Ruxolitinib Indications/Dosageexpand all | collapse all

Labeled

Off-Label

† Off-label indication

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

Oral dosage

Adults

Efficacy has not been established. Due to broad immunosuppressive effects, the National Institutes of Health (NIH) COVID-19 treatment guidelines recommend against the use of JAK inhibitors outside of clinical trials.[65314] The following dosingregimens are being evaluated: 5 mg PO twice daily [65302]; 5 mg PO twice daily for 14 to 28 days [65356]; 5 mg PO every12 hours for 7 days, then 10 mg PO every 12 hours for a total of 14 days [65304]; 10 mg PO twice daily for 14 days, then 5mg PO twice daily for 2 days, then 5 mg PO once daily for 1 day [65303]; 10 mg PO twice daily for 14 days [65301]; and 10to 20 mg PO twice daily for 7 days [65300].

Children and Adolescents 12 years and older

Efficacy has not been established. Due to broad immunosuppressive effects, the National Institutes of Health (NIH) COVID-19 treatment guidelines recommend against the use of JAK inhibitors outside of clinical trials.[65314] The following dosingregimens are being evaluated: 5 mg PO twice daily for 14 to 28 days [65356]; 10 mg PO twice daily for 14 days, then 5 mgPO twice daily for 2 days, then 5 mg PO once daily for 1 day.[65303]

For the treatment of polycythemia vera

The FDA has designated ruxolitinib as an orphan drug for the treatment of polycythemia vera.

for the treatment of polycythemia vera in patients who have had an inadequate response to or are intolerantof hydroxyurea

graft-versus-host disease (GVHD)myelofibrosis

polycythemia vera

coronavirus disease 2019 (COVID-19) † severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) infection †

Oral dosage

Adults

Initially, 10 mg orally twice daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may benecessary; review drug interactions. Titrate the ruxolitinib dosage based on response and toxicity. After the first 4 weeks oftherapy, 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 definedas the continued need for phlebotomy, WBC count greater than the upper limit of normal (ULN), platelet count greater thanthe ULN, and/or a palpable spleen that is reduced by less than 25% from baseline; a platelet count 140 x 109 cells/L ormore; hemoglobin 12 grams/dL or more; and ANC 1.5 x 109 cells/L or more.[46782] A significantly higher response rate atweek 32 was achieved with ruxolitinib compared with investigator selected best available therapy (20.9% vs. 0.9%; p lessthan 0.001) in patients with polycythemia vera who had an inadequate response to or unacceptable side effects fromhydroxyurea in a multinational, randomized, phase 3 trial (n = 222; the RESPONSE trial); additionally, this response wasmaintained at week 48 (19.1% vs. 0.9%; p less than 0.001). Eligible patients had a spleen volume of 450 cm3 or more andphlebotomy dependence, defined as 2 or more phlebotomies within 24 weeks before screening and at least 1 phlebotomywithin 16 weeks before screening. Best available therapy consisted of single-agent anagrelide (7.1%), low-dosehydroxyurea (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 baselineand hematocrit control (eligible for no more than 1 phlebotomy between randomization and study week 8 and not eligible fora phlebotomy during study weeks 8 to 32). The complete hematologic remission (CHR) rate (defined as hematocrit control,a platelet count of 400 x 109 cells/L or less, and a white blood cell count of 10 x 109 cells/L or less) at week 32 wassignificantly higher with ruxolitinib compared with best standard therapy (23.6% vs. 8.9%, p = 0.003). Crossover to theruxolitinib arm occurred in 85.7% of patients in the best standard therapy arm at or after week 32.[58808] In an extendedanalysis at week 80, 76% of patients who achieved a response at 32 weeks maintained a response, and 58% of patientswho achieved a CHR at 32 weeks maintained this response.[46782]

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 treatmentinterruptions. Consider risk to benefits ratio in patients maintained on 5 mg PO twice daily (minimum dose) as long-term use at thisdose has failed to produce clinical response.[46782]

Oral dosage

Adults with initial platelet count more than 200 x 10(9) cells/L

20 mg PO twice daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary;review drug interactions. After the first 4 weeks of therapy, and no more frequently than every 2 weeks, the dose may beincreased in 5 mg twice daily increments to a maximum dose of 25 mg PO twice daily if the patient meets all of the followingcriteria: 1) failure to achieve a reduction from baseline palpable spleen length of 50% or a 35% reduction in spleen volumeas measured by CT or MRI; 2) platelet count more than 125 x 109 cells/L at treatment week 4 and platelet counts never lessthan 100 x 109 cells/L; 3) absolute neutrophil count (ANC) more than 0.75 x 109 cells/L. Discontinue ruxolitinib if spleen sizereduction or symptom improvement is not observed after 6 months of therapy. When discontinuing therapy for any reasonother than thrombocytopenia, consider gradually tapering dose by 5 mg twice daily each week.[46782]

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

15 mg PO twice daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary;review drug interactions. After the first 4 weeks of therapy, and no more frequently than every 2 weeks, the dose may beincreased in 5 mg twice daily increments to a maximum dose of 25 mg PO twice daily if the patient meets all of the followingcriteria: 1) failure to achieve a reduction from baseline palpable spleen length of 50% or a 35% reduction in spleen volumeas 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 sizereduction or symptom improvement is not observed after 6 months of therapy. When discontinuing therapy for any reasonother than thrombocytopenia, consider gradually tapering dose by 5 mg twice daily each week.[46782]

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

5 mg PO twice daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary;review drug interactions. After the first 4 weeks of therapy, and no more frequently than every 2 weeks, the dose may beincreased in 5 mg daily increments to a maximum dose of 10 mg PO twice daily if the patient meets all of the followingcriteria: 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 adverseevent or hematological toxicity in the prior 4 weeks. Consider risk to benefits ratio in patients continuing treatment for morethan 6 months. Discontinue ruxolitinib if spleen size reduction or symptom improvement is not observed after 6 months oftherapy.[46782]

For the treatment of graft-versus-host disease (GVHD)

NOTE: The FDA has designated ruxolitinib as an orphan drug for the treatment of GVHD.

for the treatment of steroid-refractory acute GVHD

Oral dosage

Adults

Initially, 5 mg orally twice daily. After 3 days, consider increasing the dosage to 10 mg orally twice daily if the absoluteneutrophil count and platelet counts are not decreased by at least 50%. Coadministration of certain drugs may need to beavoided or dosage adjustments may be necessary; review drug interactions. Therapy interruption and/or a dosageadjustment may be necessary in patients who develop toxicity. After 6 months, consider tapering therapy every 8 weeks by1 dose level (i.e., 10 mg twice daily to 5 mg twice daily; 5mg twice daily to 5 mg once daily) in responding patients who havediscontinued therapeutic doses of corticosteroids. Consider retreatment in patients who have a recurrence of acute GVHDsigns or symptoms during or after the taper. The day 28 overall response rate was 57.1% in patients (median age, 57 years;range, 18 to 72 years) with grade 2, 3, or 4 steroid-refractory GVHD following an allogeneic hematopoietic stem-celltransplant in a multicenter, single-arm, phase 2 trial (n = 49; the REACH 1 trial). The median duration of response was 16days.[46782]

Children 12 years and Adolescents

Initially, 5 mg orally twice daily. After 3 days, consider increasing the dosage to 10 mg orally twice daily if the absoluteneutrophil count and platelet counts are not decreased by at least 50%. Coadministration of certain drugs may need to beavoided or dosage adjustments may be necessary; review drug interactions. Therapy interruption and/or a dosageadjustment may be necessary in patients who develop toxicity. After 6 months, consider tapering therapy every 8 weeks by1 dose level (i.e., 10 mg twice daily to 5 mg twice daily; 5mg twice daily to 5 mg once daily) in responding patients who havediscontinued therapeutic doses of corticosteroids. Consider retreatment in patients who have a recurrence of acute GVHDsigns or symptoms during or after the taper. Use of ruxolitinib in pediatric patients with acute GVHD is supported byevidence from a single-arm, phase 2 trial in 49 adult patients and additional pharmacokinetic and safety data in this patientpopulation.[46782]

Therapeutic Drug Monitoring

Management of Treatment-Related Toxicity

Myelofibrosis:

Thrombocytopenia

NOTE: Hold ruxolitinib regardless of platelet count for bleeding that requires intervention. In this situation, treatment may beresumed once bleeding has resolved; consider a lower dose if the underlying cause of bleeding persists.

Baseline platelet count of 100 X 109 cells/L or higher:

Current platelet count of 125 X 109 cells/L or higher: No dose adjustment. If restarting after a treatment interruption forthrombocytopenia, begin with a dose at least 5 mg twice daily less than the dose when held (maximum 20 mg twicedaily).Current platelet count of 100 to 124 X 109 cells/L: Decrease dose by 5 mg twice daily; no dose adjustment if originaldose was 15 mg twice daily or less. If restarting after a treatment interruption for thrombocytopenia, begin with a doseat least 5 mg twice daily less than the dose when held (maximum 15 mg twice daily).Current platelet count of 75 to 99 X 109 cells/L: Decrease dose to 10 mg twice daily; no dose adjustment if originaldose was 10 mg twice daily or less. If restarting after a treatment interruption for thrombocytopenia, begin with a doseat least 5 mg twice daily less than the dose when held (maximum 10 mg twice daily; if stable for at least 2 weeks, mayincrease to 15 mg twice daily).Current platelet count of 50 to 74 X 109 cells/L: Decrease dose to 5 mg twice daily; no dose adjustment if original dosewas 5 mg twice daily. If restarting after a treatment interruption for thrombocytopenia, begin with a dose at least 5 mgtwice daily less than the dose when held (maximum 5 mg twice daily; if stable for at least 2 weeks, may increase to 10mg twice daily).Current platelet count of less than 50 X 109 cells/L: Hold ruxolitinib. May restart treatment (dose dependent on plateletcount) when platelets recover to greater than 50 X 109 cells/L.

Baseline platelet count of 50 to 99 X 109 cells/L:

Current platelet count of 25 to 35 X 109 cells/L and platelet decline during prior 4 weeks is less than 20%: Decreasetotal daily dose by 5 mg; for patients on 5 mg daily before platelet decline, continue same dose.Current platelet count of 25 to 35 X 109 cells/L and platelet decline during prior 4 weeks is 20% or higher: Decreasedose by 5 mg twice daily; for patients taking 5 mg twice daily, decrease dose to 5 mg daily; for patients taking 5 mgdaily, continue same dose.Current platelet count of less than 25 X 109 cells/L: Hold ruxolitinib. May restart therapy when platelets greater than 35X 109 cells/L, starting with a dose at least 5 mg twice daily less than the dose when held, or 5 mg daily (whichever isless).

Neutropenia

For an absolute neutrophil count (ANC) of less than 0.5 X 109 cells/L: Hold ruxolitinib. When ANC greater than 0.75 X 109

cells/L, may restart treatment at 5 mg twice daily below the largest dose in the week prior to holding therapy, or 5 mg daily(whichever is higher).

Polycythemia Vera:

Hematologic Toxicity

Hemoglobin level of 12 grams/dL or higher AND a platelet count of 100 X 109 cells/L or higher: No dosage adjustmentrequired.Hemoglobin level of 10 to 11 grams/dL AND a platelet count of 75 to 99 X 109 cells/L: Consider a dosage reduction.Hemoglobin level of 8 to 9 grams/dL OR a platelet count of 50 to 74 X 109 cells/L: Reduce the current ruxolitinibdosage by 5 mg twice daily; if the current dosage is 5 mg twice daily, reduce the dosage to 5 mg once daily.Hemoglobin level of less than 8 grams/dL OR a platelet count of less than 50 X 109 cells/L OR an ANC of less than 1 X109 cells/L: Hold ruxolitinib until hematologic parameters are recovered to acceptable levels.

Determining the Maximum Restarting Dosage:

NOTE: Following therapy interruption, the final titrated daily dosage should not exceed 5 mg less than the held dosage. Theexception is for dose interruption after phlebotomy-associated anemia; the maximum total daily dose in this case would be 25 mgtwice daily.

