCI criteria) hepatic impairment at baseline: No dosage adjustment needed in patients with no liver GVHD; monitor blood counts more frequently and consider an initial dosage of 5 mg PO once daily in patients with grade 3 or 4 liver GVHD.
    Management of Treatment-Related Toxicity in Patients with GVHD
    No liver GVHD
    Total bilirubin level of 3- to 5-times the upper limit of normal (ULN): Continue therapy at a reduced dosage (i.e., from 10 mg twice daily to 5 mg twice daily or from 5mg twice daily to 5 mg once daily) until toxicity recovery.Total bilirubin level of greater than 5- to 10-times the ULN: Hold ruxolitinib for up to 14 days; resume therapy at the current dosage when the bilirubin level is 1.5-times the ULN or less.Total bilirubin level of greater than 10-times the ULN: Hold ruxolitinib for up to 14 days; resume therapy at a reduced dosage (i.e., from 10 mg twice daily to 5 mg twice daily or from 5mg twice daily to 5 mg once daily) when the bilirubin level is 1.5-times the ULN or less.
    Liver GVHD:
    Total bilirubin level greater than 3-times the ULN: Continue therapy at a reduced dosage (i.e., from 10 mg twice daily to 5 mg twice daily or from 5mg twice daily to 5 mg once daily) until toxicity recovery.

    Renal Impairment

    Myelofibrosis
    Creatinine Clearance (CrCl) 60 mL/min or higher: No dosage adjustment needed.
    CrCl 15 to 59 mL/min:
    Platelet count greater than 150 X 109 cells/L: No dosage adjustment needed.
    Platelet count of 100 to 150 X 109 cells/L: Initial dosage, 10 mg PO twice daily.
    Platelet count of 50 to 99 X 109 cells/L: Initial dosage, 5 mg PO once daily.
    Platelet count less than 50 X 109 cells/L: Avoid use.
    CrCl less than 15 mL/min, end-stage renal disease (ESRD) on intermittent dialysis:
    Platelet count greater than 200 X 109 cells/L: Initial dose, 20 mg PO once after dialysis. Make dose modifications based on frequent monitoring of safety and efficacy.
    Platelet count of 100 to 200 X 109 cells/L: Initial dose, 15 mg PO once after dialysis. Make dose modifications based on frequent monitoring of safety and efficacy.
    CrCl less than 15 mL/min, ESRD and NOT on dialysis: Avoid use.
    Polycythemia Vera (any platelet count)
    CrCl 60 mL/min or higher: No dosage adjustment needed.
    CrCl 15 to 59 mL/min: Initial dosage, 5 mg PO twice daily.
    CrCl less than 15 mL/min, ESRD on intermittent dialysis: Initial dose, 10 mg PO once after dialysis. Make dose modifications based on frequent monitoring of safety and efficacy.
    CrCl less than 15 mL/min, ESRD and NOT on dialysis: Avoid use.
    Graft-Versus-Host Disease (any platelet count)
    CrCl 60 mL/min or higher: No dosage adjustment needed.
    CrCl 15 to 59 mL/min: Initial dosage, 5 mg PO once daily.
    CrCl less than 15 mL/min, ESRD on intermittent dialysis: Initial dose, 5 mg PO once after dialysis. Make dose modifications based on frequent monitoring of safety and efficacy.
    CrCl less than 15 mL/min, ESRD and NOT on dialysis: Avoid use.

    ADMINISTRATION

    Oral Administration

    Administer with or without food.

    Extemporaneous Compounding-Oral

    Extemporaneous preparation of oral suspension:
    NOTE: Studies have not evaluated the effects of tube feeding on ruxolitinib exposure when administered through a nasogastric tube.
    Suspend 1 tablet in 40 mL of water by stirring for approximately 10 minutes.
    Using an appropriate syringe, administer the suspension via a nasogastric tube (size 8 French or larger).
    The suspension must be administered within 6 hours.
    Following administration of the suspension, rinse the nasogastric tube with approximately 75 mL of water.

    STORAGE

    Jakafi:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Anemia, bleeding, neutropenia, thrombocytopenia

    Hematologic toxicity (e.g., anemia, neutropenia, and thrombocytopenia) has been reported with ruxolitinib therapy. The initial dose is based on platelet count in patients with myelofibrosis. Obtain complete blood counts prior to therapy, every 2 to 4 weeks until the dose is stabilized, and then as clinically indicated. Therapy interruption, a dosage adjustment, and/or blood or platelet transfusions may be necessary in patients who develop severe myelosuppression. In patients with myelofibrosis, hold therapy if bleeding occurs; resume ruxolitinib after the bleeding event has resolved and consider a dose reduction if the underlying cause persists.[46782]

    Fungal infection, hepatitis, infection, mycobacterial infection, progressive multifocal leukoencephalopathy, tuberculosis, viral infection

    Serious infections such as tuberculosis (TB), progressive multifocal leukoencephalopathy (PML), bacterial and mycobacterial infection, fungal infection, and viral infection (e.g., herpes zoster) have been reported with ruxolitinib therapy; do not start ruxolitinib in patients with an active infection. Monitor patients for signs and symptoms of infection during therapy and manage promptly. Administer prophylactic antibiotics as appropriate per clinical guidelines. Discontinue treatment if PML is suspected or diagnosed. Increased hepatitis B virus (HBV) viral load with or without elevated transaminase levels has occurred in patients with chronic HBV infection; monitor and treat these patients according to clinical guidelines. Evaluate patients for risk of TB and test patients at higher risk for latent TB; consult with a physician with expertise in treating TB prior to starting ruxolitinib in patients with active or latent TB. Risk factors include history of residence or travel to countries with a high prevalence of TB, close contact with a person with active TB, and a history of active or latent TB where an adequate course of treatment cannot be confirmed.

    Hepatic disease

    Patients with preexisting hepatic disease may be at increased risk for ruxolitinib-induced adverse events. An initial ruxolitinib dosage reduction may be necessary in patients with baseline hepatic impairment; avoid ruxolitinib in patients with myelofibrosis who have a platelet count of less than 50 X 109 cells/L and hepatic impairment. Monitor complete blood counts more frequently in patients with severe liver graft-versus-host disease (GVHD). Patients with GVHD who develop hepatotoxicity may require therapy interruption or a dosage reduction.

    Renal disease, renal impairment

    Patients with preexisting renal disease may be at increased risk for ruxolitinib-induced adverse events. An initial ruxolitinib dosage reduction may be necessary in patients with baseline renal impairment; avoid ruxolitinib in patients with end-stage renal disease (Creatinine clearance less than 15 mL/min) who do not require dialysis.

    Abrupt discontinuation

    Avoid abrupt discontinuation of ruxolitinib when stopping the drug for reasons other than thrombocytopenia. Following discontinuation of ruxolitinib, symptoms of myeloproliferative neoplasms generally return to pretreatment levels in about 1 week. There have been reports of patients stopping ruxolitinib during an acute illness after which the patient's clinical course continued to worsen. However, it has not been established whether discontinuation of therapy contributed to the clinical course in these patients. Some patients have experienced fever, respiratory distress, hypotension, DIC, or multi-organ failure after ruxolitinib discontinuation. For these reasons, gradual tapering of the dose is recommended. If one or more of these symptoms occur after discontinuation of, or while tapering the dose of ruxolitinib, evaluate for and treat any illness and consider restarting or increasing the dose of ruxolitinib.

    New primary malignancy, skin cancer

    New primary malignancy has been reported with ruxolitinib therapy, specifically non-melanoma skin cancer such as basal cell, squamous cell, and Merkel cell carcinoma. Periodic skin examinations are recommended. Advise patients to report any history of skin cancer or if they develop any new or changing lesions during ruxolitinib therapy.

    Hypercholesterolemia, hypertriglyceridemia

    Hypercholesterolemia (e.g., elevated total cholesterol, elevated low-density lipoprotein (LDL) cholesterol) and hypertriglyceridemia have been reported with ruxolitinib therapy. The effect of ruxolitinib-induced high cholesterol or high triglycerides on cardiovascular morbidity and mortality is not known. Obtain a lipid panel and assess triglyceride levels about 8 to 12 weeks after starting ruxolitinib; monitor and treat patients with high cholesterol or triglycerides according to clinical guidelines.

    Pregnancy

    No well-controlled studies have been conducted evaluating the use of ruxolitinib in pregnant women. Consider the benefits versus the risk of therapy prior to administering ruxolitinib during pregnancy. Animal data involving rats and rabbits administered doses of 15, 30, or 60 mg/kg/day and 10, 30, or 60 mg/kg/day, respectively, during organogenesis, revealed no evidence of teratogenicity. However at doses of 60 mg/kg/day, reductions in fetal weights were observed in both rats and rabbits. Additionally, rabbits experienced an increase in late resorptions when exposed to the 60 mg/kg/day dose.

    Breast-feeding

    It is not known if ruxolitinib or its metabolites are secreted in human milk or if it has effects on the breast-fed infant or on milk production. Because there is a potential for adverse reactions in nursing infants, women should discontinue breast-feeding during ruxolitinib therapy and for at least 2 weeks after the last dose.

