PDR MEMBER LOGIN:
  • PDR Search

    Required field
  • Advertisement
  • CLASSES

    Protein Kinase Inhibitors

    DEA CLASS

    Rx

    DESCRIPTION

    Kinase-inhibiting biologic response modifier that inhibits Janus Associated Kinases (JAKs) JAK1 and JAK2
    Used for intermediate- to high-risk myelofibrosis and polycythemia vera in patients with an inadequate response to or who are intolerant of hydroxyurea
    Consider tapering the dose gradually rather than discontinuing abruptly

    COMMON BRAND NAMES

    Jakafi

    HOW SUPPLIED

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

    DOSAGE & INDICATIONS

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

    Initially, 10 mg orally twice daily; the starting dosage for patients taking a strong CYP3A4 inhibitor is 5 mg orally twice daily. 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 < 0.001) in patients with polycythemia vera who had an inadequate response to or unacceptable side effects from hydroxyurea in a multinational, randomized, phase III trial (n = 222; the RESPONSE trial); additionally, this response was maintained at week 48 (19.1% vs 0.9%; p < 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 <= 400 x 109 cells/L, and a white blood cell count <= 10 x 109 cells/L) 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% patients who achieved a response at 32 weeks maintained a response, and 58% 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; decrease dose to 10 mg PO twice daily if taking strong CYP3A4 inhibitor. 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; decrease dose to 10 mg PO twice daily if taking strong CYP3A4 inhibitor. 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; decrease dose to 5 mg once daily if taking strong CYP3A4 inhibitor. 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.

    MAXIMUM DOSAGE

    Adults

    50 mg/day PO.

    Geriatric

    50 mg/day PO.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    For any Hepatic Impairment (Child-Pugh A, B, or C)
    Myelofibrosis:
    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: Initial dosage, 5 mg PO twice daily.

    Renal Impairment

    Renal dose adjustments for Myelofibrosis:
    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 less 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.
     
    Renal dose adjustments for 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, end-stage renal disease (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.

    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

    Thrombocytopenia

    Patients receiving treatment with ruxolitinib are at increased risk of developing thrombocytopenia. This risk is further increased in those patients with baseline platelet counts less than 200 X 109 cells/L. Ruxolitinib-induced grade 3 or 4 thrombocytopenia has a median onset of approximately 8 weeks and is usually reversible following discontinuation of therapy. To monitor for thrombocytopenia, health care providers are advised to check complete blood counts (CBC) prior to therapy, every 2 to 4 weeks, and then as clinically indicated. Consider dose reductions, temporary treatment interruptions, and/or platelet transfusions in patients who develop thrombocytopenia.

    Anemia

    The risk of developing anemia is increased in patients receiving treatment with ruxolitinib. During clinical trials, recipients of ruxolitinib experienced decreases in hemoglobin concentrations to a mean nadir of 1.5 to 2 g/dL below baseline after 8 to 12 weeks of therapy. Hemoglobin counts gradually recovered, regardless of whether red blood cell (RBC) transfusions were administered, to a new steady state that was approximately 1 g/dL below baseline. To monitor for anemia, health care providers are advised to check complete blood counts (CBC) prior to therapy, every 2 to 4 weeks, and then as clinically indicated. Consider dose reductions and/or RBC transfusions in patients who develop anemia.

    Immunosuppression, neutropenia

    Patients treated with ruxolitinib are at increased risk of developing neutropenia, defined as an absolute neutrophil count less than 0.5 X 109 cells/L. To monitor for neutropenia and subsequent immunosuppression, health care providers are advised to check complete blood counts (CBC) prior to therapy, every 2 to 4 weeks, and then as clinically indicated. Ruxolitinib-induced neutropenia is usually reversible following discontinuation of therapy; therefore, consider temporary treatment interruptions in those patients who develop neutropenia.

    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. 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 as the mean AUC is increased in patients with any degree of hepatic impairment. In myelofibrosis patients with hepatic impairment, a reduced starting dosage is recommended for patients with baseline platelet counts between 50 to 150 X 109 cells/L; avoid the use of ruxolitinib in patients who have a baseline platelet count less than 50 X 109 cells/L. In polycythemia vera patients with hepatic impairment, a reduced starting dosage is recommended for all patients regardless of platelet count.

    Renal disease, renal failure, renal impairment

    Patients with preexisting renal disease may be at increased risk for ruxolitinib-induced adverse events; ruxolitinib metabolite AUC values increased with increasing degrees of renal impairment. In myelofibrosis patients with moderate to severe renal impairment (CrCl, 15 to 59 mL/min), a reduced starting dosage is recommended for patients with baseline platelet counts between 50 to 150 X 109 cells/L; avoid the use of ruxolitinib in patients who have a baseline platelet count less than 50 X 109 cells/L. In polycythemia vera patients with moderate to severe renal impairment, a reduced starting dosage is recommended for all patients regardless of platelet count. A reduced starting dose is also recommended in patients with end-stage renal disease (ESRD) (e.g., CrCl less than 15 mL/min) on dialysis. Avoid ruxolitinib use in patients who have renal failure/ESRD and are not receiving 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.

    Secondary malignancy, skin cancer

    Secondary 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

    anemia / Delayed / 0-45.0
    thrombocytopenia / Delayed / 5.0-13.0
    neutropenia / Delayed / 0-7.0
    dyspnea / Early / 3.0-3.0
    pyuria / Delayed / 0-1.0
    infection / Delayed / 0-1.0
    cystitis / Delayed / 0-1.0
    ecchymosis / Delayed / 0-1.0
    hematoma / Early / 0-1.0
    petechiae / Delayed / 0-1.0
    purpura / Delayed / 0-1.0
    dizziness / Early / 0-1.0
    headache / Early / 0-1.0
    vertigo / Early / 0-1.0
    weight gain / Delayed / 0-1.0
    abdominal pain / Early / 0-1.0
    elevated hepatic enzymes / Delayed / 0-1.0
    hypercholesterolemia / Delayed / 0-1.0
    pruritus / Rapid / 0-1.0
    leukoencephalopathy / Delayed / Incidence not known
    disseminated intravascular coagulation (DIC) / Delayed / Incidence not known

    Moderate

    hypertriglyceridemia / Delayed / 15.0-15.0
    constipation / Delayed / 8.0-8.0
    peripheral edema / Delayed / 0-8.0
    edema / Delayed / 8.0-8.0
    hypertension / Early / 0-6.0
    bleeding / Early / Incidence not known
    hypotension / Rapid / Incidence not known
    respiratory depression / Rapid / Incidence not known
    secondary malignancy / Delayed / Incidence not known

    Mild

    diarrhea / Early / 15.0-15.0
    fatigue / Early / 15.0-15.0
    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