Hemoglobin level of 8 to 9 grams/dL OR a platelet count of 50 to 74 X 109 cells/L OR an ANC of 1 to 1.4 X 109 cells/L:The restarting ruxolitinib dosage is 5 mg twice daily (may be increased by 5 mg twice daily if hematologic parametersare still stable after 2 weeks) or no more than 5 mg twice daily less than the held dosage.Hemoglobin level of 10 to 11 grams/dL OR a platelet count of 75 to 99 X 109 cells/L OR an ANC of 1.5 to 2 X 109

cells/L: The restarting ruxolitinib dosage is 10 mg twice daily (may be increased by 5 mg twice daily if hematologicparameters are still stable after 2 weeks) or no more than 5 mg twice daily less than the held dosage.Hemoglobin level of 12 grams/dL or higher OR a platelet count of 100 X 109 cells/L or higher OR an ANC of greaterthan 2 X 109 cells/L: The restarting ruxolitinib dosage is 15 mg twice daily (may be increased by 5 mg twice daily ifhematologic parameters are still stable after 2 weeks) or no more than 5 mg twice daily less than the held dosage.Patients receiving 5 mg twice daily when therapy was held: may restart at 5 mg once or 5 mg twice daily when thehemoglobin level is 10 grams/dL or higher the platelet count is 75 X 109 cells/L or higher, AND the ANC is 1.5 X 109

cells/L or higher.

Graft-Versus-Host Disease (GVHD):

Hematologic Toxicity

Clinically significant thrombocytopenia after supportive measures: Reduce the current ruxolitinib dosage by 5 mg twice daily; ifthe current dosage is 5 mg twice daily, reduce the dosage to 5 mg once daily. Resume therapy at the prior dosage when the plateletcounts recover to previous values.ANC less than 1 X 109 cells/L (considered related to therapy): Hold ruxolitinib for up to 14 days and then resume at a reduceddosage (i.e., from 10 mg twice daily to 5 mg twice daily or from 5mg twice daily to 5 mg once daily).

Dosage Adjustments with strong CYP3A4 inhibitors or fluconazole doses 200 mg or less (Myelofibrosis or PolycythemiaVera)

NOTE: Avoid the use of ruxolitinib with fluconazole doses greater than 200 mg/day.

Stable on ruxolitinib 10 mg PO twice daily or more: Reduce ruxolitinib dose by 50%, rounding up to the closest available tabletstrength. Additional dose modification should be made with careful monitoring of safety and efficacy.

Stable on ruxolitinib 5 mg PO twice daily: Reduce ruxolitinib dose to 5 mg PO once daily. Additional dose modification should bemade with careful monitoring of safety and efficacy.

Stable on ruxolitinib 5 mg PO once daily: Avoid the use of strong CYP3A4 inhibitors or fluconazole treatment. Alternatively,interrupt ruxolitinib therapy for the duration of strong CYP3A4 inhibitor or fluconazole use.[46782]

Maximum Dosage Limits

Adults

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

Geriatric

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

Adolescents

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

Children

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

11 years and younger: Safety and efficacy have not been established.

Infants

Safety and efficacy have not been established.

Neonates

Safety and efficacy have not been established.

Patients with Hepatic Impairment Dosing

Myelofibrosis

Mild, moderate, or severe (Child-Pugh class A, B, C) hepatic impairment at baseline:

Platelet count greater than 150 X 109 cells/L: No dosage adjustment needed.Platelet count of 100 to 150 X 109 cells/L: Initial dosage, 10 mg PO twice daily.Platelet count of 50 to 99 X 109 cells/L: Initial dosage, 5 mg PO once daily.Platelet count less than 50 X 109 cells/L: Avoid use.

Polycythemia Vera (any platelet count)

Mild, moderate, or severe (Child-Pugh class A, B, C) hepatic impairment at baseline: Initial dosage, 5 mg PO twice daily.

Graft-Versus-Host Disease (GVHD) (any platelet count)

Mild, moderate, or severe (NCI criteria) hepatic impairment at baseline: No dosage adjustment needed in patients with no liverGVHD; monitor blood counts more frequently and consider an initial dosage of 5 mg PO once daily in patients with grade 3 or 4liver GVHD.

Management of Treatment-Related Toxicity in Patients with GVHD

No liver GVHD

Total bilirubin level of 3- to 5-times the upper limit of normal (ULN): Continue therapy at a reduced dosage (i.e., from 10 mg twicedaily to 5 mg twice daily or from 5mg twice daily to 5 mg once daily) until toxicity recovery.Total bilirubin level of greater than 5- to 10-times the ULN: Hold ruxolitinib for up to 14 days; resume therapy at the currentdosage when the bilirubin level is 1.5-times the ULN or less.Total bilirubin level of greater than 10-times the ULN: Hold ruxolitinib for up to 14 days; resume therapy at a reduced dosage (i.e.,from 10 mg twice daily to 5 mg twice daily or from 5mg twice daily to 5 mg once daily) when the bilirubin level is 1.5-times theULN or less.

Liver GVHD:

Total bilirubin level greater than 3-times the ULN: Continue therapy at a reduced dosage (i.e., from 10 mg twice daily to 5 mgtwice daily or from 5mg twice daily to 5 mg once daily) until toxicity recovery.[46782]

Patients with Renal Impairment Dosing

Myelofibrosis

Creatinine Clearance (CrCl) 60 mL/min or higher: No dosage adjustment needed.

CrCl 15 to 59 mL/min:

Platelet count greater than 150 X 109 cells/L: No dosage adjustment needed.Platelet count of 100 to 150 X 109 cells/L: Initial dosage, 10 mg PO twice daily.Platelet count of 50 to 99 X 109 cells/L: Initial dosage, 5 mg PO once daily.

Platelet count less than 50 X 109 cells/L: Avoid use.

CrCl less than 15 mL/min, end-stage renal disease (ESRD) on intermittent dialysis:

Platelet count greater than 200 X 109 cells/L: Initial dose, 20 mg PO once after dialysis. Make dose modificationsbased 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 basedon frequent monitoring of safety and efficacy.

CrCl less than 15 mL/min, ESRD and NOT on dialysis: Avoid use.

Polycythemia Vera (any platelet count)

CrCl 60 mL/min or higher: No dosage adjustment needed.

CrCl 15 to 59 mL/min: Initial dosage, 5 mg PO twice daily.

CrCl less than 15 mL/min, ESRD on intermittent dialysis: Initial dose, 10 mg PO once after dialysis. Make dose modificationsbased on frequent monitoring of safety and efficacy.

CrCl less than 15 mL/min, ESRD and NOT on dialysis: Avoid use.

Graft-Versus-Host Disease (any platelet count)

CrCl 60 mL/min or higher: No dosage adjustment needed.

CrCl 15 to 59 mL/min: Initial dosage, 5 mg PO once daily.

CrCl less than 15 mL/min, ESRD on intermittent dialysis: Initial dose, 5 mg PO once after dialysis. Make dose modificationsbased on frequent monitoring of safety and efficacy.

CrCl less than 15 mL/min, ESRD and NOT on dialysis: Avoid use.[46782]

† Off-label indication

Revision Date: 04/29/2020 10:52:16 AM

References

46782 – Jakafi (ruxolitinib) tablets package insert. Wilmington, DE: Incyte Corporation; 2020 Jan.

58808 – Vannucchi AM, Kiladjian JJ, Griesshammer M, et al. Ruxolitinib versus standard therapy for the treatment ofpolycythemia vera. N Engl J Med 2015;372(5):426-435.

65300 – Hochhaus A. Ruxolitinib in COVID-19 Patients With Defined Hyperinflammation (RuxCoFlam). Retrieved April 20,2020. Available on the World Wide Web: https://clinicaltrials.gov/ct2/show/NCT04338958?term=Ruxolitinib&cond=COVID&draw=2&rank=3

65301 – University of Colorado, Denver. Safety and Efficacy of Ruxolitinib for COVID-19. Retrieved April 20, 2020. Availableon the World Wide Web: https://clinicaltrials.gov/ct2/show/NCT04348071?term=Ruxolitinib&cond=COVID&draw=2&rank=1

65302 – Grupo Cooperativo de Hemopatias Malignas. Treatment of SARS Caused by COVID-19 With Ruxolitinib. RetrievedApril 20, 2020. Available on the World Wide Web: https://clinicaltrials.gov/ct2/show/NCT04334044?term=Ruxolitinib&cond=COVID&draw=2&rank=2

65303 – University Health Network, Toronto. Study of the Efficacy and Safety of Ruxolitinib to Treat COVID-19 Pneumonia.Retrieved April 20, 2020. Available on the World Wide Web: https://clinicaltrials.gov/ct2/show/NCT04331665?term=Ruxolitinib&cond=COVID&draw=2&rank=5

65304 – Fundacion de investigacion HM. Study of Ruxolitinib Plus Simvastatin in the Prevention and Treatment of RespiratoryFailure of COVID-19. (Ruxo-Sim-20). Retrieved April 20, 2020. Available on the World Wide Web:https://clinicaltrials.gov/ct2/show/NCT04348695?term=Ruxolitinib&cond=COVID&draw=2&rank=6

65314 – COVID-19 Treatment Guidelines Panel. Coronavirus Diseases 2019 (COVID-19) Treatment Guidelines. NationalInstitutes of Health. Accessed May 12, 2020. Available at on the World Wide Web at: https://covid19treatmentguidelines.nih.gov/.

65356 – Novartis Pharmaceuticals. Phase 3 Randomized, Double-blind, Placebo-controlled Multi-center Study to Assess theEfficacy and Safety of Ruxolitinib in Patients With COVID-19 Associated Cytokine Storm (RUXCOVID). Retrieved April 29,2020. Available on the World Wide Web at: https://clinicaltrials.gov/ct2/show/NCT04362137?term=ruxcovid&draw=2&rank=1

How Supplied

Ruxolitinib Oral tablet

Jakafi 5mg Tablet (50881-0005) (Incyte Corporation)

Jakafi 10mg Tablet (50881-0010) (Incyte Corporation)

Jakafi 15mg Tablet (50881-0015) (Incyte Corporation)

Jakafi 20mg Tablet (50881-0020) (Incyte Corporation)

Ruxolitinib Oral tablet

Jakafi 25mg Tablet (50881-0025) (Incyte Corporation)

Description/Classification

Description

Ruxolitinib is a kinase inhibitor that inhibits Janus Associated Kinases (JAKs), JAK1 and JAK2. It is indicated for the treatment ofadults with intermediate- or high-risk myelofibrosis (e.g., primary myelofibrosis, post-polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis), adults with polycythemia vera who have had an inadequate response to or are intolerantof hydroxyurea, and patients 12 years and older with steroid-refractory acute graft-versus-host disease. Hematologic toxicity andinfection have been reported with ruxolitinib therapy.[46782]

Updates for coronavirus disease 2019 (COVID-19):

The use of JAK inhibitors (including ruxolitinib) is being evaluated for the treatment of patients with COVID-19 associatedcytokine storm.[65300][65301][65302][65303][65304][65305][65356] An emergency Expanded Access Program has been initiated toallow eligible patients with COVID-19 associated cytokine storm access to ruxolitinib; however, the National Institutes of Health(NIH) COVID-19 treatment guidelines recommend against the use of JAK inhibitors outside of clinical trials because of theirbroad immunosuppressive effects.[65314]

Classifications

Antineoplastic and Immunomodulating AgentsAntineoplastics

Small Molecule Antineoplastic Janus Associated Kinase (JAKs) Inhibitors

Revision Date: 04/29/2020 01:28:03 PM

References

46782 – Jakafi (ruxolitinib) tablets package insert. Wilmington, DE: Incyte Corporation; 2020 Jan.