    ADVERSE REACTIONS

    Severe

    thrombocytopenia / Delayed / 5.0-61.0
    anemia / Delayed / 0-45.0
    infection / Delayed / 0-41.0
    neutropenia / Delayed / 0-40.0
    thrombosis / Delayed / 0-25.0
    fatigue / Early / 0-14.0
    edema / Delayed / 0-13.0
    hypertension / Early / 0-13.0
    elevated hepatic enzymes / Delayed / 0-8.0
    diarrhea / Early / 0-7.0
    dyspnea / Early / 3.0-7.0
    ecchymosis / Delayed / 0-1.0
    vertigo / Early / 0-1.0
    dizziness / Early / 0-1.0
    headache / Early / 0-1.0
    weight gain / Delayed / 0-1.0
    abdominal pain / Early / 0-1.0
    hypercholesterolemia / Delayed / 0-1.0
    hypertriglyceridemia / Delayed / 0-1.0
    pruritus / Rapid / 0-1.0
    pyuria / Delayed / Incidence not known
    hematoma / Early / Incidence not known
    leukoencephalopathy / Delayed / Incidence not known
    disseminated intravascular coagulation (DIC) / Delayed / Incidence not known
    new primary malignancy / Delayed / Incidence not known

    Moderate

    bleeding / Early / 0-29.0
    constipation / Delayed / 8.0-8.0
    peripheral edema / Delayed / 0-8.0
    respiratory depression / Rapid / Incidence not known
    hypotension / Rapid / Incidence not known

    Mild

    pharyngitis / Delayed / 9.0-9.0
    cough / Delayed / 8.0-8.0
    asthenia / Delayed / 7.0-7.0
    arthralgia / Delayed / 7.0-7.0
    epistaxis / Delayed / 6.0-6.0
    nausea / Early / 6.0-6.0
    flatulence / Early / 5.0-5.0
    fever / Early / Incidence not known
    rash / Early / Incidence not known