    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) Modify the ruxolitinib dosage when coadministered with clarithromycin. Subsequent ruxolitinib dose modifications should be made with frequent monitoring of safety and efficacy. Increased ruxolitinib exposure is possible if coadministered with clarithromycin. Ruxolitinib is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ruxolitinib Cmax and AUC by 33% and 91%, respectively. Ruxolitinib dosage adjustments when coadministered with a strong CYP3A4 inhibitor are as follows: In patients with myelofibrosis (MF) and platelet counts greater than or equal to 100 x 10^9/L, initiate ruxolitinib at 10 mg PO twice daily; if platelet counts are greater than 50 x 10^9/L and less than 100 x 10^9/L, initiate ruxolitinib at 5 mg PO once daily. In patients with polycythemia vera (PV), stabilized on ruxolitinib doses greater than or equal to 10 mg PO twice daily, decrease the ruxolitinib dose by 50% rounded to the nearest available tablet strength; for PV patients stabilized on ruxolitinib 5 mg PO twice daily, decrease ruxolitinib to 5 mg PO once daily; avoid coadministration in PV patients stabilized on ruxolitinib 5 mg PO once daily or interrupt ruxolitinib therapy for the duration of clarithromycin use.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Modify the ruxolitinib dosage when coadministered with clarithromycin. Subsequent ruxolitinib dose modifications should be made with frequent monitoring of safety and efficacy. Increased ruxolitinib exposure is possible if coadministered with clarithromycin. Ruxolitinib is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ruxolitinib Cmax and AUC by 33% and 91%, respectively. Ruxolitinib dosage adjustments when coadministered with a strong CYP3A4 inhibitor are as follows: In patients with myelofibrosis (MF) and platelet counts greater than or equal to 100 x 10^9/L, initiate ruxolitinib at 10 mg PO twice daily; if platelet counts are greater than 50 x 10^9/L and less than 100 x 10^9/L, initiate ruxolitinib at 5 mg PO once daily. In patients with polycythemia vera (PV), stabilized on ruxolitinib doses greater than or equal to 10 mg PO twice daily, decrease the ruxolitinib dose by 50% rounded to the nearest available tablet strength; for PV patients stabilized on ruxolitinib 5 mg PO twice daily, decrease ruxolitinib to 5 mg PO once daily; avoid coadministration in PV patients stabilized on ruxolitinib 5 mg PO once daily or interrupt ruxolitinib therapy for the duration of clarithromycin use.
    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.
    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) Modify the ruxolitinib dosage when coadministered with atazanavir. Subsequent ruxolitinib dose modifications should be made with frequent monitoring of safety and efficacy. Increased ruxolitinib exposure is possible if coadministered with atazanavir. Ruxolitinib is a CYP3A4 substrate; atazanavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ruxolitinib Cmax and AUC by 33% and 91%, respectively. Ruxolitinib dosage adjustments when coadministered with a strong CYP3A4 inhibitor are as follows: In patients with myelofibrosis (MF) and platelet counts greater than or equal to 100 x 10^9/L, initiate ruxolitinib at 10 mg PO twice daily; if platelet counts are greater than 50 x 10^9/L and less than 100 x 10^9/L, initiate ruxolitinib at 5 mg PO once daily. In patients with polycythemia vera (PV), stabilized on ruxolitinib doses greater than or equal to 10 mg PO twice daily, decrease the ruxolitinib dose by 50% rounded to the nearest available tablet strength; for PV patients stabilized on ruxolitinib 5 mg PO twice daily, decrease ruxolitinib to 5 mg PO once daily; avoid coadministration in PV patients stabilized on ruxolitinib 5 mg PO once daily or interrupt ruxolitinib therapy for the duration of atazanavir use.
    Atazanavir; Cobicistat: (Major) Modify the ruxolitinib dosage when coadministered with atazanavir. Subsequent ruxolitinib dose modifications should be made with frequent monitoring of safety and efficacy. Increased ruxolitinib exposure is possible if coadministered with atazanavir. Ruxolitinib is a CYP3A4 substrate; atazanavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ruxolitinib Cmax and AUC by 33% and 91%, respectively. Ruxolitinib dosage adjustments when coadministered with a strong CYP3A4 inhibitor are as follows: In patients with myelofibrosis (MF) and platelet counts greater than or equal to 100 x 10^9/L, initiate ruxolitinib at 10 mg PO twice daily; if platelet counts are greater than 50 x 10^9/L and less than 100 x 10^9/L, initiate ruxolitinib at 5 mg PO once daily. In patients with polycythemia vera (PV), stabilized on ruxolitinib doses greater than or equal to 10 mg PO twice daily, decrease the ruxolitinib dose by 50% rounded to the nearest available tablet strength; for PV patients stabilized on ruxolitinib 5 mg PO twice daily, decrease ruxolitinib to 5 mg PO once daily; avoid coadministration in PV patients stabilized on ruxolitinib 5 mg PO once daily or interrupt ruxolitinib therapy for the duration of atazanavir use. (Major) Modify the ruxolitinib dosage when coadministered with cobicistat. Subsequent ruxolitinib dose modifications should be made with frequent monitoring of safety and efficacy. Increased ruxolitinib exposure is possible if coadministered with cobicistat. Ruxolitinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ruxolitinib Cmax and AUC by 33% and 91%, respectively. Ruxolitinib dosage adjustments when coadministered with a strong CYP3A4 inhibitor are as follows: In patients with myelofibrosis (MF) and platelet counts greater than or equal to 100 x 10^9/L, initiate ruxolitinib at 10 mg PO twice daily; if platelet counts are greater than 50 x 10^9/L and less than 100 x 10^9/L, initiate ruxolitinib at 5 mg PO once daily. In patients with polycythemia vera (PV), stabilized on ruxolitinib doses greater than or equal to 10 mg PO twice daily, decrease the ruxolitinib dose by 50% rounded to the nearest available tablet strength; for PV patients stabilized on ruxolitinib 5 mg PO twice daily, decrease ruxolitinib to 5 mg PO once daily; avoid coadministration in PV patients stabilized on ruxolitinib 5 mg PO once daily or interrupt ruxolitinib therapy for the duration of cobicistat use.
    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%.
    Basiliximab: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderate inhibitors of CYP3A4 such as basiliximab, 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.
    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.
    Boceprevir: (Major) Avoid coadministration of ruxolitinib and boceprevir in patients with platelet counts < 100 x 10^9/L. In patients with platelet counts >= 100 x 10^9/L, ruxolitinib may be administered with boceprevir 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; boceprevir 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.
    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.
    Brigatinib: (Moderate) Closely monitor for decreased efficacy of ruxolitinib if coadministration with brigatinib is necessary; titrate the ruxolitinib dose based on safety and efficacy. Ruxolitinib is a CYP3A substrate and brigatinib induces CYP3A in vitro. Coadministration with a strong CYP3A4 inducer decreased the AUC and Cmax of a single dose of ruxolitinib by 61% and 32%, respectively; the relative exposure to ruxolitinib's active metabolites increased by about 100%.