65300 – Hochhaus A. Ruxolitinib in COVID-19 Patients With Defined Hyperinflammation (RuxCoFlam). Retrieved April 20,2020. Available on the World Wide Web: https://clinicaltrials.gov/ct2/show/NCT04338958?term=Ruxolitinib&cond=COVID&draw=2&rank=3

65301 – University of Colorado, Denver. Safety and Efficacy of Ruxolitinib for COVID-19. Retrieved April 20, 2020. Availableon the World Wide Web: https://clinicaltrials.gov/ct2/show/NCT04348071?term=Ruxolitinib&cond=COVID&draw=2&rank=1

65302 – Grupo Cooperativo de Hemopatias Malignas. Treatment of SARS Caused by COVID-19 With Ruxolitinib. RetrievedApril 20, 2020. Available on the World Wide Web: https://clinicaltrials.gov/ct2/show/NCT04334044?

term=Ruxolitinib&cond=COVID&draw=2&rank=2

65303 – University Health Network, Toronto. Study of the Efficacy and Safety of Ruxolitinib to Treat COVID-19 Pneumonia.Retrieved April 20, 2020. Available on the World Wide Web: https://clinicaltrials.gov/ct2/show/NCT04331665?term=Ruxolitinib&cond=COVID&draw=2&rank=5

65304 – Fundacion de investigacion HM. Study of Ruxolitinib Plus Simvastatin in the Prevention and Treatment of RespiratoryFailure of COVID-19. (Ruxo-Sim-20). Retrieved April 20, 2020. Available on the World Wide Web:https://clinicaltrials.gov/ct2/show/NCT04348695?term=Ruxolitinib&cond=COVID&draw=2&rank=6

65305 – Novartis Pharmaceuticals. Ruxolitinib Managed Access Program (MAP) for Patients Diagnosed With Severe/Very SevereCOVID-19 Illness. Retrieved April 20, 2020. Available on the World Wide Web:https://clinicaltrials.gov/ct2/show/NCT04337359?term=Ruxolitinib&cond=COVID&draw=2&rank=4

65314 – COVID-19 Treatment Guidelines Panel. Coronavirus Diseases 2019 (COVID-19) Treatment Guidelines. NationalInstitutes of Health. Accessed May 12, 2020. Available at on the World Wide Web at: https://covid19treatmentguidelines.nih.gov/.

65356 – Novartis Pharmaceuticals. Phase 3 Randomized, Double-blind, Placebo-controlled Multi-center Study to Assess theEfficacy and Safety of Ruxolitinib in Patients With COVID-19 Associated Cytokine Storm (RUXCOVID). Retrieved April 29,2020. Available on the World Wide Web at: https://clinicaltrials.gov/ct2/show/NCT04362137?term=ruxcovid&draw=2&rank=1

Administration Information

General Administration Information

For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Oral Administration

Administer with or without food.[46782]

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 nasogastrictube.

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[46782].

Revision Date: 12/07/2016 03:47:23 PM

Copyright 2004-2015 by Lawrence A. Trissel. All Rights Reserved.

References

46782 – Jakafi (ruxolitinib) tablets package insert. Wilmington, DE: Incyte Corporation; 2020 Jan.

Adverse Reactions

abdominal pain abdominal pain

Hematologic toxicity including anemia (72% to 96%), neutropenia (3% to 58%), and thrombocytopenia (27% to 75%) has beenreported in patients who received ruxolitinib in clinical trials. Obtain complete blood counts prior to therapy, every 2 to 4 weeksuntil the dose is stabilized, and then as clinically indicated. Therapy interruption, a dosage adjustment, and/or blood or platelettransfusions may be necessary in patients who develop severe myelosuppression. Thrombocytopenia (70% vs. 31%), anemia (96%vs. 87%), and neutropenia (19% vs. 4%) occurred in more often in patients with myelofibrosis who received ruxolitinib (n = 155)compared with placebo (n = 151) in a randomized, phase 3 study. Additionally, grade 3 or 4 thrombocytopenia (13%), anemia(45%), and neutropenia (7%) were reported in ruxolitinib-treated patients. Thrombocytopenia (27% grade 3 or 4, less than 6%),anemia (72%; grade 3 or 4, less than 1%), and neutropenia (3%; grade 3 or 4, less than 1%) were reported in patients withpolycythemia vera who received ruxolitinib (n = 110) in a randomized, phase 3 study. Thrombocytopenia (75% grade 3 or 4,61%), anemia (75% grade 3 or 4, 45%), and neutropenia (58% grade 3 or 4, 40%) were reported in patients with acute graft-versus-host disease who received ruxolitinib in a single-arm study (n = 71).[46782]

Bacterial, mycobacterial, fungal, and viral infections have been reported in patients who received ruxolitinib in clinical trials.Monitor patients for signs and symptoms of infection, especially for tuberculosis and herpes zoster. Initiate treatment (i.e.,antibiotic, antifungal, or antiviral medication) promptly in patients who develop an infection. Herpes zoster/post-herpetic neuralgia(2% vs. less than 1%) and urinary tract infection (9% vs. 5%) occurred more often in patients with myelofibrosis who receivedruxolitinib (n = 155) compared with placebo (n = 151) in a randomized, phase 3 study. Urinary tract infection included theconditions of cystitis, urosepsis, kidney infection, pyuria, bacteria present in urine, and nitrite present in urine. Herpes zosterinfection/post-herpetic neuralgia (6%) and urinary tract infection (less than 6%) were reported in patients with polycythemia verawho received ruxolitinib (n = 110) in a randomized, phase 3 study; grade 3 and 4 herpes zoster infection occurred in less than 1%of ruxolitinib-treated patients. Infection (55% grade 3 or 4, 41%) including bacterial infections (32% grade 3 or 4, 28%) and viralinfections (31% grade 3 or 4, 14%) were reported in patients with acute graft-versus-host disease who received ruxolitinib in asingle-arm study (n = 71).[46782]

Bleeding events have been reported in 6% to 49% of patients who received ruxolitinib in clinical trials. In patients withmyelofibrosis, hold therapy if bleeding occurs; resume ruxolitinib after the bleeding event has resolved and consider a dosereduction if the underlying cause persists. Bruising/ecchymosis occurred in 23% of patients with myelofibrosis who receivedruxolitinib (n = 155) compared with 15% of patients who received placebo (n = 151) in a randomized, phase 3 study. Additionally,grade 3 bruising/ecchymosis was reported in less than 1% of ruxolitinib-treated patients. Bruising included the conditions of

anemiaanemiaarthralgiaastheniableedingconstipationcoughcystitisdiarrheadiarrheadisseminated intravascular coagulation (DIC)dizzinessdizzinessdyspneadyspneaecchymosisecchymosisedemaedemaelevated hepatic enzymeselevated hepatic enzymesepistaxisfatiguefatiguefeverflatulenceheadacheheadachehematomahematomahypercholesterolemia

hypercholesterolemiahypertensionhypertensionhypertriglyceridemiahypertriglyceridemiahypotensioninfectioninfectionleukoencephalopathynauseaneutropenianeutropenianew primary malignancyperipheral edemapetechiaepharyngitispruritusprurituspurpurapyuriapyuriarashrespiratory depressionthrombocytopeniathrombocytopeniathrombosisvertigovertigoweight gainweight gain

contusion, hematoma (injection site hematoma, periorbital hematoma, vessel puncture site hematoma), petechiae, and purpura.Epistaxis was reported in 6% of patients with polycythemia vera who received ruxolitinib (n = 110) in a randomized, phase 3study. Bleeding was reported in 49% of patients with acute graft-versus-host disease who received ruxolitinib in a single-arm study(n = 71); grade 3 or 4 bleeding occurred in 20% of patients.[46782]

Dizziness and headache have been reported in patients who received ruxolitinib in clinical trials. Dizziness (18% vs. 7%) andheadache (15% vs. 5%) occurred more often in patients with myelofibrosis who received ruxolitinib (n = 155) compared withplacebo (n = 151) in a randomized, phase 3 study; additionally, grade 3 dizziness was reported in less than 1% of ruxolitinib-treated patients. Dizziness included the conditions of balance disorder, labyrinthitis, Meniere's Disease, postural dizziness, andvertigo. Dizziness (15%) and headache (16%) were reported in patients with polycythemia vera who received ruxolitinib (n = 110)in a randomized, phase 3 study; additionally, grade 3 and 4 headache occurred in less than 1% of ruxolitinib-treated patients.Headache (21%; grade 3 or 4, 4%) and dizziness (16%) were reported in patients with acute graft-versus-host disease whoreceived ruxolitinib in a single-arm study (n = 71).[46782]

Weight gain occurred in 7% of patients with myelofibrosis who received ruxolitinib (n = 155) compared with 1% of patients whoreceived placebo (n = 151) in a randomized, phase 3 study. Additionally, grade 3 weight gain was reported in less than 1% ofruxolitinib-treated patients. Weight gain was reported in less than 6% of patients with polycythemia vera who received ruxolitinib(n = 110) in a randomized, phase 3 study.[46782]

Flatulence occurred in 5% of patients with myelofibrosis who received ruxolitinib (n = 155) compared with less than 1% ofpatients who received placebo (n = 151) in a randomized, phase 3 study. Other gastrointestinal toxicity including abdominal pain(all grade, 15%; grade 3 and 4, less than 1%), constipation (8%), diarrhea (15%), and nausea (6%) was reported in patients withpolycythemia vera who received ruxolitinib (n = 110) in a randomized, phase 3 study. Diarrhea was reported in 24% of patientswith acute graft-versus-host disease who received ruxolitinib in a single-arm study (n = 71); grade 3 or 4 diarrhea occurred in 7%of patients.[46782]

Hepatotoxicity has been reported in patients who received ruxolitinib in clinical trials; avoid ruxolitinib in patients withmyelofibrosis who have a platelet count of less than 50 X 109 cells/L and hepatic impairment. Patients with GVHD who develophepatotoxicity may require therapy interruption or a dosage reduction. New or worsening grade 1 elevated hepatic enzymesincluding increased ALT (25% vs. 7%) and AST (17% vs. 6%) levels occurred more often in patients with myelofibrosis whoreceived ruxolitinib (n = 155) compared with placebo (n = 151) in a randomized, phase 3 study; grade 2 and grade 3 increasedALT levels (1% and 1%) and grade 2 increased AST levels (less tgab1%) were reported in ruxolitinib-treated patients.Additionally, increased ALT levels (all grade, 25%; grade 3, less than 1%) and increased AST levels (23%) were reported inpatients with polycythemia vera who received ruxolitinib (n = 110) in a randomized, phase 3 study. Increased ALT (48%; grade 3or 4, 8%) and AST (48%; grade 3 or 4, 6%) levels were reported in patients with acute graft-versus-host disease who receivedruxolitinib in a single-arm study (n = 71).[46782]

Progressive multifocal leukoencephalopathy (PML) has been reported in patients with myelofibrosis who received ruxolitinibtreatment. Consider PML, an opportunistic viral infection of the brain caused by reactivated latent John Cunningham (JC) virus, inthe differential diagnosis of patients with new or worsening neurological, cognitive, or behavioral signs or symptoms. Suchsymptoms include changes in mood, vision, speech, or gait, abnormal thinking, unusual behavior, confusion, memory impairment,and decreased strength on one side of the body. PML is usually diagnosed by brain imaging, cerebrospinal fluid testing for JC viralDNA by polymerase chain reaction, and/or brain biopsy. If PML is suspected, stop treatment with ruxolitinib and evaluate;consider consultation with a neurologist and/or infectious disease specialist. Unfortunately, PML is usually fatal or leads to severedisability, and there are no known effective treatments.[46782]

There have been reports of patients stopping ruxolitinib during an acute illness after which the patient's clinical course continuedto worsen. However, it has not been established whether discontinuation of therapy contributed to the clinical course in thesepatients. Some patients have experienced fever, respiratory depression, hypotension, disseminated intravascular coagulation (DIC),or multi-organ failure after ruxolitinib discontinuation. Following abrupt discontinuation of ruxolitinib, symptoms ofmyeloproliferative disease generally return to pretreatment levels in about 1 week. For these reasons, gradual tapering of the doseis recommended with the exception of patients who develop thrombocytopenia or neutropenia. If one or more of these symptomsoccur after discontinuation of, or while tapering the dose of ruxolitinib, evaluate for and treat any illness and consider restarting orincreasing the dose of ruxolitinib.[46782]

New primary malignancy has been reported with ruxolitinib therapy, specifically non-melanoma skin cancer such as basal cell,squamous cell, and Merkel cell carcinoma. Periodic skin examinations are recommended; advise patients to report any new orchanging lesions.[46782]