    DRUG INTERACTIONS

    Aldesleukin, IL-2: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderate inhibitors of CYP3A4 such as aldesleukin, IL-2 a dose adjustment is not necessary, but monitoring patients for toxicity may be prudent. There was an 8% and 27% increase in the Cmax and AUC of a single dose of ruxolitinib 10 mg, respectively, when the dose was given after a short course of erythromycin 500 mg PO twice daily for 4 days. The change in the pharmacodynamic marker pSTAT3 inhibition was consistent with the increase in exposure.
    Amiodarone: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderate inhibitors of CYP3A4 such as amiodarone, a dose adjustment is not necessary, but monitoring patients for toxicity may be prudent. There was an 8% and 27% increase in the Cmax and AUC of a single dose of ruxolitinib 10 mg, respectively, when the dose was given after a short course of erythromycin 500 mg PO twice daily for 4 days. The change in the pharmacodynamic marker pSTAT3 inhibition was consistent with the increase in exposure.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Reduce the ruxolitinib dosage during coadministration with clarithromycin in patients with myelofibrosis (MF) or polycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur; no dose adjustments are necessary for patients with graft-versus-host disease. In MF patients, reduce the initial dose to 10 mg PO twice daily for platelet count of 100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients, reduce the initial dose to 5 mg PO twice daily. Avoid the use of clarithromycin or interrupt ruxolitinib treatment during clarithromycin use in MF or PV patients who are stable on a ruxolitinib dose of 5 mg PO once daily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by 50%; in patients stable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. Additional dose modifications should be made with frequent monitoring of safety and efficacy. Ruxolitinib is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Reduce the ruxolitinib dosage during coadministration with clarithromycin in patients with myelofibrosis (MF) or polycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur; no dose adjustments are necessary for patients with graft-versus-host disease. In MF patients, reduce the initial dose to 10 mg PO twice daily for platelet count of 100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients, reduce the initial dose to 5 mg PO twice daily. Avoid the use of clarithromycin or interrupt ruxolitinib treatment during clarithromycin use in MF or PV patients who are stable on a ruxolitinib dose of 5 mg PO once daily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by 50%; in patients stable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. Additional dose modifications should be made with frequent monitoring of safety and efficacy. Ruxolitinib is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor.
    Amprenavir: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderate inhibitors of CYP3A4 such as amprenavir, a dose adjustment is not necessary, but monitoring patients for toxicity may be prudent. There was an 8% and 27% increase in the Cmax and AUC of a single dose of ruxolitinib 10 mg, respectively, when the dose was given after a short course of erythromycin 500 mg PO twice daily for 4 days. The change in the pharmacodynamic marker pSTAT3 inhibition was consistent with the increase in exposure.
    Apalutamide: (Moderate) Monitor patients frequently and adjust the ruxolitinib dose based on safety and efficacy if coadministered with apalutamide; decreased ruxolitinib exposure is possible. Ruxolitinib is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration of another strong CYP3A4 inducer decreased ruxolitinib Cmax and AUC by 32% and 61%, respectively. The relative exposure to ruxolitinib's active metabolites increased approximately 100%.
    Aprepitant, Fosaprepitant: (Moderate) Use caution if ruxolitinib and aprepitant, fosaprepitant are used concurrently, and monitor for an increase in ruxolitinib-related adverse effects for several days after administration of a multi-day aprepitant regimen. Ruxolitinib is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of ruxolitinib. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important. Aprepitant is also a CYP2C9 inducer and ruxolitinib is a CYP2C9 substrate. Administration of a CYP2C9 substrate, tolbutamide, on days 1, 4, 8, and 15 with a 3-day regimen of oral aprepitant (125 mg/80 mg/80 mg) decreased the tolbutamide AUC by 23% on day 4, 28% on day 8, and 15% on day 15. The AUC of tolbutamide was decreased by 8% on day 2, 16% on day 4, 15% on day 8, and 10% on day 15 when given prior to oral administration of aprepitant 40 mg on day 1, and on days 2, 4, 8, and 15. The effects of aprepitant on tolbutamide were not considered significant.
    Atazanavir: (Major) Reduce the ruxolitinib dosage during coadministration with atazanavir in patients with myelofibrosis (MF) or polycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur; no dose adjustments are necessary for patients with graft-versus-host disease. In MF patients, reduce the initial dose to 10 mg PO twice daily for platelet count of 100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients, reduce the initial dose to 5 mg PO twice daily. Avoid the use of atazanavir in MF or PV patients who are stable on a ruxolitinib dose of 5 mg PO once daily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by 50%; in patients stable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. Additional dose modifications should be made with frequent monitoring of safety and efficacy. Ruxolitinib is a CYP3A4 substrate; atazanavir is a strong CYP3A4 inhibitor.
    Atazanavir; Cobicistat: (Major) Reduce the ruxolitinib dosage during coadministration with atazanavir in patients with myelofibrosis (MF) or polycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur; no dose adjustments are necessary for patients with graft-versus-host disease. In MF patients, reduce the initial dose to 10 mg PO twice daily for platelet count of 100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients, reduce the initial dose to 5 mg PO twice daily. Avoid the use of atazanavir in MF or PV patients who are stable on a ruxolitinib dose of 5 mg PO once daily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by 50%; in patients stable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. Additional dose modifications should be made with frequent monitoring of safety and efficacy. Ruxolitinib is a CYP3A4 substrate; atazanavir is a strong CYP3A4 inhibitor. (Major) Reduce the ruxolitinib dosage during coadministration with cobicistat in patients with myelofibrosis (MF) or polycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur; no dose adjustments are necessary for patients with graft-versus-host disease. In MF patients, reduce the initial dose to 10 mg PO twice daily for platelet count of 100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients, reduce the initial dose to 5 mg PO twice daily. Avoid the use of cobicistat in MF or PV patients who are stable on a ruxolitinib dose of 5 mg PO once daily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by 50%; in patients stable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. Additional dose modifications should be made with frequent monitoring of safety and efficacy. Ruxolitinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Moderate) Monitor patients frequently and adjust the ruxolitinib dose based on safety and efficacy if coadministered with phenobarbital; decreased ruxolitinib exposure is possible. Ruxolitinib is a CYP3A4 substrate; phenobarbital is a strong CYP3A4 inducer. Coadministration of another strong CYP3A4 inducer decreased ruxolitinib Cmax and AUC by 32% and 61%, respectively. The relative exposure to ruxolitinib's active metabolites increased approximately 100%.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Moderate) Monitor patients frequently and adjust the ruxolitinib dose based on safety and efficacy if coadministered with phenobarbital; decreased ruxolitinib exposure is possible. Ruxolitinib is a CYP3A4 substrate; phenobarbital is a strong CYP3A4 inducer. Coadministration of another strong CYP3A4 inducer decreased ruxolitinib Cmax and AUC by 32% and 61%, respectively. The relative exposure to ruxolitinib's active metabolites increased approximately 100%.
    Bexarotene: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are CYP3A4 inducers such as bexarotene, a dose adjustment is not necessary, but closely monitor patients and titrate the ruxolitinib dose based on safety and efficacy. The Cmax and AUC of a single 50 mg dose of ruxolitinib was decreased by 32% and 61%, respectively, after rifampin 600 mg once daily was administered for 10 days. The relative exposure to ruxolitinib's active metabolites increased by about 100%, which may partially explain the reported disproportionate 10% reduction in the pharmacodynamic marker pSTAT3 inhibition.
    Bosentan: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are CYP3A4 inducers such as bosentan, a dose adjustment is not necessary, but closely monitor patients and titrate the ruxolitinib dose based on safety and efficacy. The Cmax and AUC of a single 50 mg dose of ruxolitinib was decreased by 32% and 61%, respectively, after rifampin 600 mg once daily was administered for 10 days. The relative exposure to ruxolitinib's active metabolites increased by about 100%, which may partially explain the reported disproportionate 10% reduction in the pharmacodynamic marker pSTAT3 inhibition.
    Carbamazepine: (Moderate) Monitor patients frequently and adjust the ruxolitinib dose based on safety and efficacy if coadministered with carbamazepine; decreased ruxolitinib exposure is possible. Ruxolitinib is a CYP3A4 substrate; carbamazepine is a strong CYP3A4 inducer. Coadministration of another strong CYP3A4 inducer decreased ruxolitinib Cmax and AUC by 32% and 61%, respectively. The relative exposure to ruxolitinib's active metabolites increased approximately 100%.
    Ceritinib: (Major) Reduce the ruxolitinib dosage during coadministration with ceritinib in patients with myelofibrosis (MF) or polycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur; no dose adjustments are necessary for patients with graft-versus-host disease. In MF patients, reduce the initial dose to 10 mg PO twice daily for platelet count of 100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients, reduce the initial dose to 5 mg PO twice daily. Avoid the use of ceritinib in MF or PV patients who are stable on a ruxolitinib dose of 5 mg PO once daily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by 50%; in patients stable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. Additional dose modifications should be made with frequent monitoring of safety and efficacy. Ruxolitinib is a CYP3A4 substrate; ceritinib is a strong CYP3A4 inhibitor.
    Chloramphenicol: (Major) Reduce the ruxolitinib dosage during coadministration with chloramphenicol in patients with myelofibrosis (MF) or polycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur; no dose adjustments are necessary for patients with graft-versus-host disease. In MF patients, reduce the initial dose to 10 mg PO twice daily for platelet count of 100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients, reduce the initial dose to 5 mg PO twice daily. Avoid the use of chloramphenicol or interrupt ruxolitinib treatment during chloramphenicol use in MF or PV patients who are stable on a ruxolitinib dose of 5 mg PO once daily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by 50%; in patients stable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. Additional dose modifications should be made with frequent monitoring of safety and efficacy. Ruxolitinib is a CYP3A4 substrate; chloramphenicol is a strong CYP3A4 inhibitor.
    Cimetidine: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderate inhibitors of CYP3A4 such as cimetidine, a dose adjustment is not necessary, but monitoring patients for toxicity may be prudent. There was an 8% and 27% increase in the Cmax and AUC of a single dose of ruxolitinib 10 mg, respectively, when the dose was given after a short course of erythromycin 500 mg PO twice daily for 4 days. The change in the pharmacodynamic marker pSTAT3 inhibition was consistent with the increase in exposure.
    Clarithromycin: (Major) Reduce the ruxolitinib dosage during coadministration with clarithromycin in patients with myelofibrosis (MF) or polycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur; no dose adjustments are necessary for patients with graft-versus-host disease. In MF patients, reduce the initial dose to 10 mg PO twice daily for platelet count of 100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients, reduce the initial dose to 5 mg PO twice daily. Avoid the use of clarithromycin or interrupt ruxolitinib treatment during clarithromycin use in MF or PV patients who are stable on a ruxolitinib dose of 5 mg PO once daily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by 50%; in patients stable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. Additional dose modifications should be made with frequent monitoring of safety and efficacy. Ruxolitinib is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor.
    Clozapine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Cobicistat: (Major) Reduce the ruxolitinib dosage during coadministration with cobicistat in patients with myelofibrosis (MF) or polycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur; no dose adjustments are necessary for patients with graft-versus-host disease. In MF patients, reduce the initial dose to 10 mg PO twice daily for platelet count of 100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients, reduce the initial dose to 5 mg PO twice daily. Avoid the use of cobicistat in MF or PV patients who are stable on a ruxolitinib dose of 5 mg PO once daily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by 50%; in patients stable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. Additional dose modifications should be made with frequent monitoring of safety and efficacy. Ruxolitinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor.