    Capecitabine: (Moderate) Use caution if coadministration of capecitabine with ruxolitinib is necessary, and monitor for an increase in ruxolitinib-related adverse reactions. Ruxolitinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP2C9; capecitabine and/or its metabolites are thought to be inhibitors of CYP2C9. In a drug interaction study, the mean AUC of another CYP2C9 substrate, S-warfarin (single dose), significantly increased after coadministration with capecitabine; the maximum observed INR value also increased by 91%.
    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) Avoid coadministration of ceritinib with ruxolitinib due to increased ruxolitinib exposure. If coadministration is unavoidable, monitor for ruxolitinib -related adverse reactions; a dosage adjustment may be necessary. Ceritinib is a CYP3A4 and CYP2C9 inhibitor and ruxolitinib is primarily metabolized by CYP3A4 with lesser contribution from CYP2C9. Coadministration with another combined inhibitor of CYP3A4 and CYP2C9 is predicted to increase the AUC of ruxolitinib by 100% to 300%.
    Chloramphenicol: (Major) Modify the ruxolitinib dosage when coadministered with chloramphenicol. Subsequent ruxolitinib dose modifications should be made with frequent monitoring of safety and efficacy. Increased ruxolitinib exposure is possible if coadministered with chloramphenicol. Ruxolitinib is a CYP3A4 substrate; chloramphenicol is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ruxolitinib Cmax and AUC by 33% and 91%, respectively. Ruxolitinib dosage adjustments when coadministered with a strong CYP3A4 inhibitor are as follows: In patients with myelofibrosis (MF) and platelet counts greater than or equal to 100 x 10^9/L, initiate ruxolitinib at 10 mg PO twice daily; if platelet counts are greater than 50 x 10^9/L and less than 100 x 10^9/L, initiate ruxolitinib at 5 mg PO once daily. In patients with polycythemia vera (PV), stabilized on ruxolitinib doses greater than or equal to 10 mg PO twice daily, decrease the ruxolitinib dose by 50% rounded to the nearest available tablet strength; for PV patients stabilized on ruxolitinib 5 mg PO twice daily, decrease ruxolitinib to 5 mg PO once daily; avoid coadministration in PV patients stabilized on ruxolitinib 5 mg PO once daily or interrupt ruxolitinib therapy for the duration of chloramphenicol use.
    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) Modify the ruxolitinib dosage when coadministered with clarithromycin. Subsequent ruxolitinib dose modifications should be made with frequent monitoring of safety and efficacy. Increased ruxolitinib exposure is possible if coadministered with clarithromycin. Ruxolitinib is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ruxolitinib Cmax and AUC by 33% and 91%, respectively. Ruxolitinib dosage adjustments when coadministered with a strong CYP3A4 inhibitor are as follows: In patients with myelofibrosis (MF) and platelet counts greater than or equal to 100 x 10^9/L, initiate ruxolitinib at 10 mg PO twice daily; if platelet counts are greater than 50 x 10^9/L and less than 100 x 10^9/L, initiate ruxolitinib at 5 mg PO once daily. In patients with polycythemia vera (PV), stabilized on ruxolitinib doses greater than or equal to 10 mg PO twice daily, decrease the ruxolitinib dose by 50% rounded to the nearest available tablet strength; for PV patients stabilized on ruxolitinib 5 mg PO twice daily, decrease ruxolitinib to 5 mg PO once daily; avoid coadministration in PV patients stabilized on ruxolitinib 5 mg PO once daily or interrupt ruxolitinib therapy for the duration of clarithromycin use.
    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) Modify the ruxolitinib dosage when coadministered with cobicistat. Subsequent ruxolitinib dose modifications should be made with frequent monitoring of safety and efficacy. Increased ruxolitinib exposure is possible if coadministered with cobicistat. Ruxolitinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ruxolitinib Cmax and AUC by 33% and 91%, respectively. Ruxolitinib dosage adjustments when coadministered with a strong CYP3A4 inhibitor are as follows: In patients with myelofibrosis (MF) and platelet counts greater than or equal to 100 x 10^9/L, initiate ruxolitinib at 10 mg PO twice daily; if platelet counts are greater than 50 x 10^9/L and less than 100 x 10^9/L, initiate ruxolitinib at 5 mg PO once daily. In patients with polycythemia vera (PV), stabilized on ruxolitinib doses greater than or equal to 10 mg PO twice daily, decrease the ruxolitinib dose by 50% rounded to the nearest available tablet strength; for PV patients stabilized on ruxolitinib 5 mg PO twice daily, decrease ruxolitinib to 5 mg PO once daily; avoid coadministration in PV patients stabilized on ruxolitinib 5 mg PO once daily or interrupt ruxolitinib therapy for the duration of cobicistat use.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Major) Modify the ruxolitinib dosage when coadministered with cobicistat. Subsequent ruxolitinib dose modifications should be made with frequent monitoring of safety and efficacy. Increased ruxolitinib exposure is possible if coadministered with cobicistat. Ruxolitinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ruxolitinib Cmax and AUC by 33% and 91%, respectively. Ruxolitinib dosage adjustments when coadministered with a strong CYP3A4 inhibitor are as follows: In patients with myelofibrosis (MF) and platelet counts greater than or equal to 100 x 10^9/L, initiate ruxolitinib at 10 mg PO twice daily; if platelet counts are greater than 50 x 10^9/L and less than 100 x 10^9/L, initiate ruxolitinib at 5 mg PO once daily. In patients with polycythemia vera (PV), stabilized on ruxolitinib doses greater than or equal to 10 mg PO twice daily, decrease the ruxolitinib dose by 50% rounded to the nearest available tablet strength; for PV patients stabilized on ruxolitinib 5 mg PO twice daily, decrease ruxolitinib to 5 mg PO once daily; avoid coadministration in PV patients stabilized on ruxolitinib 5 mg PO once daily or interrupt ruxolitinib therapy for the duration of cobicistat use.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Modify the ruxolitinib dosage when coadministered with cobicistat. Subsequent ruxolitinib dose modifications should be made with frequent monitoring of safety and efficacy. Increased ruxolitinib exposure is possible if coadministered with cobicistat. Ruxolitinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ruxolitinib Cmax and AUC by 33% and 91%, respectively. Ruxolitinib dosage adjustments when coadministered with a strong CYP3A4 inhibitor are as follows: In patients with myelofibrosis (MF) and platelet counts greater than or equal to 100 x 10^9/L, initiate ruxolitinib at 10 mg PO twice daily; if platelet counts are greater than 50 x 10^9/L and less than 100 x 10^9/L, initiate ruxolitinib at 5 mg PO once daily. In patients with polycythemia vera (PV), stabilized on ruxolitinib doses greater than or equal to 10 mg PO twice daily, decrease the ruxolitinib dose by 50% rounded to the nearest available tablet strength; for PV patients stabilized on ruxolitinib 5 mg PO twice daily, decrease ruxolitinib to 5 mg PO once daily; avoid coadministration in PV patients stabilized on ruxolitinib 5 mg PO once daily or interrupt ruxolitinib therapy for the duration of cobicistat use.