Hypercholesterolemia (e.g., elevated total cholesterol, elevated low-density lipoprotein (LDL) cholesterol) andhypertriglyceridemia have been reported in patients who received ruxolitinib in clinical studies. Obtain a lipid panel and assesstriglyceride levels about 8 to 12 weeks after starting ruxolitinib; monitor and treat patients with high cholesterol or triglyceridesaccording to clinical guidelines. New or worsening grade 1 hypercholesterolemia occurred in 17% of patients with myelofibrosis

who received ruxolitinib (n = 155) compared with less than 1% of patients who received placebo (n = 151) in a randomized, phase3 study; grade 2 hypercholesterolemia was reported in less than 1% of ruxolitinib-treated patients. Additionally,hypercholesterolemia (35%) and hypertriglyceridemia (15%) were reported in patients with polycythemia vera who receivedruxolitinib (n = 110) in a randomized, phase 3 study. Hypertriglyceridemia was reported in 11% of patients with acute graft-versus-host disease who received ruxolitinib in a single-arm study (n = 71); grade 3 or 4 hypertriglyceridemia occurred in 1% of patients.[46782]

Asthenia (7%) and fatigue (15%) were reported in patients with polycythemia vera who received ruxolitinib (n = 110) in arandomized, phase 3 study. Fatigue was reported in 37% of patients with acute graft-versus-host disease who received ruxolitinibin a single-arm study (n = 71); grade 3 or 4 fatigue occurred in 14% of patients.[46782]

Pruritus was reported in 14% of patients with polycythemia vera who received ruxolitinib (n = 110) in a randomized, phase 3study; additionally, grade 3 and 4 pruritus occurred in less than 1% of ruxolitinib-treated patients.[46782]

Cough (8%), dyspnea/exertional dyspnea (all grade, 13%; grade 3 and 4, 3%) and naso-pharyngitis (9%) were reported in patientswith polycythemia vera who received ruxolitinib (n = 110) in a randomized, phase 3 study. Dyspnea was reported in 32% ofpatients with acute graft-versus-host disease who received ruxolitinib in a single-arm study (n = 71); grade 3 or 4 dyspnea occurredin 7% of patients.[46782]

Arthralgia (7%) and muscle spasms (12%; grade 3 and 4, less than 1%) were reported in patients with polycythemia vera whoreceived ruxolitinib (n = 110) in a randomized, phase 3 study.[46782]

Edema including peripheral edema was reported in 8% of patients with polycythemia vera who received ruxolitinib (n = 110) in arandomized, phase 3 study. Edema was reported in 51% of patients with acute graft-versus-host disease who received ruxolitinib ina single-arm study (n = 71); grade 3 or 4 edema occurred in 13% of patients.[46782]

Hypertension was reported in less than 6% of patients with polycythemia vera who received ruxolitinib (n = 110) in a randomized,phase 3 study. Hypertension was reported in 20% of patients with acute graft-versus-host disease who received ruxolitinib in asingle-arm study (n = 71); grade 3 or 4 hypertension occurred in 13% of patients. [46782]

Rash was reported in 23% of patients with acute graft-versus-host disease who received ruxolitinib in a single-arm study (n = 71);grade 3 or 4 rash occurred in 3% of patients.[46782]

Thrombosis was reported in 25% of patients with acute graft-versus-host disease who received ruxolitinib in a single-arm study (n= 71); grade 3 or 4 thrombosis occurred in 11% of patients.[46782]

Revision Date: 06/18/2019 03:50:11 PM

References

46782 – Jakafi (ruxolitinib) tablets package insert. Wilmington, DE: Incyte Corporation; 2020 Jan.

Contraindications/Precautions

Absolute contraindications are italicized.

abrupt discontinuationanemiableedingbreast-feedingfungal infectionhepatic diseasehepatitishypercholesterolemiahypertriglyceridemiainfectionmycobacterial infection

neutropenianew primary malignancypregnancyprogressive multifocal leukoencephalopathyrenal diseaserenal impairmentskin cancerthrombocytopeniatuberculosisviral infection

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

Serious infections such as tuberculosis (TB), progressive multifocal leukoencephalopathy (PML), bacterial and mycobacterialinfection, fungal infection, and viral infection (e.g., herpes zoster) have been reported with ruxolitinib therapy; do not startruxolitinib in patients with an active infection. Monitor patients for signs and symptoms of infection during therapy and managepromptly. Administer prophylactic antibiotics as appropriate per clinical guidelines. Discontinue treatment if PML is suspected ordiagnosed. Increased hepatitis B virus (HBV) viral load with or without elevated transaminase levels has occurred in patients withchronic HBV infection; monitor and treat these patients according to clinical guidelines. Evaluate patients for risk of TB and testpatients at higher risk for latent TB; consult with a physician with expertise in treating TB prior to starting ruxolitinib in patientswith active or latent TB. Risk factors include history of residence or travel to countries with a high prevalence of TB, close contactwith a person with active TB, and a history of active or latent TB where an adequate course of treatment cannot be confirmed.[46782]

Patients with preexisting hepatic disease may be at increased risk for ruxolitinib-induced adverse events. An initial ruxolitinibdosage reduction may be necessary in patients with baseline hepatic impairment; avoid ruxolitinib in patients with myelofibrosiswho have a platelet count of less than 50 X 109 cells/L and hepatic impairment. Monitor complete blood counts more frequently inpatients with severe liver graft-versus-host disease (GVHD). Patients with GVHD who develop hepatotoxicity may require therapyinterruption or a dosage reduction.[46782]

Patients with preexisting renal disease may be at increased risk for ruxolitinib-induced adverse events. An initial ruxolitinib dosagereduction may be necessary in patients with baseline renal impairment; avoid ruxolitinib in patients with end-stage renal disease(Creatinine clearance less than 15 mL/min) who do not require dialysis.[46782]

Avoid abrupt discontinuation of ruxolitinib when stopping the drug for reasons other than thrombocytopenia. Followingdiscontinuation 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 continuedto worsen. However, it has not been established whether discontinuation of therapy contributed to the clinical course in thesepatients. Some patients have experienced fever, respiratory distress, hypotension, DIC, or multi-organ failure after ruxolitinibdiscontinuation. For these reasons, gradual tapering of the dose is recommended. If one or more of these symptoms occur afterdiscontinuation of, or while tapering the dose of ruxolitinib, evaluate for and treat any illness and consider restarting or increasingthe dose of ruxolitinib.[46782]

New primary malignancy has been reported with ruxolitinib therapy, specifically non-melanoma skin cancer such as basal cell,squamous cell, and Merkel cell carcinoma. Periodic skin examinations are recommended. Advise patients to report any history ofskin cancer or if they develop any new or changing lesions during ruxolitinib therapy.[46782]

Hypercholesterolemia (e.g., elevated total cholesterol, elevated low-density lipoprotein (LDL) cholesterol) andhypertriglyceridemia have been reported with ruxolitinib therapy. The effect of ruxolitinib-induced high cholesterol or hightriglycerides on cardiovascular morbidity and mortality is not known. Obtain a lipid panel and assess triglyceride levels about 8 to12 weeks after starting ruxolitinib; monitor and treat patients with high cholesterol or triglycerides according to clinical guidelines.[46782]

No well-controlled studies have been conducted evaluating the use of ruxolitinib in pregnant women. Consider the benefits versusthe risk of therapy prior to administering ruxolitinib during pregnancy. Animal data involving rats and rabbits administered dosesof 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, rabbitsexperienced an increase in late resorptions when exposed to the 60 mg/kg/day dose.[46782]

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 milkproduction. Because there is a potential for adverse reactions in nursing infants, women should discontinue breast-feeding duringruxolitinib therapy and for at least 2 weeks after the last dose.[46782]

Revision Date: 06/19/2019 12:01:17 PM

References

46782 – Jakafi (ruxolitinib) tablets package insert. Wilmington, DE: Incyte Corporation; 2020 Jan.

Mechanism of Action

Ruxolitinib is a kinase inhibitor that inhibits Janus Associated Kinases (JAKs) JAK1 and JAK2. JAK signaling involvesrecruitment of signal transducers and activators of transcription to cytokine receptors and activation and subsequent localization ofsignal transducers and activators of transcription (STAT) to the nucleus, which leads to gene expression modulation. Normally,JAK1 and JAK2 mediate the signaling of several cytokines and growth factors that are important for hematopoiesis and immunefunction.

Dysregulated JAK1 and JAK2 signaling has been noted in myelofibrosis and polycythemia vera, which are myeloproliferativeneoplasms. In a mouse model of JAK2V617F-positive myeloproliferative neoplasm, oral administration of ruxolitinib preventedsplenomegaly, preferentially decreased JAK2V617F mutant cells in the spleen, and decreased circulating inflammatory cytokinessuch as TNF-alpha and IL-6.

The JAK-STAT signaling pathway regulates the development, proliferation, and activation of many types of immune cells requiredfor graft-versus-host disease (GVHD) pathogenesis. Decreased expression of inflammatory cytokines in colon homogenates andreduced immune-cell infiltration in the colon were observed in a mouse model of acute GVHD.[46782]

Revision Date: 06/03/2019 12:22:09 PM

References

46782 – Jakafi (ruxolitinib) tablets package insert. Wilmington, DE: Incyte Corporation; 2020 Jan.

Pharmacokinetics

Ruxolitinib is administered orally. The mean steady-state Vd in patients with myelofibrosis and polycythemia vera is 72 L(coefficient of variation (CV), 29%) and 75 L (CV, 23%), respectively. In vitro, it is approximately 97% bound to plasma proteins,mostly to albumin. Ruxolitinib is metabolized primarily by CYP3A4 forming active metabolites (e.g., M18 metabolite). After asingle oral radiolabeled dose to healthy adults, elimination was predominately through metabolism with 74% of radioactivityexcreted in urine and 22% excreted in feces. Unchanged drug accounted for less than 1% of the excreted total radioactivity. Themean elimination half-life of ruxolitinib is approximately 3 hours, and the mean half-life of ruxolitinib plus metabolites isapproximately 5.8 hours. Ruxolitinib clearance was 12.7 L/hour in patients with polycythemia vera (CV, 42%).[46782]

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 alterthe 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 ofCYP1A2, 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.[46782]

Route-Specific Pharmacokinetics

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 plasmaconcentrations are achieved within 1 to 2 hours after oral administration. Mean ruxolitinib Cmax and systemicexposure increased proportionally over a single dose range of 5 to 200 mg. Over this ruxolitinib dosage range, the meanCmax values ranged from 205 to 7,100 nanoMolar (nM) and the AUC values ranged from 862 to 30,700 nM x hour.[46782]

Special Populations

Hepatic Impairment

Following a single oral 25-mg dose, the mean ruxolitinib systemic exposure was increased by 1.9-fold in patients withmild hepatic impairment (Child-Pugh class A), by 1.3-fold in patients with moderate hepatic impairment (Child-Pughclass B), and by 1.7-fold in subjects with severe hepatic impairment (Child-Pugh class C) compared with data fromsubjects with normal hepatic function. Any degree of hepatic impairment does not clinically impact thepharmacokinetic parameters of ruxolitinib in patients with acute graft-versus-host disease.[46782]

Renal Impairment

Following a single oral 25-mg dose, the total systemic exposure of ruxolitinib and its active metabolites was increasedby 1.3-fold in subjects with mild renal impairment (CrCl, 60 to 89 mL/min), by 1.5-fold in subjects with moderate renalimpairment (CrCl, 30 to 59 mL/min), by 1.9-fold in subjects with severe renal impairment (CrCl, 15 to 29 mL/min),and by 1.6-fold in subjects with end-stage renal disease after dialysis compared with data from subjects with normalrenal function (CrCl , 90 mL/min or greater). Ruxolitinib is not removed by dialysis; however, it is not known if someactive metabolites are removed by dialysis.[46782]

Geriatric

Age does not clinically impact the pharmacokinetic parameters of ruxolitinib.[46782]

Gender Differences

Among healthy patients, no significant differences in ruxolitinib pharmacokinetic parameters were observed withregard to gender. In patients with myelofibrosis, clearance was 17.7 L/hr for women and 22.1 L/hr for men; intersubjectvariability was 39%.[46782]

Ethnic Differences

Ethnicity does not clinically impact the pharmacokinetic parameters of ruxolitinib.[46782]

Obesity

Weight does not clinically impact the pharmacokinetic parameters of ruxolitinib.[46782]

Revision Date: 06/03/2019 12:25:12 PM

References

46782 – Jakafi (ruxolitinib) tablets package insert. Wilmington, DE: Incyte Corporation; 2020 Jan.