    Conivaptan: (Major) Reduce the ruxolitinib dosage during coadministration with conivaptan in patients with myelofibrosis (MF) or polycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur; no dose adjustments are necessary for patients with graft-versus-host disease. In MF patients, reduce the initial dose to 10 mg PO twice daily for platelet count of 100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients, reduce the initial dose to 5 mg PO twice daily. Avoid the use of conivaptan or interrupt ruxolitinib treatment during conivaptan use in MF or PV patients who are stable on a ruxolitinib dose of 5 mg PO once daily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by 50%; in patients stable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. Additional dose modifications should be made with frequent monitoring of safety and efficacy. Ruxolitinib is a CYP3A4 substrate; conivaptan is a strong CYP3A4 inhibitor.
    Danazol: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderate inhibitors of CYP3A4 such as danazol, a dose adjustment is not necessary, but monitoring patients for toxicity may be prudent. There was an 8% and 27% increase in the Cmax and AUC of a single dose of ruxolitinib 10 mg, respectively, when the dose was given after a short course of erythromycin 500 mg PO twice daily for 4 days. The change in the pharmacodynamic marker pSTAT3 inhibition was consistent with the increase in exposure.
    Darunavir: (Major) Reduce the ruxolitinib dosage during coadministration with darunavir in patients with myelofibrosis (MF) or polycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur; no dose adjustments are necessary for patients with graft-versus-host disease. In MF patients, reduce the initial dose to 10 mg PO twice daily for platelet count of 100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients, reduce the initial dose to 5 mg PO twice daily. Avoid the use of darunavir in MF or PV patients who are stable on a ruxolitinib dose of 5 mg PO once daily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by 50%; in patients stable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. Additional dose modifications should be made with frequent monitoring of safety and efficacy. Ruxolitinib is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor.
    Darunavir; Cobicistat: (Major) Reduce the ruxolitinib dosage during coadministration with cobicistat in patients with myelofibrosis (MF) or polycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur; no dose adjustments are necessary for patients with graft-versus-host disease. In MF patients, reduce the initial dose to 10 mg PO twice daily for platelet count of 100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients, reduce the initial dose to 5 mg PO twice daily. Avoid the use of cobicistat in MF or PV patients who are stable on a ruxolitinib dose of 5 mg PO once daily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by 50%; in patients stable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. Additional dose modifications should be made with frequent monitoring of safety and efficacy. Ruxolitinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. (Major) Reduce the ruxolitinib dosage during coadministration with darunavir in patients with myelofibrosis (MF) or polycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur; no dose adjustments are necessary for patients with graft-versus-host disease. In MF patients, reduce the initial dose to 10 mg PO twice daily for platelet count of 100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients, reduce the initial dose to 5 mg PO twice daily. Avoid the use of darunavir in MF or PV patients who are stable on a ruxolitinib dose of 5 mg PO once daily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by 50%; in patients stable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. Additional dose modifications should be made with frequent monitoring of safety and efficacy. Ruxolitinib is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Reduce the ruxolitinib dosage during coadministration with cobicistat in patients with myelofibrosis (MF) or polycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur; no dose adjustments are necessary for patients with graft-versus-host disease. In MF patients, reduce the initial dose to 10 mg PO twice daily for platelet count of 100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients, reduce the initial dose to 5 mg PO twice daily. Avoid the use of cobicistat in MF or PV patients who are stable on a ruxolitinib dose of 5 mg PO once daily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by 50%; in patients stable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. Additional dose modifications should be made with frequent monitoring of safety and efficacy. Ruxolitinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. (Major) Reduce the ruxolitinib dosage during coadministration with darunavir in patients with myelofibrosis (MF) or polycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur; no dose adjustments are necessary for patients with graft-versus-host disease. In MF patients, reduce the initial dose to 10 mg PO twice daily for platelet count of 100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients, reduce the initial dose to 5 mg PO twice daily. Avoid the use of darunavir in MF or PV patients who are stable on a ruxolitinib dose of 5 mg PO once daily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by 50%; in patients stable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. Additional dose modifications should be made with frequent monitoring of safety and efficacy. Ruxolitinib is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Reduce the ruxolitinib dosage during coadministration with ritonavir in patients with myelofibrosis (MF) or polycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur; no dose adjustments are necessary for patients with graft-versus-host disease. In MF patients, reduce the initial dose to 10 mg PO twice daily for platelet count of 100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients, reduce the initial dose to 5 mg PO twice daily. Avoid the use of ritonavir in MF or PV patients who are stable on a ruxolitinib dose of 5 mg PO once daily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by 50%; in patients stable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. Additional dose modifications should be made with frequent monitoring of safety and efficacy. Ruxolitinib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor.
    Delavirdine: (Major) Reduce the ruxolitinib dosage during coadministration with delavirdine in patients with myelofibrosis (MF) or polycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur; no dose adjustments are necessary for patients with graft-versus-host disease. In MF patients, reduce the initial dose to 10 mg PO twice daily for platelet count of 100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients, reduce the initial dose to 5 mg PO twice daily. Avoid the use of delavirdine in MF or PV patients who are stable on a ruxolitinib dose of 5 mg PO once daily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by 50%; in patients stable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. Additional dose modifications should be made with frequent monitoring of safety and efficacy. Ruxolitinib is a CYP3A4 substrate; delavirdine is a strong CYP3A4 inhibitor.
    Dexamethasone: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are CYP3A4 inducers such as dexamethasone, a dose adjustment is not necessary, but closely monitor patients and titrate the ruxolitinib dose based on safety and efficacy. The Cmax and AUC of a single 50 mg dose of ruxolitinib was decreased by 32% and 61%, respectively, after rifampin 600 mg once daily was administered for 10 days. The relative exposure to ruxolitinib's active metabolites increased by about 100%, which may partially explain the reported disproportionate 10% reduction in the pharmacodynamic marker pSTAT3 inhibition.
    Diltiazem: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderate inhibitors of CYP3A4 such as diltiazem, a dose adjustment is not necessary, but monitoring patients for toxicity may be prudent. There was an 8% and 27% increase in the Cmax and AUC of a single dose of ruxolitinib 10 mg, respectively, when the dose was given after a short course of erythromycin 500 mg PO twice daily for 4 days. The change in the pharmacodynamic marker pSTAT3 inhibition was consistent with the increase in exposure.
    Dronedarone: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderate inhibitors of CYP3A4 such as dronedarone, a dose adjustment is not necessary, but monitoring patients for toxicity may be prudent. There was an 8% and 27% increase in the Cmax and AUC of a single dose of ruxolitinib 10 mg, respectively, when the dose was given after a short course of erythromycin 500 mg PO twice daily for 4 days. The change in the pharmacodynamic marker pSTAT3 inhibition was consistent with the increase in exposure.
    Drospirenone; Ethinyl Estradiol: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderate inhibitors of CYP3A4 such as ethinyl estradiol, a dose adjustment is not necessary, but monitoring patients for toxicity may be prudent. There was an 8% and 27% increase in the Cmax and AUC of a single dose of ruxolitinib 10 mg, respectively, when the dose was given after a short course of erythromycin 500 mg PO twice daily for 4 days. The change in the pharmacodynamic marker pSTAT3 inhibition was consistent with the increase in exposure.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderate inhibitors of CYP3A4 such as ethinyl estradiol, a dose adjustment is not necessary, but monitoring patients for toxicity may be prudent. There was an 8% and 27% increase in the Cmax and AUC of a single dose of ruxolitinib 10 mg, respectively, when the dose was given after a short course of erythromycin 500 mg PO twice daily for 4 days. The change in the pharmacodynamic marker pSTAT3 inhibition was consistent with the increase in exposure.
    Efavirenz: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are CYP3A4 inducers such as efavirenz, a dose adjustment is not necessary, but closely monitor patients and titrate the ruxolitinib dose based on safety and efficacy. The Cmax and AUC of a single 50 mg dose of ruxolitinib was decreased by 32% and 61%, respectively, after rifampin 600 mg once daily was administered for 10 days. The relative exposure to ruxolitinib's active metabolites increased by about 100%, which may partially explain the reported disproportionate 10% reduction in the pharmacodynamic marker pSTAT3 inhibition.
    Efavirenz; Emtricitabine; Tenofovir: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are CYP3A4 inducers such as efavirenz, a dose adjustment is not necessary, but closely monitor patients and titrate the ruxolitinib dose based on safety and efficacy. The Cmax and AUC of a single 50 mg dose of ruxolitinib was decreased by 32% and 61%, respectively, after rifampin 600 mg once daily was administered for 10 days. The relative exposure to ruxolitinib's active metabolites increased by about 100%, which may partially explain the reported disproportionate 10% reduction in the pharmacodynamic marker pSTAT3 inhibition.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are CYP3A4 inducers such as efavirenz, a dose adjustment is not necessary, but closely monitor patients and titrate the ruxolitinib dose based on safety and efficacy. The Cmax and AUC of a single 50 mg dose of ruxolitinib was decreased by 32% and 61%, respectively, after rifampin 600 mg once daily was administered for 10 days. The relative exposure to ruxolitinib's active metabolites increased by about 100%, which may partially explain the reported disproportionate 10% reduction in the pharmacodynamic marker pSTAT3 inhibition.
    Elbasvir; Grazoprevir: (Moderate) Administering ruxolitinib with elbasvir; grazoprevir may result in elevated ruxolitinib plasma concentrations. Ruxolitinib is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Reduce the ruxolitinib dosage during coadministration with cobicistat in patients with myelofibrosis (MF) or polycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur; no dose adjustments are necessary for patients with graft-versus-host disease. In MF patients, reduce the initial dose to 10 mg PO twice daily for platelet count of 100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients, reduce the initial dose to 5 mg PO twice daily. Avoid the use of cobicistat in MF or PV patients who are stable on a ruxolitinib dose of 5 mg PO once daily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by 50%; in patients stable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. Additional dose modifications should be made with frequent monitoring of safety and efficacy. Ruxolitinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Reduce the ruxolitinib dosage during coadministration with cobicistat in patients with myelofibrosis (MF) or polycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur; no dose adjustments are necessary for patients with graft-versus-host disease. In MF patients, reduce the initial dose to 10 mg PO twice daily for platelet count of 100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients, reduce the initial dose to 5 mg PO twice daily. Avoid the use of cobicistat in MF or PV patients who are stable on a ruxolitinib dose of 5 mg PO once daily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by 50%; in patients stable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. Additional dose modifications should be made with frequent monitoring of safety and efficacy. Ruxolitinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor.
    Enzalutamide: (Moderate) Monitor patients frequently and adjust the ruxolitinib dose based on safety and efficacy if coadministered with enzalutamide; decreased ruxolitinib exposure is possible. Ruxolitinib is a CYP3A4 substrate; enzalutamide is a strong CYP3A4 inducer. Coadministration of another strong CYP3A4 inducer decreased ruxolitinib Cmax and AUC by 32% and 61%, respectively. The relative exposure to ruxolitinib's active metabolites increased approximately 100%.
    Erythromycin: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderate inhibitors of CYP3A4 such as erythromycin, a dose adjustment is not necessary, but monitoring patients for toxicity may be prudent. There was an 8% and 27% increase in the Cmax and AUC of a single dose of ruxolitinib 10 mg, respectively, when the dose was given after a short course of erythromycin 500 mg PO twice daily for 4 days. The change in the pharmacodynamic marker pSTAT3 inhibition was consistent with the increase in exposure.
    Erythromycin; Sulfisoxazole: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderate inhibitors of CYP3A4 such as erythromycin, a dose adjustment is not necessary, but monitoring patients for toxicity may be prudent. There was an 8% and 27% increase in the Cmax and AUC of a single dose of ruxolitinib 10 mg, respectively, when the dose was given after a short course of erythromycin 500 mg PO twice daily for 4 days. The change in the pharmacodynamic marker pSTAT3 inhibition was consistent with the increase in exposure.