    Conivaptan: (Major) Modify the ruxolitinib dosage when coadministered with conivaptan. Subsequent ruxolitinib dose modifications should be made with frequent monitoring of safety and efficacy. Increased ruxolitinib exposure is possible if coadministered with conivaptan. Ruxolitinib is a CYP3A4 substrate; conivaptan is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ruxolitinib Cmax and AUC by 33% and 91%, respectively. Ruxolitinib dosage adjustments when coadministered with a strong CYP3A4 inhibitor are as follows: In patients with myelofibrosis (MF) and platelet counts greater than or equal to 100 x 10^9/L, initiate ruxolitinib at 10 mg PO twice daily; if platelet counts are greater than 50 x 10^9/L and less than 100 x 10^9/L, initiate ruxolitinib at 5 mg PO once daily. In patients with polycythemia vera (PV), stabilized on ruxolitinib doses greater than or equal to 10 mg PO twice daily, decrease the ruxolitinib dose by 50% rounded to the nearest available tablet strength; for PV patients stabilized on ruxolitinib 5 mg PO twice daily, decrease ruxolitinib to 5 mg PO once daily; avoid coadministration in PV patients stabilized on ruxolitinib 5 mg PO once daily or interrupt ruxolitinib therapy for the duration of conivaptan use.
    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) Modify the ruxolitinib dosage when coadministered with darunavir. Subsequent ruxolitinib dose modifications should be made with frequent monitoring of safety and efficacy. Increased ruxolitinib exposure is possible if coadministered with darunavir. Ruxolitinib is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ruxolitinib Cmax and AUC by 33% and 91%, respectively. Ruxolitinib dosage adjustments when coadministered with a strong CYP3A4 inhibitor are as follows: In patients with myelofibrosis (MF) and platelet counts greater than or equal to 100 x 10^9/L, initiate ruxolitinib at 10 mg PO twice daily; if platelet counts are greater than 50 x 10^9/L and less than 100 x 10^9/L, initiate ruxolitinib at 5 mg PO once daily. In patients with polycythemia vera (PV), stabilized on ruxolitinib doses greater than or equal to 10 mg PO twice daily, decrease the ruxolitinib dose by 50% rounded to the nearest available tablet strength; for PV patients stabilized on ruxolitinib 5 mg PO twice daily, decrease ruxolitinib to 5 mg PO once daily; avoid coadministration in PV patients stabilized on ruxolitinib 5 mg PO once daily or interrupt ruxolitinib therapy for the duration of darunavir use.
    Darunavir; Cobicistat: (Major) Modify the ruxolitinib dosage when coadministered with cobicistat. Subsequent ruxolitinib dose modifications should be made with frequent monitoring of safety and efficacy. Increased ruxolitinib exposure is possible if coadministered with cobicistat. Ruxolitinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ruxolitinib Cmax and AUC by 33% and 91%, respectively. Ruxolitinib dosage adjustments when coadministered with a strong CYP3A4 inhibitor are as follows: In patients with myelofibrosis (MF) and platelet counts greater than or equal to 100 x 10^9/L, initiate ruxolitinib at 10 mg PO twice daily; if platelet counts are greater than 50 x 10^9/L and less than 100 x 10^9/L, initiate ruxolitinib at 5 mg PO once daily. In patients with polycythemia vera (PV), stabilized on ruxolitinib doses greater than or equal to 10 mg PO twice daily, decrease the ruxolitinib dose by 50% rounded to the nearest available tablet strength; for PV patients stabilized on ruxolitinib 5 mg PO twice daily, decrease ruxolitinib to 5 mg PO once daily; avoid coadministration in PV patients stabilized on ruxolitinib 5 mg PO once daily or interrupt ruxolitinib therapy for the duration of cobicistat use. (Major) Modify the ruxolitinib dosage when coadministered with darunavir. Subsequent ruxolitinib dose modifications should be made with frequent monitoring of safety and efficacy. Increased ruxolitinib exposure is possible if coadministered with darunavir. Ruxolitinib is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ruxolitinib Cmax and AUC by 33% and 91%, respectively. Ruxolitinib dosage adjustments when coadministered with a strong CYP3A4 inhibitor are as follows: In patients with myelofibrosis (MF) and platelet counts greater than or equal to 100 x 10^9/L, initiate ruxolitinib at 10 mg PO twice daily; if platelet counts are greater than 50 x 10^9/L and less than 100 x 10^9/L, initiate ruxolitinib at 5 mg PO once daily. In patients with polycythemia vera (PV), stabilized on ruxolitinib doses greater than or equal to 10 mg PO twice daily, decrease the ruxolitinib dose by 50% rounded to the nearest available tablet strength; for PV patients stabilized on ruxolitinib 5 mg PO twice daily, decrease ruxolitinib to 5 mg PO once daily; avoid coadministration in PV patients stabilized on ruxolitinib 5 mg PO once daily or interrupt ruxolitinib therapy for the duration of darunavir use.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Modify the ruxolitinib dosage when coadministered with ritonavir. Subsequent ruxolitinib dose modifications should be made with frequent monitoring of safety and efficacy. Increased ruxolitinib exposure is possible if coadministered with ritonavir. Ruxolitinib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ruxolitinib Cmax and AUC by 33% and 91%, respectively. Ruxolitinib dosage adjustments when coadministered with a strong CYP3A4 inhibitor are as follows: In patients with myelofibrosis (MF) and platelet counts greater than or equal to 100 x 10^9/L, initiate ruxolitinib at 10 mg PO twice daily; if platelet counts are greater than 50 x 10^9/L and less than 100 x 10^9/L, initiate ruxolitinib at 5 mg PO once daily. In patients with polycythemia vera (PV), stabilized on ruxolitinib doses greater than or equal to 10 mg PO twice daily, decrease the ruxolitinib dose by 50% rounded to the nearest available tablet strength; for PV patients stabilized on ruxolitinib 5 mg PO twice daily, decrease ruxolitinib to 5 mg PO once daily; avoid coadministration in PV patients stabilized on ruxolitinib 5 mg PO once daily or interrupt ruxolitinib therapy for the duration of ritonavir use.
    Dasatinib: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderate inhibitors of CYP3A4 such as dasatinib, 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.
    Delavirdine: (Major) Modify the ruxolitinib dosage when coadministered with delavirdine. Subsequent ruxolitinib dose modifications should be made with frequent monitoring of safety and efficacy. Increased ruxolitinib exposure is possible if coadministered with delavirdine. Ruxolitinib is a CYP3A4 substrate; delavirdine is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ruxolitinib Cmax and AUC by 33% and 91%, respectively. Ruxolitinib dosage adjustments when coadministered with a strong CYP3A4 inhibitor are as follows: In patients with myelofibrosis (MF) and platelet counts greater than or equal to 100 x 10^9/L, initiate ruxolitinib at 10 mg PO twice daily; if platelet counts are greater than 50 x 10^9/L and less than 100 x 10^9/L, initiate ruxolitinib at 5 mg PO once daily. In patients with polycythemia vera (PV), stabilized on ruxolitinib doses greater than or equal to 10 mg PO twice daily, decrease the ruxolitinib dose by 50% rounded to the nearest available tablet strength; for PV patients stabilized on ruxolitinib 5 mg PO twice daily, decrease ruxolitinib to 5 mg PO once daily; avoid coadministration in PV patients stabilized on ruxolitinib 5 mg PO once daily or interrupt ruxolitinib therapy for the duration of delavirdine use.