Pregnancy/Breast-feeding

Pregnancy

No well-controlled studies have been conducted evaluating the use of ruxolitinib in pregnant women. Consider the benefits versusthe risk of therapy prior to administering ruxolitinib during pregnancy. Animal data involving rats and rabbits administered dosesof 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, rabbitsexperienced an increase in late resorptions when exposed to the 60 mg/kg/day dose.[46782]

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 milkproduction. Because there is a potential for adverse reactions in nursing infants, women should discontinue breast-feeding duringruxolitinib therapy and for at least 2 weeks after the last dose.[46782]

Revision Date: 06/19/2019 12:01:17 PM

References

46782 – Jakafi (ruxolitinib) tablets package insert. Wilmington, DE: Incyte Corporation; 2020 Jan.

Interactions

Level 1 (Severe)

Level 2 (Major)

Level 3 (Moderate)

Upadacitinib

Amoxicillin; Clarithromycin; LansoprazoleAmoxicillin; Clarithromycin; OmeprazoleAtazanavirAtazanavir; CobicistatCeritinibChloramphenicolClarithromycinClozapineCobicistatConivaptanDarunavirDarunavir; CobicistatDarunavir; Cobicistat; Emtricitabine; TenofoviralafenamideDasabuvir; Ombitasvir; Paritaprevir; RitonavirDelavirdineElvitegravir; Cobicistat; Emtricitabine; TenofovirAlafenamideElvitegravir; Cobicistat; Emtricitabine; TenofovirDisoproxil FumarateFluconazole

Fosamprenavirgrapefruit juiceIdelalisibIndinavirItraconazoleKetoconazoleLopinavir; RitonavirMifepristoneNefazodoneNelfinavirOmbitasvir; Paritaprevir; RitonavirPosaconazoleRibociclibRibociclib; LetrozoleRitonavirSaquinavirTelaprevirTelithromycinTipranavirTucatinibVoriconazole

Aldesleukin, IL-2AmiodaroneAmprenavirApalutamideAprepitant, FosaprepitantAtropine; Hyoscyamine; Phenobarbital; ScopolamineBelladonna Alkaloids; Ergotamine; PhenobarbitalBexaroteneBosentanCarbamazepineCimetidineDanazolDexamethasoneDiltiazemDronedarone

Drospirenone; Ethinyl EstradiolDrospirenone; Ethinyl Estradiol; LevomefolateEfavirenzEfavirenz; Emtricitabine; TenofovirEfavirenz; Lamivudine; Tenofovir Disoproxil FumarateElbasvir; GrazoprevirEnzalutamideErythromycinErythromycin; SulfisoxazoleEthinyl EstradiolEthinyl Estradiol; DesogestrelEthinyl Estradiol; Ethynodiol DiacetateEthinyl Estradiol; EtonogestrelEthinyl Estradiol; LevonorgestrelEthinyl Estradiol; Levonorgestrel; Ferrous bisglycinate

Level 4 (Minor)

Aldesleukin, IL-2: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderate inhibitors ofCYP3A4 such as aldesleukin, IL-2 a dose adjustment is not necessary, but monitoring patients for toxicity may be prudent. Therewas an 8% and 27% increase in the Cmax and AUC of a single dose of ruxolitinib 10 mg, respectively, when the dose was givenafter a short course of erythromycin 500 mg PO twice daily for 4 days. The change in the pharmacodynamic marker pSTAT3inhibition was consistent with the increase in exposure. [2356] [34540] [46782]

Amiodarone: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderate inhibitors ofCYP3A4 such as amiodarone, a dose adjustment is not necessary, but monitoring patients for toxicity may be prudent. There wasan 8% and 27% increase in the Cmax and AUC of a single dose of ruxolitinib 10 mg, respectively, when the dose was given after ashort course of erythromycin 500 mg PO twice daily for 4 days. The change in the pharmacodynamic marker pSTAT3 inhibitionwas consistent with the increase in exposure. [46782] [4950]

Amoxicillin; Clarithromycin; Lansoprazole: (Major) Reduce the ruxolitinib dosage during coadministration with clarithromycin inpatients with myelofibrosis (MF) or polycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur; no doseadjustments are necessary for patients with graft-versus-host disease. In MF patients, reduce the initial dose to 10 mg PO twicedaily for platelet count of 100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. InPV patients, reduce the initial dose to 5 mg PO twice daily. Avoid the use of clarithromycin or interrupt ruxolitinib treatmentduring clarithromycin use in MF or PV patients who are stable on a ruxolitinib dose of 5 mg PO once daily. In MF or PV patientsstable on ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by 50%; in patients stable on ruxolitinib dose of 5 mg POtwice daily, reduce ruxolitinib to 5 mg PO once daily. Additional dose modifications should be made with frequent monitoring ofsafety and efficacy. Ruxolitinib is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. [28238] [46782]

Amoxicillin; Clarithromycin; Omeprazole: (Major) Reduce the ruxolitinib dosage during coadministration with clarithromycin inpatients with myelofibrosis (MF) or polycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur; no doseadjustments are necessary for patients with graft-versus-host disease. In MF patients, reduce the initial dose to 10 mg PO twicedaily for platelet count of 100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. InPV patients, reduce the initial dose to 5 mg PO twice daily. Avoid the use of clarithromycin or interrupt ruxolitinib treatmentduring clarithromycin use in MF or PV patients who are stable on a ruxolitinib dose of 5 mg PO once daily. In MF or PV patientsstable on ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by 50%; in patients stable on ruxolitinib dose of 5 mg POtwice daily, reduce ruxolitinib to 5 mg PO once daily. Additional dose modifications should be made with frequent monitoring ofsafety and efficacy. Ruxolitinib is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. [28238] [46782]

Amprenavir: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderate inhibitors ofCYP3A4 such as amprenavir, a dose adjustment is not necessary, but monitoring patients for toxicity may be prudent. There wasan 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

Ethinyl Estradiol; Levonorgestrel; Folic Acid;LevomefolateEthinyl Estradiol; NorelgestrominEthinyl Estradiol; NorethindroneEthinyl Estradiol; Norethindrone AcetateEthinyl Estradiol; Norethindrone Acetate; FerrousfumarateEthinyl Estradiol; Norethindrone; Ferrous fumarateEthinyl Estradiol; NorgestimateEthinyl Estradiol; NorgestrelEtravirineFluoxetineFluoxetine; OlanzapineFlutamideFluvoxamineFosphenytoinImatinibIsavuconazoniumIsoniazid, INH; Pyrazinamide, PZA; RifampinIsoniazid, INH; Rifampin

LetermovirLumacaftor; IvacaftorLumacaftor; IvacaftorMitotaneModafinilNafcillinNetupitant, Fosnetupitant; PalonosetronNevirapineNicardipineOctreotideOritavancinPhenobarbitalPhenytoinPrimidoneRanolazineRifampinSegesterone Acetate; Ethinyl EstradiolSt. John's Wort, Hypericum perforatumTelotristat EthylZafirlukast

Trandolapril; Verapamil Verapamil

short course of erythromycin 500 mg PO twice daily for 4 days. The change in the pharmacodynamic marker pSTAT3 inhibitionwas consistent with the increase in exposure. [46782]

Apalutamide: (Moderate) Monitor patients frequently and adjust the ruxolitinib dose based on safety and efficacy ifcoadministered with apalutamide; decreased ruxolitinib exposure is possible. Ruxolitinib is a CYP3A4 substrate and apalutamideis 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%. [46782] [62874]

Aprepitant, Fosaprepitant: (Moderate) Use caution if ruxolitinib and aprepitant, fosaprepitant are used concurrently, and monitorfor 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 moderateCYP3A4 inhibitor and inducer and may increase plasma concentrations of ruxolitinib. For example, a 5-day oral aprepitantregimen 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 thendecreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect ofaprepitant 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 mgintravenous 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 onday 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% onday 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 effectsof aprepitant on tolbutamide were not considered significant. [30676] [40027] [46782]

Atazanavir: (Major) Reduce the ruxolitinib dosage during coadministration with atazanavir in patients with myelofibrosis (MF) orpolycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur; no dose adjustments are necessary for patientswith graft-versus-host disease. In MF patients, reduce the initial dose to 10 mg PO twice daily for platelet count of 100,000cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients, reduce the initialdose to 5 mg PO twice daily. Avoid the use of atazanavir in MF or PV patients who are stable on a ruxolitinib dose of 5 mg POonce daily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by 50%; in patientsstable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. Additional dose modifications shouldbe made with frequent monitoring of safety and efficacy. Ruxolitinib is a CYP3A4 substrate; atazanavir is a strong CYP3A4inhibitor. [28142] [46782]

Atazanavir; Cobicistat: (Major) Reduce the ruxolitinib dosage during coadministration with atazanavir in patients withmyelofibrosis (MF) or polycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur; no dose adjustments arenecessary for patients with graft-versus-host disease. In MF patients, reduce the initial dose to 10 mg PO twice daily for plateletcount of 100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients,reduce the initial dose to 5 mg PO twice daily. Avoid the use of atazanavir in MF or PV patients who are stable on a ruxolitinibdose of 5 mg PO once daily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by50%; in patients stable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. Additional dosemodifications should be made with frequent monitoring of safety and efficacy. Ruxolitinib is a CYP3A4 substrate; atazanavir is astrong CYP3A4 inhibitor. [28142] [46782] (Major) Reduce the ruxolitinib dosage during coadministration with cobicistat in patientswith myelofibrosis (MF) or polycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur; no dose adjustmentsare necessary for patients with graft-versus-host disease. In MF patients, reduce the initial dose to 10 mg PO twice daily forplatelet count of 100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PVpatients, reduce the initial dose to 5 mg PO twice daily. Avoid the use of cobicistat in MF or PV patients who are stable on aruxolitinib dose of 5 mg PO once daily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily or more, reducedose by 50%; in patients stable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. Additionaldose modifications should be made with frequent monitoring of safety and efficacy. Ruxolitinib is a CYP3A4 substrate; cobicistatis a strong CYP3A4 inhibitor. [46782] [58000]

Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Moderate) Monitor patients frequently and adjust the ruxolitinib dosebased on safety and efficacy if coadministered with phenobarbital; decreased ruxolitinib exposure is possible. Ruxolitinib is aCYP3A4 substrate; phenobarbital is a strong CYP3A4 inducer. Coadministration of another strong CYP3A4 inducer decreasedruxolitinib Cmax and AUC by 32% and 61%, respectively. The relative exposure to ruxolitinib's active metabolites increasedapproximately 100%. [22005] [46782] [55436] [57046] [57048] [57080]

Belladonna Alkaloids; Ergotamine; Phenobarbital: (Moderate) Monitor patients frequently and adjust the ruxolitinib dose based onsafety and efficacy if coadministered with phenobarbital; decreased ruxolitinib exposure is possible. Ruxolitinib is a CYP3A4substrate; 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 approximately100%. [22005] [46782] [55436] [57046] [57048] [57080]

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. TheCmax and AUC of a single 50 mg dose of ruxolitinib was decreased by 32% and 61%, respectively, after rifampin 600 mg oncedaily was administered for 10 days. The relative exposure to ruxolitinib's active metabolites increased by about 100%, which maypartially explain the reported disproportionate 10% reduction in the pharmacodynamic marker pSTAT3 inhibition. [46782] [4791]

Bosentan: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are CYP3A4 inducers such as bosentan, adose adjustment is not necessary, but closely monitor patients and titrate the ruxolitinib dose based on safety and efficacy. TheCmax and AUC of a single 50 mg dose of ruxolitinib was decreased by 32% and 61%, respectively, after rifampin 600 mg oncedaily was administered for 10 days. The relative exposure to ruxolitinib's active metabolites increased by about 100%, which maypartially explain the reported disproportionate 10% reduction in the pharmacodynamic marker pSTAT3 inhibition. [46782] [5226]

Carbamazepine: (Moderate) Monitor patients frequently and adjust the ruxolitinib dose based on safety and efficacy ifcoadministered 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 andAUC by 32% and 61%, respectively. The relative exposure to ruxolitinib's active metabolites increased approximately 100%. [41237] [46782]