    Ethinyl Estradiol: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderate inhibitors of CYP3A4 such as ethinyl estradiol, a dose adjustment is not necessary, but monitoring patients for toxicity may be prudent. There was an 8% and 27% increase in the Cmax and AUC of a single dose of ruxolitinib 10 mg, respectively, when the dose was given after a short course of erythromycin 500 mg PO twice daily for 4 days. The change in the pharmacodynamic marker pSTAT3 inhibition was consistent with the increase in exposure.
    Ethinyl Estradiol; Desogestrel: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderate inhibitors of CYP3A4 such as ethinyl estradiol, a dose adjustment is not necessary, but monitoring patients for toxicity may be prudent. There was an 8% and 27% increase in the Cmax and AUC of a single dose of ruxolitinib 10 mg, respectively, when the dose was given after a short course of erythromycin 500 mg PO twice daily for 4 days. The change in the pharmacodynamic marker pSTAT3 inhibition was consistent with the increase in exposure.
    Ethinyl Estradiol; Ethynodiol Diacetate: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderate inhibitors of CYP3A4 such as ethinyl estradiol, a dose adjustment is not necessary, but monitoring patients for toxicity may be prudent. There was an 8% and 27% increase in the Cmax and AUC of a single dose of ruxolitinib 10 mg, respectively, when the dose was given after a short course of erythromycin 500 mg PO twice daily for 4 days. The change in the pharmacodynamic marker pSTAT3 inhibition was consistent with the increase in exposure.
    Ethinyl Estradiol; Etonogestrel: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderate inhibitors of CYP3A4 such as ethinyl estradiol, a dose adjustment is not necessary, but monitoring patients for toxicity may be prudent. There was an 8% and 27% increase in the Cmax and AUC of a single dose of ruxolitinib 10 mg, respectively, when the dose was given after a short course of erythromycin 500 mg PO twice daily for 4 days. The change in the pharmacodynamic marker pSTAT3 inhibition was consistent with the increase in exposure.
    Ethinyl Estradiol; Levonorgestrel: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderate inhibitors of CYP3A4 such as ethinyl estradiol, a dose adjustment is not necessary, but monitoring patients for toxicity may be prudent. There was an 8% and 27% increase in the Cmax and AUC of a single dose of ruxolitinib 10 mg, respectively, when the dose was given after a short course of erythromycin 500 mg PO twice daily for 4 days. The change in the pharmacodynamic marker pSTAT3 inhibition was consistent with the increase in exposure.
    Ethinyl Estradiol; Levonorgestrel; Ferrous bisglycinate: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderate inhibitors of CYP3A4 such as ethinyl estradiol, a dose adjustment is not necessary, but monitoring patients for toxicity may be prudent. There was an 8% and 27% increase in the Cmax and AUC of a single dose of ruxolitinib 10 mg, respectively, when the dose was given after a short course of erythromycin 500 mg PO twice daily for 4 days. The change in the pharmacodynamic marker pSTAT3 inhibition was consistent with the increase in exposure.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderate inhibitors of CYP3A4 such as ethinyl estradiol, a dose adjustment is not necessary, but monitoring patients for toxicity may be prudent. There was an 8% and 27% increase in the Cmax and AUC of a single dose of ruxolitinib 10 mg, respectively, when the dose was given after a short course of erythromycin 500 mg PO twice daily for 4 days. The change in the pharmacodynamic marker pSTAT3 inhibition was consistent with the increase in exposure.
    Ethinyl Estradiol; Norelgestromin: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderate inhibitors of CYP3A4 such as ethinyl estradiol, a dose adjustment is not necessary, but monitoring patients for toxicity may be prudent. There was an 8% and 27% increase in the Cmax and AUC of a single dose of ruxolitinib 10 mg, respectively, when the dose was given after a short course of erythromycin 500 mg PO twice daily for 4 days. The change in the pharmacodynamic marker pSTAT3 inhibition was consistent with the increase in exposure.
    Ethinyl Estradiol; Norethindrone Acetate: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderate inhibitors of CYP3A4 such as ethinyl estradiol, a dose adjustment is not necessary, but monitoring patients for toxicity may be prudent. There was an 8% and 27% increase in the Cmax and AUC of a single dose of ruxolitinib 10 mg, respectively, when the dose was given after a short course of erythromycin 500 mg PO twice daily for 4 days. The change in the pharmacodynamic marker pSTAT3 inhibition was consistent with the increase in exposure.
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderate inhibitors of CYP3A4 such as ethinyl estradiol, a dose adjustment is not necessary, but monitoring patients for toxicity may be prudent. There was an 8% and 27% increase in the Cmax and AUC of a single dose of ruxolitinib 10 mg, respectively, when the dose was given after a short course of erythromycin 500 mg PO twice daily for 4 days. The change in the pharmacodynamic marker pSTAT3 inhibition was consistent with the increase in exposure.
    Ethinyl Estradiol; Norethindrone: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderate inhibitors of CYP3A4 such as ethinyl estradiol, a dose adjustment is not necessary, but monitoring patients for toxicity may be prudent. There was an 8% and 27% increase in the Cmax and AUC of a single dose of ruxolitinib 10 mg, respectively, when the dose was given after a short course of erythromycin 500 mg PO twice daily for 4 days. The change in the pharmacodynamic marker pSTAT3 inhibition was consistent with the increase in exposure.
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderate inhibitors of CYP3A4 such as ethinyl estradiol, a dose adjustment is not necessary, but monitoring patients for toxicity may be prudent. There was an 8% and 27% increase in the Cmax and AUC of a single dose of ruxolitinib 10 mg, respectively, when the dose was given after a short course of erythromycin 500 mg PO twice daily for 4 days. The change in the pharmacodynamic marker pSTAT3 inhibition was consistent with the increase in exposure.
    Ethinyl Estradiol; Norgestimate: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderate inhibitors of CYP3A4 such as ethinyl estradiol, a dose adjustment is not necessary, but monitoring patients for toxicity may be prudent. There was an 8% and 27% increase in the Cmax and AUC of a single dose of ruxolitinib 10 mg, respectively, when the dose was given after a short course of erythromycin 500 mg PO twice daily for 4 days. The change in the pharmacodynamic marker pSTAT3 inhibition was consistent with the increase in exposure.
    Ethinyl Estradiol; Norgestrel: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderate inhibitors of CYP3A4 such as ethinyl estradiol, a dose adjustment is not necessary, but monitoring patients for toxicity may be prudent. There was an 8% and 27% increase in the Cmax and AUC of a single dose of ruxolitinib 10 mg, respectively, when the dose was given after a short course of erythromycin 500 mg PO twice daily for 4 days. The change in the pharmacodynamic marker pSTAT3 inhibition was consistent with the increase in exposure.
    Etravirine: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are CYP3A4 inducers such as etravirine, a dose adjustment is not necessary, but closely monitor patients and titrate the ruxolitinib dose based on safety and efficacy. The Cmax and AUC of a single 50 mg dose of ruxolitinib was decreased by 32% and 61%, respectively, after rifampin 600 mg once daily was administered for 10 days. The relative exposure to ruxolitinib's active metabolites increased by about 100%, which may partially explain the reported disproportionate 10% reduction in the pharmacodynamic marker pSTAT3 inhibition.
    Fluconazole: (Major) Avoid coadministration of ruxolitinib with fluconazole doses greater than 200 mg/day in patients with myelofibrosis (MF) or polycythemia vera (PV). Fluconazole and ruxolitinib may be coadministered at usual doses in patients with acute graft-versus-host disease (GVHD). Taking these drugs together may result in increased ruxolitinib exposure and toxicity. Modify the ruxolitinib as follows in patients with MF or PV who require concomitant use with fluconazole at doses of 200 mg/day or less: In MF patients, reduce the initial dose to 10 mg PO twice daily for platelet count of 100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3; in PV patients, reduce the initial dose to 5 mg PO twice daily. Avoid the use of fluconazole or interrupt ruxolitinib treatment during fluconazole use in MF or PV patients who are stable on a ruxolitinib dose of 5 mg PO once daily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by 50%; in patients stable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. Additional dose modifications should be made with frequent monitoring of safety and efficacy. Ruxolitinib is a CYP3A4 substrate; fluconazole is a moderate CYP3A4 inhibitor.
    Fluoxetine: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderate inhibitors of CYP3A4 such as fluoxetine, a dose adjustment is not necessary, but monitoring patients for toxicity may be prudent. There was an 8% and 27% increase in the Cmax and AUC of a single dose of ruxolitinib 10 mg, respectively, when the dose was given after a short course of erythromycin 500 mg PO twice daily for 4 days. The change in the pharmacodynamic marker pSTAT3 inhibition was consistent with the increase in exposure.
    Fluoxetine; Olanzapine: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderate inhibitors of CYP3A4 such as fluoxetine, a dose adjustment is not necessary, but monitoring patients for toxicity may be prudent. There was an 8% and 27% increase in the Cmax and AUC of a single dose of ruxolitinib 10 mg, respectively, when the dose was given after a short course of erythromycin 500 mg PO twice daily for 4 days. The change in the pharmacodynamic marker pSTAT3 inhibition was consistent with the increase in exposure.
    Flutamide: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are CYP3A4 inducers such as flutamide, a dose adjustment is not necessary, but closely monitor patients and titrate the ruxolitinib dose based on safety and efficacy. The Cmax and AUC of a single 50 mg dose of ruxolitinib was decreased by 32% and 61%, respectively, after rifampin 600 mg once daily was administered for 10 days. The relative exposure to ruxolitinib's active metabolites increased by about 100%, which may partially explain the reported disproportionate 10% reduction in the pharmacodynamic marker pSTAT3 inhibition.
    Fluvoxamine: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderate inhibitors of CYP3A4 such as fluvoxamine, a dose adjustment is not necessary, but monitoring patients for toxicity may be prudent. There was an 8% and 27% increase in the Cmax and AUC of a single dose of ruxolitinib 10 mg, respectively, when the dose was given after a short course of erythromycin 500 mg PO twice daily for 4 days. The change in the pharmacodynamic marker pSTAT3 inhibition was consistent with the increase in exposure.
    Fosamprenavir: (Major) Reduce the ruxolitinib dosage during coadministration with fosamprenavir in patients with myelofibrosis (MF) or polycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur; no dose adjustments are necessary for patients with graft-versus-host disease. In MF patients, reduce the initial dose to 10 mg PO twice daily for platelet count of 100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients, reduce the initial dose to 5 mg PO twice daily. Avoid the use of fosamprenavir in MF or PV patients who are stable on a ruxolitinib dose of 5 mg PO once daily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by 50%; in patients stable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. Additional dose modifications should be made with frequent monitoring of safety and efficacy. Ruxolitinib is a CYP3A4 substrate; fosamprenavir is a strong CYP3A4 inhibitor.
    Fosphenytoin: (Moderate) Monitor patients frequently and adjust the ruxolitinib dose based on safety and efficacy if coadministered with fosphenytoin; decreased ruxolitinib exposure is possible. Ruxolitinib is a CYP3A4 substrate; fosphenytoin is a strong CYP3A4 inducer. Coadministration of another strong CYP3A4 inducer decreased ruxolitinib Cmax and AUC by 32% and 61%, respectively. The relative exposure to ruxolitinib's active metabolites increased approximately 100%.
    Grapefruit juice: (Major) Avoid the concomitant use of ruxolitinib and grapefruit juice. Increased ruxolitinib exposure is possible if a patient regularly consumes grapefruit/grapefruit juice.
    Idelalisib: (Major) Reduce the ruxolitinib dosage during coadministration with idelalisib in patients with myelofibrosis (MF) or polycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur; no dose adjustments are necessary for patients with graft-versus-host disease. In MF patients, reduce the initial dose to 10 mg PO twice daily for platelet count of 100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients, reduce the initial dose to 5 mg PO twice daily. Avoid the use of idelalisib in MF or PV patients who are stable on a ruxolitinib dose of 5 mg PO once daily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by 50%; in patients stable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. Additional dose modifications should be made with frequent monitoring of safety and efficacy. Ruxolitinib is a CYP3A4 substrate; idelalisib is a strong CYP3A4 inhibitor.
    Imatinib: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderate inhibitors of CYP3A4 such as imatinib, STI-571, a dose adjustment is not necessary, but monitoring patients for toxicity may be prudent. There was an 8% and 27% increase in the Cmax and AUC of a single dose of ruxolitinib 10 mg, respectively, when the dose was given after a short course of erythromycin 500 mg PO twice daily for 4 days. The change in the pharmacodynamic marker pSTAT3 inhibition was consistent with the increase in exposure.