    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.
    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.
    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; 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 and fluconazole doses greater than 200 mg PO daily. Modify the ruxolitinib dosage when coadministered with fluconazole doses less than or equal to 200 mg PO daily. Subsequent dose modifications should be made with frequent monitoring of safety and efficacy. Increased ruxolitinib exposure is possible if coadministered with fluconazole. Ruxolitinib is a CYP3A4 and CYP2C9 substrate; fluconazole is a moderate CYP3A4 and strong CYP2C9 inhibitor. The AUC of ruxolitinib is predicted to increase by approximately 100% and 300% following administration with fluconazole 100 mg and 400 mg, respectively. Ruxolitinib dosage adjustments when coadministered with fluconazole doses less than or equal to 200 mg PO daily are as follows: In patients with myelofibrosis (MF) and platelet counts greater than or equal to 100 x 10^9/L, initiate ruxolitinib at 10 mg PO twice daily; if platelet counts are greater than 50 x 10^9/L and less than 100x 10^9/L, initiate ruxolitinib at 5 mg PO once daily. In patients with polycythemia vera (PV), stabilized on ruxolitinib doses greater than or equal to 10 mg PO twice daily, decrease the ruxolitinib dose by 50% rounded to the nearest available tablet strength; for PV patients stabilized on ruxolitinib 5 mg PO twice daily, decrease ruxolitinib to 5 mg PO once daily; avoid coadministration in PV patients stabilized on ruxolitinib 5 mg PO once daily or interrupt ruxolitinib therapy for the duration of fluconazole use.
    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) Modify the ruxolitinib dosage when coadministered with fosamprenavir. Subsequent ruxolitinib dose modifications should be made with frequent monitoring of safety and efficacy. Increased ruxolitinib exposure is possible if coadministered with fosamprenavir. Ruxolitinib is a CYP3A4 substrate; fosamprenavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ruxolitinib Cmax and AUC by 33% and 91%, respectively. Ruxolitinib dosage adjustments when coadministered with a strong CYP3A4 inhibitor are as follows: In patients with myelofibrosis (MF) and platelet counts greater than or equal to 100 x 10^9/L, initiate ruxolitinib at 10 mg PO twice daily; if platelet counts are greater than 50 x 10^9/L and less than 100 x 10^9/L, initiate ruxolitinib at 5 mg PO once daily. In patients with polycythemia vera (PV), stabilized on ruxolitinib doses greater than or equal to 10 mg PO twice daily, decrease the ruxolitinib dose by 50% rounded to the nearest available tablet strength; for PV patients stabilized on ruxolitinib 5 mg PO twice daily, decrease ruxolitinib to 5 mg PO once daily; avoid coadministration in PV patients stabilized on ruxolitinib 5 mg PO once daily or interrupt ruxolitinib therapy for the duration of fosamprenavir use.
    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) Increased ruxolitinib exposure is possible if a patient regularly consumes grapefruit/grapefruit juice. Frequent monitoring of safety and efficacy along with a ruxolitinib dose modification may be advisable in these patients. Ruxolitinib is a CYP3A4 substrate; grapefruit juice is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ruxolitinib Cmax and AUC by 33% and 91%, respectively. Ruxolitinib dosage adjustments when coadministered with a strong CYP3A4 inhibitor are as follows: In patients with myelofibrosis (MF) and platelet counts greater than or equal to 100 x 10^9/L, initiate ruxolitinib at 10 mg twice daily; if platelet counts are greater than 50 x 10^9/L and less than 100x 10^9/L, initiate ruxolitinib at 5 mg once daily. In patients with polycythemia vera (PV), stabilized on ruxolitinib doses greater than or equal to 10 mg twice daily, decrease the ruxolitinib dose by 50% rounded to the nearest available tablet strength; for PV patients stabilized on ruxolitinib 5 mg twice daily, decrease ruxolitinib to 5 mg once daily; avoid coadministration in PV patients stabilized on ruxolitinib 5 mg once daily.
    Griseofulvin: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are CYP3A4 inducers such as griseofulvin, 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.
    Idelalisib: (Major) Modify the ruxolitinib dosage when coadministered with idelalisib. Subsequent ruxolitinib dose modifications should be made with frequent monitoring of safety and efficacy. Increased ruxolitinib exposure is possible if coadministered with idelalisib. Ruxolitinib is a CYP3A4 substrate; idelalisib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ruxolitinib Cmax and AUC by 33% and 91%, respectively. Ruxolitinib dosage adjustments when coadministered with a strong CYP3A4 inhibitor are as follows: In patients with myelofibrosis (MF) and platelet counts greater than or equal to 100 x 10^9/L, initiate ruxolitinib at 10 mg PO twice daily; if platelet counts are greater than 50 x 10^9/L and less than 100 x 10^9/L, initiate ruxolitinib at 5 mg PO once daily. In patients with polycythemia vera (PV), stabilized on ruxolitinib doses greater than or equal to 10 mg PO twice daily, decrease the ruxolitinib dose by 50% rounded to the nearest available tablet strength; for PV patients stabilized on ruxolitinib 5 mg PO twice daily, decrease ruxolitinib to 5 mg PO once daily; avoid coadministration in PV patients stabilized on ruxolitinib 5 mg PO once daily or interrupt ruxolitinib therapy for the duration of idelalisib use.
    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) Modify the ruxolitinib dosage when coadministered with indinavir. Subsequent ruxolitinib dose modifications should be made with frequent monitoring of safety and efficacy. Increased ruxolitinib exposure is possible if coadministered with indinavir. Ruxolitinib is a CYP3A4 substrate; indinavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ruxolitinib Cmax and AUC by 33% and 91%, respectively. Ruxolitinib dosage adjustments when coadministered with a strong CYP3A4 inhibitor are as follows: In patients with myelofibrosis (MF) and platelet counts greater than or equal to 100 x 10^9/L, initiate ruxolitinib at 10 mg PO twice daily; if platelet counts are greater than 50 x 10^9/L and less than 100 x 10^9/L, initiate ruxolitinib at 5 mg PO once daily. In patients with polycythemia vera (PV), stabilized on ruxolitinib doses greater than or equal to 10 mg PO twice daily, decrease the ruxolitinib dose by 50% rounded to the nearest available tablet strength; for PV patients stabilized on ruxolitinib 5 mg PO twice daily, decrease ruxolitinib to 5 mg PO once daily; avoid coadministration in PV patients stabilized on ruxolitinib 5 mg PO once daily or interrupt ruxolitinib therapy for the duration of indinavir use.