Ceritinib: (Major) Reduce the ruxolitinib dosage during coadministration with ceritinib in patients with myelofibrosis (MF) orpolycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur; no dose adjustments are necessary for patientswith graft-versus-host disease. In MF patients, reduce the initial dose to 10 mg PO twice daily for platelet count of 100,000cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients, reduce the initialdose to 5 mg PO twice daily. Avoid the use of ceritinib in MF or PV patients who are stable on a ruxolitinib dose of 5 mg PO oncedaily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by 50%; in patients stable onruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. Additional dose modifications should be madewith frequent monitoring of safety and efficacy. Ruxolitinib is a CYP3A4 substrate; ceritinib is a strong CYP3A4 inhibitor. [46782][57094]

Chloramphenicol: (Major) Reduce the ruxolitinib dosage during coadministration with chloramphenicol in patients withmyelofibrosis (MF) or polycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur; no dose adjustments arenecessary for patients with graft-versus-host disease. In MF patients, reduce the initial dose to 10 mg PO twice daily for plateletcount of 100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients,reduce the initial dose to 5 mg PO twice daily. Avoid the use of chloramphenicol or interrupt ruxolitinib treatment duringchloramphenicol use in MF or PV patients who are stable on a ruxolitinib dose of 5 mg PO once daily. In MF or PV patients stableon ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by 50%; in patients stable on ruxolitinib dose of 5 mg PO twicedaily, reduce ruxolitinib to 5 mg PO once daily. Additional dose modifications should be made with frequent monitoring of safetyand efficacy. Ruxolitinib is a CYP3A4 substrate; chloramphenicol is a strong CYP3A4 inhibitor. [29624] [46782]

Cimetidine: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderate inhibitors ofCYP3A4 such as cimetidine, a dose adjustment is not necessary, but monitoring patients for toxicity may be prudent. There was an8% and 27% increase in the Cmax and AUC of a single dose of ruxolitinib 10 mg, respectively, when the dose was given after ashort course of erythromycin 500 mg PO twice daily for 4 days. The change in the pharmacodynamic marker pSTAT3 inhibitionwas consistent with the increase in exposure. [34364] [46782] [57012]

Clarithromycin: (Major) Reduce the ruxolitinib dosage during coadministration with clarithromycin in patients with myelofibrosis(MF) or polycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur; no dose adjustments are necessary forpatients with graft-versus-host disease. In MF patients, reduce the initial dose to 10 mg PO twice daily for platelet count of100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients, reduce theinitial dose to 5 mg PO twice daily. Avoid the use of clarithromycin or interrupt ruxolitinib treatment during clarithromycin use inMF or PV patients who are stable on a ruxolitinib dose of 5 mg PO once daily. In MF or PV patients stable on ruxolitinib dose of10 mg PO twice daily or more, reduce dose by 50%; in patients stable on ruxolitinib dose of 5 mg PO twice daily, reduceruxolitinib to 5 mg PO once daily. Additional dose modifications should be made with frequent monitoring of safety and efficacy.Ruxolitinib is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. [28238] [46782]

Clozapine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increasesthe risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treatedwith these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist. [28262]

Cobicistat: (Major) Reduce the ruxolitinib dosage during coadministration with cobicistat in patients with myelofibrosis (MF) orpolycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur; no dose adjustments are necessary for patients

with graft-versus-host disease. In MF patients, reduce the initial dose to 10 mg PO twice daily for platelet count of 100,000cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients, reduce the initialdose to 5 mg PO twice daily. Avoid the use of cobicistat in MF or PV patients who are stable on a ruxolitinib dose of 5 mg POonce daily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by 50%; in patientsstable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. Additional dose modifications shouldbe made with frequent monitoring of safety and efficacy. Ruxolitinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4inhibitor. [46782] [58000]

Conivaptan: (Major) Reduce the ruxolitinib dosage during coadministration with conivaptan in patients with myelofibrosis (MF)or polycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur; no dose adjustments are necessary forpatients with graft-versus-host disease. In MF patients, reduce the initial dose to 10 mg PO twice daily for platelet count of100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients, reduce theinitial dose to 5 mg PO twice daily. Avoid the use of conivaptan or interrupt ruxolitinib treatment during conivaptan use in MF orPV patients who are stable on a ruxolitinib dose of 5 mg PO once daily. In MF or PV patients stable on ruxolitinib dose of 10 mgPO twice daily or more, reduce dose by 50%; in patients stable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5mg PO once daily. Additional dose modifications should be made with frequent monitoring of safety and efficacy. Ruxolitinib is aCYP3A4 substrate; conivaptan is a strong CYP3A4 inhibitor. [31764] [46782]

Danazol: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderate inhibitors of CYP3A4such as danazol, a dose adjustment is not necessary, but monitoring patients for toxicity may be prudent. There was an 8% and27% increase in the Cmax and AUC of a single dose of ruxolitinib 10 mg, respectively, when the dose was given after a shortcourse of erythromycin 500 mg PO twice daily for 4 days. The change in the pharmacodynamic marker pSTAT3 inhibition wasconsistent with the increase in exposure. [11576] [46782]

Darunavir: (Major) Reduce the ruxolitinib dosage during coadministration with darunavir in patients with myelofibrosis (MF) orpolycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur; no dose adjustments are necessary for patientswith graft-versus-host disease. In MF patients, reduce the initial dose to 10 mg PO twice daily for platelet count of 100,000cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients, reduce the initialdose to 5 mg PO twice daily. Avoid the use of darunavir in MF or PV patients who are stable on a ruxolitinib dose of 5 mg POonce daily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by 50%; in patientsstable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. Additional dose modifications shouldbe made with frequent monitoring of safety and efficacy. Ruxolitinib is a CYP3A4 substrate; darunavir is a strong CYP3A4inhibitor. [32432] [46782]

Darunavir; Cobicistat: (Major) Reduce the ruxolitinib dosage during coadministration with cobicistat in patients withmyelofibrosis (MF) or polycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur; no dose adjustments arenecessary for patients with graft-versus-host disease. In MF patients, reduce the initial dose to 10 mg PO twice daily for plateletcount of 100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients,reduce the initial dose to 5 mg PO twice daily. Avoid the use of cobicistat in MF or PV patients who are stable on a ruxolitinibdose of 5 mg PO once daily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by50%; in patients stable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. Additional dosemodifications should be made with frequent monitoring of safety and efficacy. Ruxolitinib is a CYP3A4 substrate; cobicistat is astrong CYP3A4 inhibitor. [46782] [58000] (Major) Reduce the ruxolitinib dosage during coadministration with darunavir in patientswith myelofibrosis (MF) or polycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur; no dose adjustmentsare necessary for patients with graft-versus-host disease. In MF patients, reduce the initial dose to 10 mg PO twice daily forplatelet count of 100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PVpatients, reduce the initial dose to 5 mg PO twice daily. Avoid the use of darunavir in MF or PV patients who are stable on aruxolitinib dose of 5 mg PO once daily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily or more, reducedose by 50%; in patients stable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. Additionaldose modifications should be made with frequent monitoring of safety and efficacy. Ruxolitinib is a CYP3A4 substrate; darunaviris a strong CYP3A4 inhibitor. [32432] [46782]

Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Reduce the ruxolitinib dosage during coadministration withcobicistat in patients with myelofibrosis (MF) or polycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur;no dose adjustments are necessary for patients with graft-versus-host disease. In MF patients, reduce the initial dose to 10 mg POtwice daily for platelet count of 100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999cells/mm3. In PV patients, reduce the initial dose to 5 mg PO twice daily. Avoid the use of cobicistat in MF or PV patients who arestable on a ruxolitinib dose of 5 mg PO once daily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily ormore, reduce dose by 50%; in patients stable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily.Additional dose modifications should be made with frequent monitoring of safety and efficacy. Ruxolitinib is a CYP3A4 substrate;cobicistat is a strong CYP3A4 inhibitor. [46782] [58000] (Major) Reduce the ruxolitinib dosage during coadministration withdarunavir in patients with myelofibrosis (MF) or polycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur;no dose adjustments are necessary for patients with graft-versus-host disease. In MF patients, reduce the initial dose to 10 mg PO

twice daily for platelet count of 100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999cells/mm3. In PV patients, reduce the initial dose to 5 mg PO twice daily. Avoid the use of darunavir in MF or PV patients who arestable on a ruxolitinib dose of 5 mg PO once daily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily ormore, reduce dose by 50%; in patients stable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily.Additional dose modifications should be made with frequent monitoring of safety and efficacy. Ruxolitinib is a CYP3A4 substrate;darunavir is a strong CYP3A4 inhibitor. [32432] [46782]

Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Reduce the ruxolitinib dosage during coadministration with ritonavir inpatients with myelofibrosis (MF) or polycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur; no doseadjustments are necessary for patients with graft-versus-host disease. In MF patients, reduce the initial dose to 10 mg PO twicedaily for platelet count of 100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. InPV patients, reduce the initial dose to 5 mg PO twice daily. Avoid the use of ritonavir in MF or PV patients who are stable on aruxolitinib dose of 5 mg PO once daily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily or more, reducedose by 50%; in patients stable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. Additionaldose modifications should be made with frequent monitoring of safety and efficacy. Ruxolitinib is a CYP3A4 substrate; ritonavir isa strong CYP3A4 inhibitor. [46782] [47165]

Delavirdine: (Major) Reduce the ruxolitinib dosage during coadministration with delavirdine in patients with myelofibrosis (MF)or polycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur; no dose adjustments are necessary forpatients with graft-versus-host disease. In MF patients, reduce the initial dose to 10 mg PO twice daily for platelet count of100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients, reduce theinitial dose to 5 mg PO twice daily. Avoid the use of delavirdine in MF or PV patients who are stable on a ruxolitinib dose of 5 mgPO once daily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by 50%; in patientsstable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. Additional dose modifications shouldbe made with frequent monitoring of safety and efficacy. Ruxolitinib is a CYP3A4 substrate; delavirdine is a strong CYP3A4inhibitor. [28476] [46782]

Dexamethasone: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are CYP3A4 inducers such asdexamethasone, a dose adjustment is not necessary, but closely monitor patients and titrate the ruxolitinib dose based on safety andefficacy. The Cmax and AUC of a single 50 mg dose of ruxolitinib was decreased by 32% and 61%, respectively, after rifampin600 mg once daily was administered for 10 days. The relative exposure to ruxolitinib's active metabolites increased by about100%, which may partially explain the reported disproportionate 10% reduction in the pharmacodynamic marker pSTAT3inhibition. [11334] [46782] [6759]

Diltiazem: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderate inhibitors of CYP3A4such as diltiazem, a dose adjustment is not necessary, but monitoring patients for toxicity may be prudent. There was an 8% and27% increase in the Cmax and AUC of a single dose of ruxolitinib 10 mg, respectively, when the dose was given after a shortcourse of erythromycin 500 mg PO twice daily for 4 days. The change in the pharmacodynamic marker pSTAT3 inhibition wasconsistent with the increase in exposure. [11352] [46782] [5004]

Dronedarone: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderate inhibitors ofCYP3A4 such as dronedarone, a dose adjustment is not necessary, but monitoring patients for toxicity may be prudent. There wasan 8% and 27% increase in the Cmax and AUC of a single dose of ruxolitinib 10 mg, respectively, when the dose was given after ashort course of erythromycin 500 mg PO twice daily for 4 days. The change in the pharmacodynamic marker pSTAT3 inhibitionwas consistent with the increase in exposure. [36101] [46782]

Drospirenone; Ethinyl Estradiol: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderateinhibitors of CYP3A4 such as ethinyl estradiol, a dose adjustment is not necessary, but monitoring patients for toxicity may beprudent. There was an 8% and 27% increase in the Cmax and AUC of a single dose of ruxolitinib 10 mg, respectively, when thedose was given after a short course of erythromycin 500 mg PO twice daily for 4 days. The change in the pharmacodynamicmarker pSTAT3 inhibition was consistent with the increase in exposure. [46782]

Drospirenone; Ethinyl Estradiol; Levomefolate: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that aremild or moderate inhibitors of CYP3A4 such as ethinyl estradiol, a dose adjustment is not necessary, but monitoring patients fortoxicity 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 thepharmacodynamic marker pSTAT3 inhibition was consistent with the increase in exposure. [46782]