    Indinavir: (Major) Reduce the ruxolitinib dosage during coadministration with indinavir in patients with myelofibrosis (MF) or polycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur; no dose adjustments are necessary for patients with graft-versus-host disease. In MF patients, reduce the initial dose to 10 mg PO twice daily for platelet count of 100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients, reduce the initial dose to 5 mg PO twice daily. Avoid the use of indinavir in MF or PV patients who are stable on a ruxolitinib dose of 5 mg PO once daily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by 50%; in patients stable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. Additional dose modifications should be made with frequent monitoring of safety and efficacy. Ruxolitinib is a CYP3A4 substrate; indinavir is a strong CYP3A4 inhibitor.
    Isavuconazonium: (Moderate) The plasma concentrations of ruxolitinib may be elevated when administered concurrently with isavuconazonium. Ruxolitinib is a CYP3A4 substrate; isavuconazole, the active moiety of isavuconazonium, is a moderate inhibitor of this enzyme. Although a dose adjustment is not necessary when used with drugs that are mild or moderate inhibitors of CYP3A4 such as isavuconazole, monitoring patients for ruxolitinib toxicity may be prudent when these drugs are given concurrently. There was an 8% and 27% increase in the Cmax and AUC of a single dose of ruxolitinib 10 mg, respectively, when the dose was given after a short course of erythromycin 500 mg PO twice daily for 4 days (another moderate CYP3A4 inhibitor). The change in the pharmacodynamic marker pSTAT3 inhibition was consistent with the increase in exposure.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Moderate) Monitor patients frequently and adjust the ruxolitinib dose based on safety and efficacy if coadministered with rifampin; decreased ruxolitinib exposure is possible. Ruxolitinib is a CYP3A4 substrate; rifampin is a strong CYP3A4 inducer. Coadministration of rifampin decreased ruxolitinib Cmax and AUC by 32% and 61%, respectively. The relative exposure to ruxolitinib's active metabolites increased approximately 100%.
    Isoniazid, INH; Rifampin: (Moderate) Monitor patients frequently and adjust the ruxolitinib dose based on safety and efficacy if coadministered with rifampin; decreased ruxolitinib exposure is possible. Ruxolitinib is a CYP3A4 substrate; rifampin is a strong CYP3A4 inducer. Coadministration of rifampin decreased ruxolitinib Cmax and AUC by 32% and 61%, respectively. The relative exposure to ruxolitinib's active metabolites increased approximately 100%.
    Itraconazole: (Major) Reduce the ruxolitinib dosage during coadministration with itraconazole in patients with myelofibrosis (MF) or polycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur. No initial dose adjustments are necessary for patients with graft-versus-host disease; however, monitor blood counts more frequently for toxicity and adjust the dose of ruxolitinib if necessary. In MF patients, reduce the initial dose to 10 mg PO twice daily for platelet count of 100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients, reduce the initial dose to 5 mg PO twice daily. Avoid the use of itraconazole or interrupt ruxolitinib treatment during itraconazole use in MF or PV patients who are stable on a ruxolitinib dose of 5 mg PO once daily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by 50%; in patients stable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. Additional dose modifications should be made with frequent monitoring of safety and efficacy. Ruxolitinib is a CYP3A4 substrate; itraconazole is a strong CYP3A4 inhibitor.
    Ketoconazole: (Major) Reduce the ruxolitinib dosage during coadministration with ketoconazole as increased ruxolitinib exposure and toxicity may occur. In myelofibrosis (MF) patients, reduce the initial dose to 10 mg PO twice daily for platelet count of 100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In polycythemia vera (PV) patients, reduce the initial dose to 5 mg PO twice daily. Avoid the use of ketoconazole or interrupt ruxolitinib treatment during ketoconazole use in MF or PV patients who are stable on a ruxolitinib dose of 5 mg PO once daily. For patients with MF or PV patient stable on ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by 50%; in patients stable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. In graft-versus-host disease patients, reduce the dose to 5 mg PO once daily. Additional dose modifications should be made with frequent monitoring of safety and efficacy. Ruxolitinib is a CYP3A4 substrate; ketoconazole is a strong CYP3A4 inhibitor.
    Letermovir: (Moderate) Plasma concentrations of ruxolitinib could increase when administered concurrently with letermovir. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine. Frequently monitor safety and efficacy of ruxolitinib, and modify dose as needed. Ruxolitinib is a substrate of the enzymes CYP3A4. Letermovir is moderate inhibitor of CYP3A4. When given with cyclosporine, the combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. In a drug interaction study, administration of ruxolitinib with another strong CYP3A4 inhibitor increased ruxolitinib maximum plasma concentration (Cmax) and exposure (AUC) by 33% and 91%, respectively. In addition, ruxolitinib half-life was increased from 3.7 to 6 hours. In another study, administration with a moderate CYP3A4 inhibitor increased ruxolitinib Cmax and AUC by 8% and 27%, respectively.
    Lopinavir; Ritonavir: (Major) Reduce the ruxolitinib dosage during coadministration with ritonavir in patients with myelofibrosis (MF) or polycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur; no dose adjustments are necessary for patients with graft-versus-host disease. In MF patients, reduce the initial dose to 10 mg PO twice daily for platelet count of 100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients, reduce the initial dose to 5 mg PO twice daily. Avoid the use of ritonavir in MF or PV patients who are stable on a ruxolitinib dose of 5 mg PO once daily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by 50%; in patients stable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. Additional dose modifications should be made with frequent monitoring of safety and efficacy. Ruxolitinib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor.
    Lumacaftor; Ivacaftor: (Moderate) Monitor patients frequently and adjust the ruxolitinib dose based on safety and efficacy if coadministered with lumacaftor; ivacaftor; decreased ruxolitinib exposure is possible. Ruxolitinib is a CYP3A4 substrate; lumacaftor; ivacaftor is a strong CYP3A4 inducer. Coadministration of another strong CYP3A4 inducer decreased ruxolitinib Cmax and AUC by 32% and 61%, respectively. The relative exposure to ruxolitinib's active metabolites increased approximately 100%.
    Lumacaftor; Ivacaftor: (Moderate) Monitor patients frequently and adjust the ruxolitinib dose based on safety and efficacy if coadministered with lumacaftor; ivacaftor; decreased ruxolitinib exposure is possible. Ruxolitinib is a CYP3A4 substrate; lumacaftor; ivacaftor is a strong CYP3A4 inducer. Coadministration of another strong CYP3A4 inducer decreased ruxolitinib Cmax and AUC by 32% and 61%, respectively. The relative exposure to ruxolitinib's active metabolites increased approximately 100%.
    Mifepristone: (Major) Reduce the ruxolitinib dosage during coadministration with mifepristone in patients with myelofibrosis (MF) or polycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur; no dose adjustments are necessary for patients with graft-versus-host disease. In MF patients, reduce the initial dose to 10 mg PO twice daily for platelet count of 100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients, reduce the initial dose to 5 mg PO twice daily. Avoid the use of mifepristone or interrupt ruxolitinib treatment during mifepristone use in MF or PV patients who are stable on a ruxolitinib dose of 5 mg PO once daily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by 50%; in patients stable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. Additional dose modifications should be made with frequent monitoring of safety and efficacy. Ruxolitinib is a CYP3A4 substrate; mifepristone is a strong CYP3A4 inhibitor.
    Mitotane: (Moderate) Monitor patients frequently and adjust the ruxolitinib dose based on safety and efficacy if coadministered with mitotane; decreased ruxolitinib exposure is possible. Ruxolitinib is a CYP3A4 substrate; mitotane is a strong CYP3A4 inducer. Coadministration of another strong CYP3A4 inducer decreased ruxolitinib Cmax and AUC by 32% and 61%, respectively. The relative exposure to ruxolitinib's active metabolites increased approximately 100%.
    Modafinil: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are CYP3A4 inducers such as modafinil, a dose adjustment is not necessary, but closely monitor patients and titrate the ruxolitinib dose based on safety and efficacy. The Cmax and AUC of a single 50 mg dose of ruxolitinib was decreased by 32% and 61%, respectively, after rifampin 600 mg once daily was administered for 10 days. The relative exposure to ruxolitinib's active metabolites increased by about 100%, which may partially explain the reported disproportionate 10% reduction in the pharmacodynamic marker pSTAT3 inhibition.
    Nafcillin: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are CYP3A4 inducers such as nafcillin, a dose adjustment is not necessary, but closely monitor patients and titrate the ruxolitinib dose based on safety and efficacy. The Cmax and AUC of a single 50 mg dose of ruxolitinib was decreased by 32% and 61%, respectively, after rifampin 600 mg once daily was administered for 10 days. The relative exposure to ruxolitinib's active metabolites increased by about 100%, which may partially explain the reported disproportionate 10% reduction in the pharmacodynamic marker pSTAT3 inhibition.
    Nefazodone: (Major) Reduce the ruxolitinib dosage during coadministration with nefazodone in patients with myelofibrosis (MF) or polycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur; no dose adjustments are necessary for patients with graft-versus-host disease. In MF patients, reduce the initial dose to 10 mg PO twice daily for platelet count of 100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients, reduce the initial dose to 5 mg PO twice daily. Avoid the use of nefazodone in MF or PV patients who are stable on a ruxolitinib dose of 5 mg PO once daily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by 50%; in patients stable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. Additional dose modifications should be made with frequent monitoring of safety and efficacy. Ruxolitinib is a CYP3A4 substrate; nefazodone is a strong CYP3A4 inhibitor.
    Nelfinavir: (Major) Reduce the ruxolitinib dosage during coadministration with nelfinavir in patients with myelofibrosis (MF) or polycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur; no dose adjustments are necessary for patients with graft-versus-host disease. In MF patients, reduce the initial dose to 10 mg PO twice daily for platelet count of 100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients, reduce the initial dose to 5 mg PO twice daily. Avoid the use of nelfinavir in MF or PV patients who are stable on a ruxolitinib dose of 5 mg PO once daily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by 50%; in patients stable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. Additional dose modifications should be made with frequent monitoring of safety and efficacy. Ruxolitinib is a CYP3A4 substrate; nelfinavir is a strong CYP3A4 inhibitor.
    Netupitant, Fosnetupitant; Palonosetron: (Moderate) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4, such as ruxolitinib. The plasma concentrations of ruxolitinib can increase when co-administered with netupitant; the inhibitory effect on CYP3A4 can last for multiple days.
    Nevirapine: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are CYP3A4 inducers such as nevirapine, a dose adjustment is not necessary, but closely monitor patients and titrate the ruxolitinib dose based on safety and efficacy. The Cmax and AUC of a single 50 mg dose of ruxolitinib was decreased by 32% and 61%, respectively, after rifampin 600 mg once daily was administered for 10 days. The relative exposure to ruxolitinib's active metabolites increased by about 100%, which may partially explain the reported disproportionate 10% reduction in the pharmacodynamic marker pSTAT3 inhibition.
    Nicardipine: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderate inhibitors of CYP3A4 such as nicardipine, a dose adjustment is not necessary, but monitoring patients for toxicity may be prudent. There was an 8% and 27% increase in the Cmax and AUC of a single dose of ruxolitinib 10 mg, respectively, when the dose was given after a short course of erythromycin 500 mg PO twice daily for 4 days. The change in the pharmacodynamic marker pSTAT3 inhibition was consistent with the increase in exposure.
    Octreotide: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderate inhibitors of CYP3A4 such as octreotide, a dose adjustment is not necessary, but monitoring patients for toxicity may be prudent. There was an 8% and 27% increase in the Cmax and AUC of a single dose of ruxolitinib 10 mg, respectively, when the dose was given after a short course of erythromycin 500 mg PO twice daily for 4 days. The change in the pharmacodynamic marker pSTAT3 inhibition was consistent with the increase in exposure.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Reduce the ruxolitinib dosage during coadministration with ritonavir in patients with myelofibrosis (MF) or polycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur; no dose adjustments are necessary for patients with graft-versus-host disease. In MF patients, reduce the initial dose to 10 mg PO twice daily for platelet count of 100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients, reduce the initial dose to 5 mg PO twice daily. Avoid the use of ritonavir in MF or PV patients who are stable on a ruxolitinib dose of 5 mg PO once daily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by 50%; in patients stable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. Additional dose modifications should be made with frequent monitoring of safety and efficacy. Ruxolitinib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor.
    Oritavancin: (Moderate) Coadministration of oritavancin and ruxolitinib may result in increases or decreases in ruxolitinib exposure and may increase side effects or decrease efficacy of ruxolitinib. Ruxolitinib is primarily metabolized by CYP3A4, but is also metabolized by CYP2C9. Oritavancin weakly induces CYP3A4, while weakly inhibiting CYP2C9. If these drugs are administered concurrently, monitor the patient for signs of toxicity or lack of efficacy.