    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: (Major) Avoid coadministration of ruxolitinib and isoniazid, INH 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 isoniazid 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; isoniazid 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.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid coadministration of ruxolitinib and isoniazid, INH 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 isoniazid 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; isoniazid 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. (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: (Major) Avoid coadministration of ruxolitinib and isoniazid, INH 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 isoniazid 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; isoniazid 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. (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) Modify the ruxolitinib dosage when coadministered with itraconazole. Subsequent ruxolitinib dose modifications should be made with frequent monitoring of safety and efficacy. Increased ruxolitinib exposure is possible if coadministered with itraconazole. Ruxolitinib is a CYP3A4 substrate; itraconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ruxolitinib Cmax and AUC by 33% and 91%, respectively. Ruxolitinib dosage adjustments when coadministered with a strong CYP3A4 inhibitor are as follows: In patients with myelofibrosis (MF) and platelet counts greater than or equal to 100 x 10^9/L, initiate ruxolitinib at 10 mg PO twice daily; if platelet counts are greater than 50 x 10^9/L and less than 100 x 10^9/L, initiate ruxolitinib at 5 mg PO once daily. In patients with polycythemia vera (PV), stabilized on ruxolitinib doses greater than or equal to 10 mg PO twice daily, decrease the ruxolitinib dose by 50% rounded to the nearest available tablet strength; for PV patients stabilized on ruxolitinib 5 mg PO twice daily, decrease ruxolitinib to 5 mg PO once daily; avoid coadministration in PV patients stabilized on ruxolitinib 5 mg PO once daily or interrupt ruxolitinib therapy for the duration of itraconazole use.
    Ketoconazole: (Major) Modify the ruxolitinib dosage when coadministered with ketoconazole. Subsequent ruxolitinib dose modifications should be made with frequent monitoring of safety and efficacy. Increased ruxolitinib exposure is possible if coadministered with ketoconazole. Ruxolitinib is a CYP3A4 substrate; ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole increased the ruxolitinib Cmax and AUC by 33% and 91%, respectively. Ruxolitinib dosage adjustments when coadministered with a strong CYP3A4 inhibitor are as follows: In patients with myelofibrosis (MF) and platelet counts greater than or equal to 100 x 10^9/L, initiate ruxolitinib at 10 mg PO twice daily; if platelet counts are greater than 50 x 10^9/L and less than 100 x 10^9/L, initiate ruxolitinib at 5 mg PO once daily. In patients with polycythemia vera (PV), stabilized on ruxolitinib doses greater than or equal to 10 mg PO twice daily, decrease the ruxolitinib dose by 50% rounded to the nearest available tablet strength; for PV patients stabilized on ruxolitinib 5 mg PO twice daily, decrease ruxolitinib to 5 mg PO once daily; avoid coadministration in PV patients stabilized on ruxolitinib 5 mg PO once daily or interrupt ruxolitinib therapy for the duration of ketoconazole use.
    Lapatinib: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderate inhibitors of CYP3A4 such as lapatinib, 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.
    Lopinavir; Ritonavir: (Major) Modify the ruxolitinib dosage when coadministered with lopinavir; ritonavir. Subsequent ruxolitinib dose modifications should be made with frequent monitoring of safety and efficacy. Increased ruxolitinib exposure is possible if coadministered with lopinavir; ritonavir. Ruxolitinib is a CYP3A4 substrate; lopinavir; ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ruxolitinib Cmax and AUC by 33% and 91%, respectively. Ruxolitinib dosage adjustments when coadministered with a strong CYP3A4 inhibitor are as follows: In patients with myelofibrosis (MF) and platelet counts greater than or equal to 100 x 10^9/L, initiate ruxolitinib at 10 mg PO twice daily; if platelet counts are greater than 50 x 10^9/L and less than 100 x 10^9/L, initiate ruxolitinib at 5 mg PO once daily. In patients with polycythemia vera (PV), stabilized on ruxolitinib doses greater than or equal to 10 mg PO twice daily, decrease the ruxolitinib dose by 50% rounded to the nearest available tablet strength; for PV patients stabilized on ruxolitinib 5 mg PO twice daily, decrease ruxolitinib to 5 mg PO once daily; avoid coadministration in PV patients stabilized on ruxolitinib 5 mg PO once daily or interrupt ruxolitinib therapy for the duration of lopinavir; ritonavir use. (Major) Modify the ruxolitinib dosage when coadministered with ritonavir. Subsequent ruxolitinib dose modifications should be made with frequent monitoring of safety and efficacy. Increased ruxolitinib exposure is possible if coadministered with ritonavir. Ruxolitinib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ruxolitinib Cmax and AUC by 33% and 91%, respectively. Ruxolitinib dosage adjustments when coadministered with a strong CYP3A4 inhibitor are as follows: In patients with myelofibrosis (MF) and platelet counts greater than or equal to 100 x 10^9/L, initiate ruxolitinib at 10 mg PO twice daily; if platelet counts are greater than 50 x 10^9/L and less than 100 x 10^9/L, initiate ruxolitinib at 5 mg PO once daily. In patients with polycythemia vera (PV), stabilized on ruxolitinib doses greater than or equal to 10 mg PO twice daily, decrease the ruxolitinib dose by 50% rounded to the nearest available tablet strength; for PV patients stabilized on ruxolitinib 5 mg PO twice daily, decrease ruxolitinib to 5 mg PO once daily; avoid coadministration in PV patients stabilized on ruxolitinib 5 mg PO once daily or interrupt ruxolitinib therapy for the duration of ritonavir use.
    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%.
    Metyrapone: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are CYP3A4 inducers such as metyrapone, 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.
    Mifepristone, RU-486: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderate inhibitors of CYP3A4 such as mifepristone, RU-486 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.
    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) Modify the ruxolitinib dosage when coadministered with nefazodone. Subsequent ruxolitinib dose modifications should be made with frequent monitoring of safety and efficacy. Increased ruxolitinib exposure is possible if coadministered with nefazodone. Ruxolitinib is a CYP3A4 substrate; nefazodone is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ruxolitinib Cmax and AUC by 33% and 91%, respectively. Ruxolitinib dosage adjustments when coadministered with a strong CYP3A4 inhibitor are as follows: In patients with myelofibrosis (MF) and platelet counts greater than or equal to 100 x 10^9/L, initiate ruxolitinib at 10 mg PO twice daily; if platelet counts are greater than 50 x 10^9/L and less than 100 x 10^9/L, initiate ruxolitinib at 5 mg PO once daily. In patients with polycythemia vera (PV), stabilized on ruxolitinib doses greater than or equal to 10 mg PO twice daily, decrease the ruxolitinib dose by 50% rounded to the nearest available tablet strength; for PV patients stabilized on ruxolitinib 5 mg PO twice daily, decrease ruxolitinib to 5 mg PO once daily; avoid coadministration in PV patients stabilized on ruxolitinib 5 mg PO once daily or interrupt ruxolitinib therapy for the duration of nefazodone use.