Efavirenz: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are CYP3A4 inducers such as efavirenz, adose adjustment is not necessary, but closely monitor patients and titrate the ruxolitinib dose based on safety and efficacy. TheCmax and AUC of a single 50 mg dose of ruxolitinib was decreased by 32% and 61%, respectively, after rifampin 600 mg oncedaily was administered for 10 days. The relative exposure to ruxolitinib's active metabolites increased by about 100%, which maypartially explain the reported disproportionate 10% reduction in the pharmacodynamic marker pSTAT3 inhibition. [46782] [5172]

Efavirenz; Emtricitabine; Tenofovir: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are CYP3A4inducers such as efavirenz, a dose adjustment is not necessary, but closely monitor patients and titrate the ruxolitinib dose based onsafety and efficacy. The Cmax and AUC of a single 50 mg dose of ruxolitinib was decreased by 32% and 61%, respectively, afterrifampin 600 mg once daily was administered for 10 days. The relative exposure to ruxolitinib's active metabolites increased byabout 100%, which may partially explain the reported disproportionate 10% reduction in the pharmacodynamic marker pSTAT3inhibition. [46782] [5172]

Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugsthat are CYP3A4 inducers such as efavirenz, a dose adjustment is not necessary, but closely monitor patients and titrate theruxolitinib dose based on safety and efficacy. The Cmax and AUC of a single 50 mg dose of ruxolitinib was decreased by 32% and61%, respectively, after rifampin 600 mg once daily was administered for 10 days. The relative exposure to ruxolitinib's activemetabolites increased by about 100%, which may partially explain the reported disproportionate 10% reduction in thepharmacodynamic marker pSTAT3 inhibition. [46782] [5172]

Elbasvir; Grazoprevir: (Moderate) Administering ruxolitinib with elbasvir; grazoprevir may result in elevated ruxolitinib plasmaconcentrations. 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. [46782] [60523]

Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Reduce the ruxolitinib dosage during coadministrationwith cobicistat in patients with myelofibrosis (MF) or polycythemia vera (PV) as increased ruxolitinib exposure and toxicity mayoccur; no dose adjustments are necessary for patients with graft-versus-host disease. In MF patients, reduce the initial dose to 10mg PO twice daily for platelet count of 100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999cells/mm3. In PV patients, reduce the initial dose to 5 mg PO twice daily. Avoid the use of cobicistat in MF or PV patients who arestable on a ruxolitinib dose of 5 mg PO once daily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily ormore, reduce dose by 50%; in patients stable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily.Additional dose modifications should be made with frequent monitoring of safety and efficacy. Ruxolitinib is a CYP3A4 substrate;cobicistat is a strong CYP3A4 inhibitor. [46782] [58000]

Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Reduce the ruxolitinib dosage duringcoadministration with cobicistat in patients with myelofibrosis (MF) or polycythemia vera (PV) as increased ruxolitinib exposureand toxicity may occur; no dose adjustments are necessary for patients with graft-versus-host disease. In MF patients, reduce theinitial dose to 10 mg PO twice daily for platelet count of 100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of50,000 to 99,999 cells/mm3. In PV patients, reduce the initial dose to 5 mg PO twice daily. Avoid the use of cobicistat in MF orPV patients who are stable on a ruxolitinib dose of 5 mg PO once daily. In MF or PV patients stable on ruxolitinib dose of 10 mgPO twice daily or more, reduce dose by 50%; in patients stable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5mg PO once daily. Additional dose modifications should be made with frequent monitoring of safety and efficacy. Ruxolitinib is aCYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. [46782] [58000]

Enzalutamide: (Moderate) Monitor patients frequently and adjust the ruxolitinib dose based on safety and efficacy ifcoadministered with enzalutamide; decreased ruxolitinib exposure is possible. Ruxolitinib is a CYP3A4 substrate; enzalutamide isa strong CYP3A4 inducer. Coadministration of another strong CYP3A4 inducer decreased ruxolitinib Cmax and AUC by 32% and61%, respectively. The relative exposure to ruxolitinib's active metabolites increased approximately 100%. [46782] [51727]

Erythromycin: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderate inhibitors ofCYP3A4 such as erythromycin, a dose adjustment is not necessary, but monitoring patients for toxicity may be prudent. There wasan 8% and 27% increase in the Cmax and AUC of a single dose of ruxolitinib 10 mg, respectively, when the dose was given after ashort course of erythromycin 500 mg PO twice daily for 4 days. The change in the pharmacodynamic marker pSTAT3 inhibitionwas consistent with the increase in exposure. [46782]

Erythromycin; Sulfisoxazole: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderateinhibitors of CYP3A4 such as erythromycin, a dose adjustment is not necessary, but monitoring patients for toxicity may beprudent. There was an 8% and 27% increase in the Cmax and AUC of a single dose of ruxolitinib 10 mg, respectively, when thedose was given after a short course of erythromycin 500 mg PO twice daily for 4 days. The change in the pharmacodynamicmarker pSTAT3 inhibition was consistent with the increase in exposure. [46782]

Ethinyl Estradiol: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderate inhibitors ofCYP3A4 such as ethinyl estradiol, a dose adjustment is not necessary, but monitoring patients for toxicity may be prudent. Therewas an 8% and 27% increase in the Cmax and AUC of a single dose of ruxolitinib 10 mg, respectively, when the dose was givenafter a short course of erythromycin 500 mg PO twice daily for 4 days. The change in the pharmacodynamic marker pSTAT3inhibition was consistent with the increase in exposure. [46782]

Ethinyl Estradiol; Desogestrel: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderateinhibitors 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 thedose was given after a short course of erythromycin 500 mg PO twice daily for 4 days. The change in the pharmacodynamicmarker pSTAT3 inhibition was consistent with the increase in exposure. [46782]

Ethinyl Estradiol; Ethynodiol Diacetate: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild ormoderate inhibitors of CYP3A4 such as ethinyl estradiol, a dose adjustment is not necessary, but monitoring patients for toxicitymay 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 thepharmacodynamic marker pSTAT3 inhibition was consistent with the increase in exposure. [46782]

Ethinyl Estradiol; Etonogestrel: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderateinhibitors of CYP3A4 such as ethinyl estradiol, a dose adjustment is not necessary, but monitoring patients for toxicity may beprudent. There was an 8% and 27% increase in the Cmax and AUC of a single dose of ruxolitinib 10 mg, respectively, when thedose was given after a short course of erythromycin 500 mg PO twice daily for 4 days. The change in the pharmacodynamicmarker pSTAT3 inhibition was consistent with the increase in exposure. [46782]

Ethinyl Estradiol; Levonorgestrel: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderateinhibitors of CYP3A4 such as ethinyl estradiol, a dose adjustment is not necessary, but monitoring patients for toxicity may beprudent. There was an 8% and 27% increase in the Cmax and AUC of a single dose of ruxolitinib 10 mg, respectively, when thedose was given after a short course of erythromycin 500 mg PO twice daily for 4 days. The change in the pharmacodynamicmarker pSTAT3 inhibition was consistent with the increase in exposure. [46782]

Ethinyl Estradiol; Levonorgestrel; Ferrous bisglycinate: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs thatare mild or moderate inhibitors of CYP3A4 such as ethinyl estradiol, a dose adjustment is not necessary, but monitoring patientsfor 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 thepharmacodynamic marker pSTAT3 inhibition was consistent with the increase in exposure. [46782]

Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used withdrugs that are mild or moderate inhibitors of CYP3A4 such as ethinyl estradiol, a dose adjustment is not necessary, but monitoringpatients for toxicity may be prudent. There was an 8% and 27% increase in the Cmax and AUC of a single dose of ruxolitinib 10mg, respectively, when the dose was given after a short course of erythromycin 500 mg PO twice daily for 4 days. The change inthe pharmacodynamic marker pSTAT3 inhibition was consistent with the increase in exposure. [46782]

Ethinyl Estradiol; Norelgestromin: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild ormoderate inhibitors of CYP3A4 such as ethinyl estradiol, a dose adjustment is not necessary, but monitoring patients for toxicitymay 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 thepharmacodynamic marker pSTAT3 inhibition was consistent with the increase in exposure. [46782]

Ethinyl Estradiol; Norethindrone Acetate: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild ormoderate inhibitors of CYP3A4 such as ethinyl estradiol, a dose adjustment is not necessary, but monitoring patients for toxicitymay 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 thepharmacodynamic marker pSTAT3 inhibition was consistent with the increase in exposure. [46782]

Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugsthat are mild or moderate inhibitors of CYP3A4 such as ethinyl estradiol, a dose adjustment is not necessary, but monitoringpatients for toxicity may be prudent. There was an 8% and 27% increase in the Cmax and AUC of a single dose of ruxolitinib 10mg, respectively, when the dose was given after a short course of erythromycin 500 mg PO twice daily for 4 days. The change inthe pharmacodynamic marker pSTAT3 inhibition was consistent with the increase in exposure. [46782]

Ethinyl Estradiol; Norethindrone: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderateinhibitors of CYP3A4 such as ethinyl estradiol, a dose adjustment is not necessary, but monitoring patients for toxicity may beprudent. There was an 8% and 27% increase in the Cmax and AUC of a single dose of ruxolitinib 10 mg, respectively, when thedose was given after a short course of erythromycin 500 mg PO twice daily for 4 days. The change in the pharmacodynamicmarker pSTAT3 inhibition was consistent with the increase in exposure. [46782]

Ethinyl Estradiol; Norethindrone; Ferrous fumarate: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that aremild or moderate inhibitors of CYP3A4 such as ethinyl estradiol, a dose adjustment is not necessary, but monitoring patients fortoxicity 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 thepharmacodynamic marker pSTAT3 inhibition was consistent with the increase in exposure. [46782]

Ethinyl Estradiol; Norgestimate: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderateinhibitors of CYP3A4 such as ethinyl estradiol, a dose adjustment is not necessary, but monitoring patients for toxicity may beprudent. There was an 8% and 27% increase in the Cmax and AUC of a single dose of ruxolitinib 10 mg, respectively, when thedose was given after a short course of erythromycin 500 mg PO twice daily for 4 days. The change in the pharmacodynamicmarker pSTAT3 inhibition was consistent with the increase in exposure. [46782]

Ethinyl Estradiol; Norgestrel: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderateinhibitors of CYP3A4 such as ethinyl estradiol, a dose adjustment is not necessary, but monitoring patients for toxicity may beprudent. There was an 8% and 27% increase in the Cmax and AUC of a single dose of ruxolitinib 10 mg, respectively, when thedose was given after a short course of erythromycin 500 mg PO twice daily for 4 days. The change in the pharmacodynamicmarker pSTAT3 inhibition was consistent with the increase in exposure. [46782]

Etravirine: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are CYP3A4 inducers such as etravirine, adose adjustment is not necessary, but closely monitor patients and titrate the ruxolitinib dose based on safety and efficacy. TheCmax and AUC of a single 50 mg dose of ruxolitinib was decreased by 32% and 61%, respectively, after rifampin 600 mg oncedaily was administered for 10 days. The relative exposure to ruxolitinib's active metabolites increased by about 100%, which maypartially explain the reported disproportionate 10% reduction in the pharmacodynamic marker pSTAT3 inhibition. [33718] [46782]

Fluconazole: (Major) Avoid coadministration of ruxolitinib with fluconazole doses greater than 200 mg/day in patients withmyelofibrosis (MF) or polycythemia vera (PV). Fluconazole and ruxolitinib may be coadministered at usual doses in patients withacute graft-versus-host disease (GVHD). Taking these drugs together may result in increased ruxolitinib exposure and toxicity.Modify the ruxolitinib as follows in patients with MF or PV who require concomitant use with fluconazole at doses of 200 mg/dayor less: In MF patients, reduce the initial dose to 10 mg PO twice daily for platelet count of 100,000 cells/mm3 or more and 5 mgPO once daily for platelet count of 50,000 to 99,999 cells/mm3; in PV patients, reduce the initial dose to 5 mg PO twice daily.Avoid the use of fluconazole or interrupt ruxolitinib treatment during fluconazole use in MF or PV patients who are stable on aruxolitinib dose of 5 mg PO once daily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily or more, reducedose by 50%; in patients stable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. Additionaldose modifications should be made with frequent monitoring of safety and efficacy. Ruxolitinib is a CYP3A4 substrate;fluconazole is a moderate CYP3A4 inhibitor. [46782]