    Phenobarbital: (Moderate) Monitor patients frequently and adjust the ruxolitinib dose based on safety and efficacy if coadministered with phenobarbital; decreased ruxolitinib exposure is possible. Ruxolitinib is a CYP3A4 substrate; phenobarbital is a strong CYP3A4 inducer. Coadministration of another strong CYP3A4 inducer decreased ruxolitinib Cmax and AUC by 32% and 61%, respectively. The relative exposure to ruxolitinib's active metabolites increased approximately 100%.
    Phenytoin: (Moderate) Monitor patients frequently and adjust the ruxolitinib dose based on safety and efficacy if coadministered with phenytoin; decreased ruxolitinib exposure is possible. Ruxolitinib is a CYP3A4 substrate; phenytoin is a strong CYP3A4 inducer. Coadministration of another strong CYP3A4 inducer decreased ruxolitinib Cmax and AUC by 32% and 61%, respectively. The relative exposure to ruxolitinib's active metabolites increased approximately 100%.
    Posaconazole: (Major) Reduce the ruxolitinib dosage during coadministration with posaconazole in patients with myelofibrosis (MF) or polycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur; no dose adjustments are necessary for patients with graft-versus-host disease. In MF patients, reduce the initial dose to 10 mg PO twice daily for platelet count of 100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients, reduce the initial dose to 5 mg PO twice daily. Avoid the use of posaconazole or interrupt ruxolitinib treatment during posaconazole use in MF or PV patients who are stable on a ruxolitinib dose of 5 mg PO once daily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by 50%; in patients stable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. Additional dose modifications should be made with frequent monitoring of safety and efficacy. Ruxolitinib is a CYP3A4 substrate; posaconazole is a strong CYP3A4 inhibitor.
    Primidone: (Moderate) Monitor patients frequently and adjust the ruxolitinib dose based on safety and efficacy if coadministered with primidone; decreased ruxolitinib exposure is possible. Ruxolitinib is a CYP3A4 substrate; primidone is a strong CYP3A4 inducer. Coadministration of another strong CYP3A4 inducer decreased ruxolitinib Cmax and AUC by 32% and 61%, respectively. The relative exposure to ruxolitinib's active metabolites increased approximately 100%.
    Ranolazine: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderate inhibitors of CYP3A4 such as ranolazine, a dose adjustment is not necessary, but monitoring patients for toxicity may be prudent. There was an 8% and 27% increase in the Cmax and AUC of a single dose of ruxolitinib 10 mg, respectively, when the dose was given after a short course of erythromycin 500 mg PO twice daily for 4 days. The change in the pharmacodynamic marker pSTAT3 inhibition was consistent with the increase in exposure.
    Ribociclib: (Major) Reduce the ruxolitinib dosage during coadministration with ribociclib in patients with myelofibrosis (MF) or polycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur; no dose adjustments are necessary for patients with graft-versus-host disease. In MF patients, reduce the initial dose to 10 mg PO twice daily for platelet count of 100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients, reduce the initial dose to 5 mg PO twice daily. Avoid the use of ribociclib in MF or PV patients who are stable on a ruxolitinib dose of 5 mg PO once daily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by 50%; in patients stable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. Additional dose modifications should be made with frequent monitoring of safety and efficacy. Ruxolitinib is a CYP3A4 substrate; ribociclib is a strong CYP3A4 inhibitor.
    Ribociclib; Letrozole: (Major) Reduce the ruxolitinib dosage during coadministration with ribociclib in patients with myelofibrosis (MF) or polycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur; no dose adjustments are necessary for patients with graft-versus-host disease. In MF patients, reduce the initial dose to 10 mg PO twice daily for platelet count of 100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients, reduce the initial dose to 5 mg PO twice daily. Avoid the use of ribociclib in MF or PV patients who are stable on a ruxolitinib dose of 5 mg PO once daily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by 50%; in patients stable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. Additional dose modifications should be made with frequent monitoring of safety and efficacy. Ruxolitinib is a CYP3A4 substrate; ribociclib is a strong CYP3A4 inhibitor.
    Rifampin: (Moderate) Monitor patients frequently and adjust the ruxolitinib dose based on safety and efficacy if coadministered with rifampin; decreased ruxolitinib exposure is possible. Ruxolitinib is a CYP3A4 substrate; rifampin is a strong CYP3A4 inducer. Coadministration of rifampin decreased ruxolitinib Cmax and AUC by 32% and 61%, respectively. The relative exposure to ruxolitinib's active metabolites increased approximately 100%.
    Ritonavir: (Major) Reduce the ruxolitinib dosage during coadministration with ritonavir in patients with myelofibrosis (MF) or polycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur; no dose adjustments are necessary for patients with graft-versus-host disease. In MF patients, reduce the initial dose to 10 mg PO twice daily for platelet count of 100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients, reduce the initial dose to 5 mg PO twice daily. Avoid the use of ritonavir in MF or PV patients who are stable on a ruxolitinib dose of 5 mg PO once daily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by 50%; in patients stable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. Additional dose modifications should be made with frequent monitoring of safety and efficacy. Ruxolitinib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor.
    Saquinavir: (Major) Reduce the ruxolitinib dosage during coadministration with saquinavir in patients with myelofibrosis (MF) or polycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur; no dose adjustments are necessary for patients with graft-versus-host disease. In MF patients, reduce the initial dose to 10 mg PO twice daily for platelet count of 100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients, reduce the initial dose to 5 mg PO twice daily. Avoid the use of saquinavir in MF or PV patients who are stable on a ruxolitinib dose of 5 mg PO once daily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by 50%; in patients stable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. Additional dose modifications should be made with frequent monitoring of safety and efficacy. Ruxolitinib is a CYP3A4 substrate; saquinavir is a strong CYP3A4 inhibitor.
    Segesterone Acetate; Ethinyl Estradiol: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderate inhibitors of CYP3A4 such as ethinyl estradiol, a dose adjustment is not necessary, but monitoring patients for toxicity may be prudent. There was an 8% and 27% increase in the Cmax and AUC of a single dose of ruxolitinib 10 mg, respectively, when the dose was given after a short course of erythromycin 500 mg PO twice daily for 4 days. The change in the pharmacodynamic marker pSTAT3 inhibition was consistent with the increase in exposure.
    St. John's Wort, Hypericum perforatum: (Moderate) Monitor patients frequently and adjust the ruxolitinib dose based on safety and efficacy if coadministered with St. John's Wort; decreased ruxolitinib exposure is possible. Ruxolitinib is a CYP3A4 substrate; St. John's Wort is a strong CYP3A4 inducer. Coadministration of another strong CYP3A4 inducer decreased ruxolitinib Cmax and AUC by 32% and 61%, respectively. The relative exposure to ruxolitinib's active metabolites increased approximately 100%.
    Telaprevir: (Major) Avoid coadministration of ruxolitinib and telaprevir in patients with platelet counts < 100 x 10^9/L. In patients with platelet counts >= 100 x 10^9/L, ruxolitinib may be administered concurrently with telaprevir if the initial ruxolitinib dose is reduced to 10 mg PO twice daily. Additional dose modification should be made only after close monitoring of ruxolitinib's safety and efficacy. Predictions about the interaction can be made based on the metabolic pathway of ruxolitinib. Ruxolitinib is primarily metabolized by CYP3A4; telaprevir is a potent inhibitor of this isoenzyme. Coadministration may result in a large increase in ruxolitinib serum concentrations, which could cause adverse events such as thrombocytopenia, anemia, neutropenia, or infection.
    Telithromycin: (Major) Reduce the ruxolitinib dosage during coadministration with telithromycin in patients with myelofibrosis (MF) or polycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur; no dose adjustments are necessary for patients with graft-versus-host disease. In MF patients, reduce the initial dose to 10 mg PO twice daily for platelet count of 100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients, reduce the initial dose to 5 mg PO twice daily. Avoid the use of telithromycin or interrupt ruxolitinib treatment during telithromycin use in MF or PV patients who are stable on a ruxolitinib dose of 5 mg PO once daily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by 50%; in patients stable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. Additional dose modifications should be made with frequent monitoring of safety and efficacy. Ruxolitinib is a CYP3A4 substrate; telithromycin is a strong CYP3A4 inhibitor.
    Telotristat Ethyl: (Moderate) Use caution if coadministration of telotristat ethyl and ruxolitinib is necessary, as the systemic exposure of ruxolitinib may be decreased resulting in reduced efficacy. If these drugs are used together, monitor patients for suboptimal efficacy of ruxolitinib; consider increasing the dose of ruxolitinib if necessary. Ruxolitinib is a CYP3A4 substrate. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate.
    Tipranavir: (Major) Reduce the ruxolitinib dosage during coadministration with tipranavir in patients with myelofibrosis (MF) or polycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur; no dose adjustments are necessary for patients with graft-versus-host disease. In MF patients, reduce the initial dose to 10 mg PO twice daily for platelet count of 100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients, reduce the initial dose to 5 mg PO twice daily. Avoid the use of tipranavir in MF or PV patients who are stable on a ruxolitinib dose of 5 mg PO once daily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by 50%; in patients stable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. Additional dose modifications should be made with frequent monitoring of safety and efficacy. Ruxolitinib is a CYP3A4 substrate; tipranavir is a strong CYP3A4 inhibitor.
    Trandolapril; Verapamil: (Minor) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderate inhibitors of CYP3A4 such as verapamil, a dose adjustment is not necessary, but monitoring patients for toxicity may be prudent. There was an 8% and 27% increase in the Cmax and AUC of a single dose of ruxolitinib 10 mg, respectively, when the dose was given after a short course of erythromycin 500 mg PO twice daily for 4 days. The change in the pharmacodynamic marker pSTAT3 inhibition was consistent with the increase in exposure.
    Tucatinib: (Major) Reduce the ruxolitinib dosage during coadministration with tucatinib in patients with myelofibrosis (MF) or polycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur; no dose adjustments are necessary for patients with graft-versus-host disease. In MF patients, reduce the initial dose to 10 mg PO twice daily for platelet count of 100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients, reduce the initial dose to 5 mg PO twice daily. Avoid the use of tucatinib in MF or PV patients who are stable on a ruxolitinib dose of 5 mg PO once daily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by 50%; in patients stable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. Additional dose modifications should be made with frequent monitoring of safety and efficacy. Ruxolitinib is a CYP3A4 substrate; tucatinib is a strong CYP3A4 inhibitor.
    Upadacitinib: (Severe) Concomitant use of ruxolitinib with upadacitinib is not recommended because of the duplication of the mechanism of action (both are Janus kinase inhibitors, also known as JAK inhibitors) and the possibility of increased immunosuppression and increased infection risk. Both drugs are known to cause elevations in hepatic enzymes and gastrointestinal perforation, and a possibility for increased thrombotic risk.
    Verapamil: (Minor) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderate inhibitors of CYP3A4 such as verapamil, a dose adjustment is not necessary, but monitoring patients for toxicity may be prudent. There was an 8% and 27% increase in the Cmax and AUC of a single dose of ruxolitinib 10 mg, respectively, when the dose was given after a short course of erythromycin 500 mg PO twice daily for 4 days. The change in the pharmacodynamic marker pSTAT3 inhibition was consistent with the increase in exposure.
    Voriconazole: (Major) Reduce the ruxolitinib dosage during coadministration with voriconazole in patients with myelofibrosis (MF) or polycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur; no dose adjustments are necessary for patients with graft-versus-host disease. In MF patients, reduce the initial dose to 10 mg PO twice daily for platelet count of 100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients, reduce the initial dose to 5 mg PO twice daily. Avoid the use of voriconazole or interrupt ruxolitinib treatment during voriconazole use in MF or PV patients who are stable on a ruxolitinib dose of 5 mg PO once daily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by 50%; in patients stable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. Additional dose modifications should be made with frequent monitoring of safety and efficacy. Ruxolitinib is a CYP3A4 substrate; voriconazole is a strong CYP3A4 inhibitor.
    Zafirlukast: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderate inhibitors of CYP3A4 such as zafirlukast, a dose adjustment is not necessary, but monitoring patients for toxicity may be prudent. There was an 8% and 27% increase in the Cmax and AUC of a single dose of ruxolitinib 10 mg, respectively, when the dose was given after a short course of erythromycin 500 mg PO twice daily for 4 days. The change in the pharmacodynamic marker pSTAT3 inhibition was consistent with the increase in exposure.