    Nelfinavir: (Major) Modify the ruxolitinib dosage when coadministered with nelfinavir. Subsequent ruxolitinib dose modifications should be made with frequent monitoring of safety and efficacy. Increased ruxolitinib exposure is possible if coadministered with nelfinavir. Ruxolitinib is a CYP3A4 substrate; nelfinavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ruxolitinib Cmax and AUC by 33% and 91%, respectively. Ruxolitinib dosage adjustments when coadministered with a strong CYP3A4 inhibitor are as follows: In patients with myelofibrosis (MF) and platelet counts greater than or equal to 100 x 10^9/L, initiate ruxolitinib at 10 mg PO twice daily; if platelet counts are greater than 50 x 10^9/L and less than 100 x 10^9/L, initiate ruxolitinib at 5 mg PO once daily. In patients with polycythemia vera (PV), stabilized on ruxolitinib doses greater than or equal to 10 mg PO twice daily, decrease the ruxolitinib dose by 50% rounded to the nearest available tablet strength; for PV patients stabilized on ruxolitinib 5 mg PO twice daily, decrease ruxolitinib to 5 mg PO once daily; avoid coadministration in PV patients stabilized on ruxolitinib 5 mg PO once daily or interrupt ruxolitinib therapy for the duration of nelfinavir use.
    Netupitant; 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) Modify the ruxolitinib dosage when coadministered with ritonavir. Subsequent ruxolitinib dose modifications should be made with frequent monitoring of safety and efficacy. Increased ruxolitinib exposure is possible if coadministered with ritonavir. Ruxolitinib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ruxolitinib Cmax and AUC by 33% and 91%, respectively. Ruxolitinib dosage adjustments when coadministered with a strong CYP3A4 inhibitor are as follows: In patients with myelofibrosis (MF) and platelet counts greater than or equal to 100 x 10^9/L, initiate ruxolitinib at 10 mg PO twice daily; if platelet counts are greater than 50 x 10^9/L and less than 100 x 10^9/L, initiate ruxolitinib at 5 mg PO once daily. In patients with polycythemia vera (PV), stabilized on ruxolitinib doses greater than or equal to 10 mg PO twice daily, decrease the ruxolitinib dose by 50% rounded to the nearest available tablet strength; for PV patients stabilized on ruxolitinib 5 mg PO twice daily, decrease ruxolitinib to 5 mg PO once daily; avoid coadministration in PV patients stabilized on ruxolitinib 5 mg PO once daily or interrupt ruxolitinib therapy for the duration of ritonavir use.
    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.
    Oxcarbazepine: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are CYP3A4 inducers such as oxcarbazepine, 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.
    Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
    Pantoprazole: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderate inhibitors of CYP3A4 such as pantoprazole, 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.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    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) Modify the ruxolitinib dosage when coadministered with posaconazole. Subsequent ruxolitinib dose modifications should be made with frequent monitoring of safety and efficacy. Increased ruxolitinib exposure is possible if coadministered with posaconazole. Ruxolitinib is a CYP3A4 substrate; posaconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ruxolitinib Cmax and AUC by 33% and 91%, respectively. Ruxolitinib dosage adjustments when coadministered with a strong CYP3A4 inhibitor are as follows: In patients with myelofibrosis (MF) and platelet counts greater than or equal to 100 x 10^9/L, initiate ruxolitinib at 10 mg PO twice daily; if platelet counts are greater than 50 x 10^9/L and less than 100 x 10^9/L, initiate ruxolitinib at 5 mg PO once daily. In patients with polycythemia vera (PV), stabilized on ruxolitinib doses greater than or equal to 10 mg PO twice daily, decrease the ruxolitinib dose by 50% rounded to the nearest available tablet strength; for PV patients stabilized on ruxolitinib 5 mg PO twice daily, decrease ruxolitinib to 5 mg PO once daily; avoid coadministration in PV patients stabilized on ruxolitinib 5 mg PO once daily or interrupt ruxolitinib therapy for the duration of posaconazole use.
    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: (Moderate) Coadministration of ribociclib, a moderate CYP3A4 inhibitor, may increase the exposure to ruxolitinib, a CYP3A4 substrate. Although concurrent use of a moderate CYP3A4 inhibitor is not expected to result in clinically significant increases in ruxolitinib serum concentrations, caution is advised if a moderate CYP3A4 inhibitor is added to a stable dose of ruxolitinib, especially in patients with low platelet counts, as thrombocytopenia is the dose-limiting toxicity of ruxolitinib.
    Ribociclib; Letrozole: (Moderate) Coadministration of ribociclib, a moderate CYP3A4 inhibitor, may increase the exposure to ruxolitinib, a CYP3A4 substrate. Although concurrent use of a moderate CYP3A4 inhibitor is not expected to result in clinically significant increases in ruxolitinib serum concentrations, caution is advised if a moderate CYP3A4 inhibitor is added to a stable dose of ruxolitinib, especially in patients with low platelet counts, as thrombocytopenia is the dose-limiting toxicity of ruxolitinib.
    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) Modify the ruxolitinib dosage when coadministered with ritonavir. Subsequent ruxolitinib dose modifications should be made with frequent monitoring of safety and efficacy. Increased ruxolitinib exposure is possible if coadministered with ritonavir. Ruxolitinib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ruxolitinib Cmax and AUC by 33% and 91%, respectively. Ruxolitinib dosage adjustments when coadministered with a strong CYP3A4 inhibitor are as follows: In patients with myelofibrosis (MF) and platelet counts greater than or equal to 100 x 10^9/L, initiate ruxolitinib at 10 mg PO twice daily; if platelet counts are greater than 50 x 10^9/L and less than 100 x 10^9/L, initiate ruxolitinib at 5 mg PO once daily. In patients with polycythemia vera (PV), stabilized on ruxolitinib doses greater than or equal to 10 mg PO twice daily, decrease the ruxolitinib dose by 50% rounded to the nearest available tablet strength; for PV patients stabilized on ruxolitinib 5 mg PO twice daily, decrease ruxolitinib to 5 mg PO once daily; avoid coadministration in PV patients stabilized on ruxolitinib 5 mg PO once daily or interrupt ruxolitinib therapy for the duration of ritonavir use.
    Saquinavir: (Major) Modify the ruxolitinib dosage when coadministered with saquinavir. Subsequent ruxolitinib dose modifications should be made with frequent monitoring of safety and efficacy. Increased ruxolitinib exposure is possible if coadministered with saquinavir. Ruxolitinib is a CYP3A4 substrate; saquinavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ruxolitinib Cmax and AUC by 33% and 91%, respectively. Ruxolitinib dosage adjustments when coadministered with a strong CYP3A4 inhibitor are as follows: In patients with myelofibrosis (MF) and platelet counts greater than or equal to 100 x 10^9/L, initiate ruxolitinib at 10 mg PO twice daily; if platelet counts are greater than 50 x 10^9/L and less than 100 x 10^9/L, initiate ruxolitinib at 5 mg PO once daily. In patients with polycythemia vera (PV), stabilized on ruxolitinib doses greater than or equal to 10 mg PO twice daily, decrease the ruxolitinib dose by 50% rounded to the nearest available tablet strength; for PV patients stabilized on ruxolitinib 5 mg PO twice daily, decrease ruxolitinib to 5 mg PO once daily; avoid coadministration in PV patients stabilized on ruxolitinib 5 mg PO once daily or interrupt ruxolitinib therapy for the duration of saquinavir use.
    Sipuleucel-T: (Major) Concomitant use of sipuleucel-T and antineoplastic agents should be avoided. Concurrent administration of antineoplastic agents with the leukapheresis procedure that occurs prior to sipuleucel-T infusion has not been studied. Sipuleucel-T stimulates the immune system and patients receiving antineoplastic agents may have a diminished response to sipuleucel-T. When appropriate, consider discontinuing or reducing the dose of antineoplastic agents prior to initiating therapy with sipuleucel-T.
    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%.
    Streptogramins: (Major) Modify the ruxolitinib dosage when coadministered with dalfopristin; quinupristin. Subsequent ruxolitinib dose modifications should be made with frequent monitoring of safety and efficacy. Increased ruxolitinib exposure is possible if coadministered with dalfopristin; quinupristin. Ruxolitinib is a CYP3A4 substrate; dalfopristin; quinupristin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ruxolitinib Cmax and AUC by 33% and 91%, respectively. Ruxolitinib dosage adjustments when coadministered with a strong CYP3A4 inhibitor are as follows: In patients with myelofibrosis (MF) and platelet counts greater than or equal to 100 x 10^9/L, initiate ruxolitinib at 10 mg PO twice daily; if platelet counts are greater than 50 x 10^9/L and less than 100 x 10^9/L, initiate ruxolitinib at 5 mg PO once daily. In patients with polycythemia vera (PV), stabilized on ruxolitinib doses greater than or equal to 10 mg PO twice daily, decrease the ruxolitinib dose by 50% rounded to the nearest available tablet strength; for PV patients stabilized on ruxolitinib 5 mg PO twice daily, decrease ruxolitinib to 5 mg PO once daily; avoid coadministration in PV patients stabilized on ruxolitinib 5 mg PO once daily or interrupt ruxolitinib therapy for the duration of dalfopristin; quinupristin use.
    Tamoxifen: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderate inhibitors of CYP3A4 such as tamoxifen, 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.
    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) Modify the ruxolitinib dosage when coadministered with telithromycin. Subsequent ruxolitinib dose modifications should be made with frequent monitoring of safety and efficacy. Increased ruxolitinib exposure is possible if coadministered with telithromycin. Ruxolitinib is a CYP3A4 substrate; telithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ruxolitinib Cmax and AUC by 33% and 91%, respectively. Ruxolitinib dosage adjustments when coadministered with a strong CYP3A4 inhibitor are as follows: In patients with myelofibrosis (MF) and platelet counts greater than or equal to 100 x 10^9/L, initiate ruxolitinib at 10 mg PO twice daily; if platelet counts are greater than 50 x 10^9/L and less than 100 x 10^9/L, initiate ruxolitinib at 5 mg PO once daily. In patients with polycythemia vera (PV), stabilized on ruxolitinib doses greater than or equal to 10 mg PO twice daily, decrease the ruxolitinib dose by 50% rounded to the nearest available tablet strength; for PV patients stabilized on ruxolitinib 5 mg PO twice daily, decrease ruxolitinib to 5 mg PO once daily; avoid coadministration in PV patients stabilized on ruxolitinib 5 mg PO once daily or interrupt ruxolitinib therapy for the duration of telithromycin use.
    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) Modify the ruxolitinib dosage when coadministered with tipranavir. Subsequent ruxolitinib dose modifications should be made with frequent monitoring of safety and efficacy. Increased ruxolitinib exposure is possible if coadministered with tipranavir. Ruxolitinib is a CYP3A4 substrate; tipranavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ruxolitinib Cmax and AUC by 33% and 91%, respectively. Ruxolitinib dosage adjustments when coadministered with a strong CYP3A4 inhibitor are as follows: In patients with myelofibrosis (MF) and platelet counts greater than or equal to 100 x 10^9/L, initiate ruxolitinib at 10 mg PO twice daily; if platelet counts are greater than 50 x 10^9/L and less than 100 x 10^9/L, initiate ruxolitinib at 5 mg PO once daily. In patients with polycythemia vera (PV), stabilized on ruxolitinib doses greater than or equal to 10 mg PO twice daily, decrease the ruxolitinib dose by 50% rounded to the nearest available tablet strength; for PV patients stabilized on ruxolitinib 5 mg PO twice daily, decrease ruxolitinib to 5 mg PO once daily; avoid coadministration in PV patients stabilized on ruxolitinib 5 mg PO once daily or interrupt ruxolitinib therapy for the duration of tipranavir use.
    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.
    Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
    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) Modify the ruxolitinib dosage when coadministered with voriconazole. Subsequent ruxolitinib dose modifications should be made with frequent monitoring of safety and efficacy. Increased ruxolitinib exposure is possible if coadministered with voriconazole. Ruxolitinib is a CYP3A4 substrate; voriconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ruxolitinib Cmax and AUC by 33% and 91%, respectively. Ruxolitinib dosage adjustments when coadministered with a strong CYP3A4 inhibitor are as follows: In patients with myelofibrosis (MF) and platelet counts greater than or equal to 100 x 10^9/L, initiate ruxolitinib at 10 mg PO twice daily; if platelet counts are greater than 50 x 10^9/L and less than 100 x 10^9/L, initiate ruxolitinib at 5 mg PO once daily. In patients with polycythemia vera (PV), stabilized on ruxolitinib doses greater than or equal to 10 mg PO twice daily, decrease the ruxolitinib dose by 50% rounded to the nearest available tablet strength; for PV patients stabilized on ruxolitinib 5 mg PO twice daily, decrease ruxolitinib to 5 mg PO once daily; avoid coadministration in PV patients stabilized on ruxolitinib 5 mg PO once daily or interrupt ruxolitinib therapy for the duration of voriconazole use.
    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 to the nucleus, which leads to gene expression modulation. Normally, JAK1 and JAK2 mediate the signaling of a number of 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.

    PHARMACOKINETICS

    Ruxolitinib is administered orally. The mean steady-state Vd in patients with myelofibrosis and polycythemia vera is 72 L (intersubject variability of 29%) and 75 L (intersubject variability of 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 (intersubject variability of 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.