    PREGNANCY AND LACTATION

    Pregnancy

    No well-controlled studies have been conducted evaluating the use of ruxolitinib in pregnant women. Consider the benefits versus the risk of therapy prior to administering ruxolitinib during pregnancy. Animal data involving rats and rabbits administered doses of 15, 30, or 60 mg/kg/day and 10, 30, or 60 mg/kg/day, respectively, during organogenesis, revealed no evidence of teratogenicity. However at doses of 60 mg/kg/day, reductions in fetal weights were observed in both rats and rabbits. Additionally, rabbits experienced an increase in late resorptions when exposed to the 60 mg/kg/day dose.

    It is not known if ruxolitinib or its metabolites are secreted in human milk or if it has effects on the breast-fed infant or on milk production. Because there is a potential for adverse reactions in nursing infants, women should discontinue breast-feeding during ruxolitinib therapy and for at least 2 weeks after the last dose.

    MECHANISM OF ACTION

    Ruxolitinib is a kinase inhibitor that inhibits Janus Associated Kinases (JAKs) JAK1 and JAK2. JAK signaling involves recruitment of signal transducers and activators of transcription to cytokine receptors and activation and subsequent localization of signal transducers and activators of transcription (STAT) to the nucleus, which leads to gene expression modulation. Normally, JAK1 and JAK2 mediate the signaling of several cytokines and growth factors that are important for hematopoiesis and immune function.
    Dysregulated JAK1 and JAK2 signaling has been noted in myelofibrosis and polycythemia vera, which are myeloproliferative neoplasms. In a mouse model of JAK2V617F-positive myeloproliferative neoplasm, oral administration of ruxolitinib prevented splenomegaly, preferentially decreased JAK2V617F mutant cells in the spleen, and decreased circulating inflammatory cytokines such as TNF-alpha and IL-6.
    The JAK-STAT signaling pathway regulates the development, proliferation, and activation of many types of immune cells required for graft-versus-host disease (GVHD) pathogenesis. Decreased expression of inflammatory cytokines in colon homogenates and reduced immune-cell infiltration in the colon were observed in a mouse model of acute GVHD.

    PHARMACOKINETICS

    Ruxolitinib is administered orally. The mean steady-state Vd in patients with myelofibrosis and polycythemia vera is 72 L (coefficient of variation (CV), 29%) and 75 L (CV, 23%), respectively. In vitro, it is approximately 97% bound to plasma proteins, mostly to albumin. Ruxolitinib is metabolized primarily by CYP3A4 forming active metabolites (e.g., M18 metabolite). After a single oral radiolabeled dose to healthy adults, elimination was predominately through metabolism with 74% of radioactivity excreted in urine and 22% excreted in feces. Unchanged drug accounted for less than 1% of the excreted total radioactivity. The mean elimination half-life of ruxolitinib is approximately 3 hours, and the mean half-life of ruxolitinib plus metabolites is approximately 5.8 hours. Ruxolitinib clearance was 12.7 L/hour in patients with polycythemia vera (CV, 42%).
    Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, CYP2C9
    Ruxolitinib is a substrate of the hepatic isoenzymes CYP3A4 (major) and CYP2C9. Inhibitors and inducers of CYP3A4 may alter the pharmacokinetic parameters of ruxolitinib. In vitro, ruxolitinib and its M18 metabolite are not inhibitors of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4. At clinically relevant concentrations, ruxolitinib is not an inducer of CYP1A2, CYP2B6, or CYP3A4, and ruxolitinib and its M18 metabolite are not inhibitors of the P-gp, BCRP, OATP1B1, OATP1B3, OCT1, OCT2, OAT1 or OAT3 transport systems. Ruxolitinib is not a substrate for the P-gp transporter.

    Oral Route

    Ruxolitinib appears to be well absorbed; oral absorption was estimated to be at least 95%. Administration with a high-fat, high-calorie meal does not cause clinically relevant changes in absorption. Maximal ruxolitinib plasma concentrations are achieved within 1 to 2 hours after oral administration. Mean ruxolitinib Cmax and systemic exposure increased proportionally over a single dose range of 5 to 200 mg. Over this ruxolitinib dosage range, the mean Cmax values ranged from 205 to 7,100 nanoMolar (nM) and the AUC values ranged from 862 to 30,700 nM x hour.