Fluoxetine: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderate inhibitors of CYP3A4such as fluoxetine, a dose adjustment is not necessary, but monitoring patients for toxicity may be prudent. There was an 8% and27% increase in the Cmax and AUC of a single dose of ruxolitinib 10 mg, respectively, when the dose was given after a shortcourse of erythromycin 500 mg PO twice daily for 4 days. The change in the pharmacodynamic marker pSTAT3 inhibition wasconsistent with the increase in exposure. [46782] [5738] [5928] [8873] [8874]

Fluoxetine; Olanzapine: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderate inhibitorsof CYP3A4 such as fluoxetine, a dose adjustment is not necessary, but monitoring patients for toxicity may be prudent. There wasan 8% and 27% increase in the Cmax and AUC of a single dose of ruxolitinib 10 mg, respectively, when the dose was given after ashort course of erythromycin 500 mg PO twice daily for 4 days. The change in the pharmacodynamic marker pSTAT3 inhibitionwas consistent with the increase in exposure. [46782] [5738] [5928] [8873] [8874]

Flutamide: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are CYP3A4 inducers such as flutamide, adose adjustment is not necessary, but closely monitor patients and titrate the ruxolitinib dose based on safety and efficacy. TheCmax and AUC of a single 50 mg dose of ruxolitinib was decreased by 32% and 61%, respectively, after rifampin 600 mg oncedaily was administered for 10 days. The relative exposure to ruxolitinib's active metabolites increased by about 100%, which maypartially explain the reported disproportionate 10% reduction in the pharmacodynamic marker pSTAT3 inhibition. [34706] [46782] [48644]

Fluvoxamine: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderate inhibitors ofCYP3A4 such as fluvoxamine, a dose adjustment is not necessary, but monitoring patients for toxicity may be prudent. There wasan 8% and 27% increase in the Cmax and AUC of a single dose of ruxolitinib 10 mg, respectively, when the dose was given after ashort course of erythromycin 500 mg PO twice daily for 4 days. The change in the pharmacodynamic marker pSTAT3 inhibitionwas consistent with the increase in exposure. [46782] [8874]

Fosamprenavir: (Major) Reduce the ruxolitinib dosage during coadministration with fosamprenavir in patients with myelofibrosis(MF) or polycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur; no dose adjustments are necessary forpatients with graft-versus-host disease. In MF patients, reduce the initial dose to 10 mg PO twice daily for platelet count of100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients, reduce theinitial dose to 5 mg PO twice daily. Avoid the use of fosamprenavir in MF or PV patients who are stable on a ruxolitinib dose of 5mg PO once daily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by 50%; inpatients stable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. Additional dose modifications

should be made with frequent monitoring of safety and efficacy. Ruxolitinib is a CYP3A4 substrate; fosamprenavir is a strongCYP3A4 inhibitor. [29012] [34489] [46782]

Fosphenytoin: (Moderate) Monitor patients frequently and adjust the ruxolitinib dose based on safety and efficacy ifcoadministered with fosphenytoin; decreased ruxolitinib exposure is possible. Ruxolitinib is a CYP3A4 substrate; fosphenytoin isa strong CYP3A4 inducer. Coadministration of another strong CYP3A4 inducer decreased ruxolitinib Cmax and AUC by 32% and61%, respectively. The relative exposure to ruxolitinib's active metabolites increased approximately 100%. [22005] [46782] [55436] [56579] [57046] [57048] [57080] [57105]

Grapefruit juice: (Major) Avoid the concomitant use of ruxolitinib and grapefruit juice. Increased ruxolitinib exposure is possibleif a patient regularly consumes grapefruit/grapefruit juice. [29087] [46782] [58104]

Idelalisib: (Major) Reduce the ruxolitinib dosage during coadministration with idelalisib in patients with myelofibrosis (MF) orpolycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur; no dose adjustments are necessary for patientswith graft-versus-host disease. In MF patients, reduce the initial dose to 10 mg PO twice daily for platelet count of 100,000cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients, reduce the initialdose to 5 mg PO twice daily. Avoid the use of idelalisib in MF or PV patients who are stable on a ruxolitinib dose of 5 mg PO oncedaily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by 50%; in patients stable onruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. Additional dose modifications should be madewith frequent monitoring of safety and efficacy. Ruxolitinib is a CYP3A4 substrate; idelalisib is a strong CYP3A4 inhibitor. [46782] [57675]

Imatinib: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderate inhibitors of CYP3A4such as imatinib, STI-571, a dose adjustment is not necessary, but monitoring patients for toxicity may be prudent. There was an8% and 27% increase in the Cmax and AUC of a single dose of ruxolitinib 10 mg, respectively, when the dose was given after ashort course of erythromycin 500 mg PO twice daily for 4 days. The change in the pharmacodynamic marker pSTAT3 inhibitionwas consistent with the increase in exposure. [11372] [46782] [4966]

Indinavir: (Major) Reduce the ruxolitinib dosage during coadministration with indinavir in patients with myelofibrosis (MF) orpolycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur; no dose adjustments are necessary for patientswith graft-versus-host disease. In MF patients, reduce the initial dose to 10 mg PO twice daily for platelet count of 100,000cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients, reduce the initialdose to 5 mg PO twice daily. Avoid the use of indinavir in MF or PV patients who are stable on a ruxolitinib dose of 5 mg PO oncedaily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by 50%; in patients stable onruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. Additional dose modifications should be madewith frequent monitoring of safety and efficacy. Ruxolitinib is a CYP3A4 substrate; indinavir is a strong CYP3A4 inhibitor. [28731] [46782]

Isavuconazonium: (Moderate) The plasma concentrations of ruxolitinib may be elevated when administered concurrently withisavuconazonium. Ruxolitinib is a CYP3A4 substrate; isavuconazole, the active moiety of isavuconazonium, is a moderateinhibitor of this enzyme. Although a dose adjustment is not necessary when used with drugs that are mild or moderate inhibitors ofCYP3A4 such as isavuconazole, monitoring patients for ruxolitinib toxicity may be prudent when these drugs are givenconcurrently. There was an 8% and 27% increase in the Cmax and AUC of a single dose of ruxolitinib 10 mg, respectively, whenthe 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. [46782] [59042]

Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Moderate) Monitor patients frequently and adjust the ruxolitinib dose based onsafety 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%. [28840] [29812] [34550] [46782]

Isoniazid, INH; Rifampin: (Moderate) Monitor patients frequently and adjust the ruxolitinib dose based on safety and efficacy ifcoadministered with rifampin; decreased ruxolitinib exposure is possible. Ruxolitinib is a CYP3A4 substrate; rifampin is a strongCYP3A4 inducer. Coadministration of rifampin decreased ruxolitinib Cmax and AUC by 32% and 61%, respectively. The relativeexposure to ruxolitinib's active metabolites increased approximately 100%. [28840] [29812] [34550] [46782]

Itraconazole: (Major) Reduce the ruxolitinib dosage during coadministration with itraconazole in patients with myelofibrosis (MF)or polycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur. No initial dose adjustments are necessary forpatients with graft-versus-host disease; however, monitor blood counts more frequently for toxicity and adjust the dose ofruxolitinib if necessary. In MF patients, reduce the initial dose to 10 mg PO twice daily for platelet count of 100,000 cells/mm3 ormore and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients, reduce the initial dose to 5 mg POtwice daily. Avoid the use of itraconazole or interrupt ruxolitinib treatment during itraconazole use in MF or PV patients who arestable on a ruxolitinib dose of 5 mg PO once daily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily or

more, reduce dose by 50%; in patients stable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily.Additional dose modifications should be made with frequent monitoring of safety and efficacy. Ruxolitinib is a CYP3A4 substrate;itraconazole is a strong CYP3A4 inhibitor. [46782]

Ketoconazole: (Major) Reduce the ruxolitinib dosage during coadministration with ketoconazole as increased ruxolitinib exposureand toxicity may occur. In myelofibrosis (MF) patients, reduce the initial dose to 10 mg PO twice daily for platelet count of100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In polycythemia vera (PV)patients, reduce the initial dose to 5 mg PO twice daily. Avoid the use of ketoconazole or interrupt ruxolitinib treatment duringketoconazole use in MF or PV patients who are stable on a ruxolitinib dose of 5 mg PO once daily. For patients with MF or PVpatient stable on ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by 50%; in patients stable on ruxolitinib dose of 5mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. In graft-versus-host disease patients, reduce the dose to 5 mg POonce daily. Additional dose modifications should be made with frequent monitoring of safety and efficacy. Ruxolitinib is aCYP3A4 substrate; ketoconazole is a strong CYP3A4 inhibitor. [46782]

Letermovir: (Moderate) Plasma concentrations of ruxolitinib could increase when administered concurrently with letermovir. Themagnitude of this interaction may be increased in patients who are also receiving cyclosporine. Frequently monitor safety andefficacy of ruxolitinib, and modify dose as needed. Ruxolitinib is a substrate of the enzymes CYP3A4. Letermovir is moderateinhibitor of CYP3A4. When given with cyclosporine, the combined effect of letermovir and cyclosporine on CYP3A4 substratesmay be similar to a strong CYP3A4 inhibitor. In a drug interaction study, administration of ruxolitinib with another strongCYP3A4 inhibitor increased ruxolitinib maximum plasma concentration (Cmax) and exposure (AUC) by 33% and 91%,respectively. In addition, ruxolitinib half-life was increased from 3.7 to 6 hours. In another study, administration with a moderateCYP3A4 inhibitor increased ruxolitinib Cmax and AUC by 8% and 27%, respectively. [46782] [62611]

Lopinavir; Ritonavir: (Major) Reduce the ruxolitinib dosage during coadministration with ritonavir in patients with myelofibrosis(MF) or polycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur; no dose adjustments are necessary forpatients with graft-versus-host disease. In MF patients, reduce the initial dose to 10 mg PO twice daily for platelet count of100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients, reduce theinitial dose to 5 mg PO twice daily. Avoid the use of ritonavir in MF or PV patients who are stable on a ruxolitinib dose of 5 mgPO once daily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by 50%; in patientsstable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. Additional dose modifications shouldbe made with frequent monitoring of safety and efficacy. Ruxolitinib is a CYP3A4 substrate; ritonavir is a strong CYP3A4inhibitor. [46782] [47165]

Lumacaftor; Ivacaftor: (Moderate) Monitor patients frequently and adjust the ruxolitinib dose based on safety and efficacy ifcoadministered 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 ruxolitinibCmax and AUC by 32% and 61%, respectively. The relative exposure to ruxolitinib's active metabolites increased approximately100%. [46782] [59891]

Lumacaftor; Ivacaftor: (Moderate) Monitor patients frequently and adjust the ruxolitinib dose based on safety and efficacy ifcoadministered 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 ruxolitinibCmax and AUC by 32% and 61%, respectively. The relative exposure to ruxolitinib's active metabolites increased approximately100%. [46782] [59891]

Mifepristone: (Major) Reduce the ruxolitinib dosage during coadministration with mifepristone in patients with myelofibrosis(MF) or polycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur; no dose adjustments are necessary forpatients with graft-versus-host disease. In MF patients, reduce the initial dose to 10 mg PO twice daily for platelet count of100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients, reduce theinitial dose to 5 mg PO twice daily. Avoid the use of mifepristone or interrupt ruxolitinib treatment during mifepristone use in MFor PV patients who are stable on a ruxolitinib dose of 5 mg PO once daily. In MF or PV patients stable on ruxolitinib dose of 10mg PO twice daily or more, reduce dose by 50%; in patients stable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinibto 5 mg PO once daily. Additional dose modifications should be made with frequent monitoring of safety and efficacy. Ruxolitinibis a CYP3A4 substrate; mifepristone is a strong CYP3A4 inhibitor. [28003] [34716] [46782] [48697]

Mitotane: (Moderate) Monitor patients frequently and adjust the ruxolitinib dose based on safety and efficacy if coadministeredwith mitotane; decreased ruxolitinib exposure is possible. Ruxolitinib is a CYP3A4 substrate; mitotane is a strong CYP3A4inducer. 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%. [41934] [46782]

Modafinil: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are CYP3A4 inducers such as modafinil, adose adjustment is not necessary, but closely monitor patients and titrate the ruxolitinib dose based on safety and efficacy. TheCmax 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 maypartially explain the reported disproportionate 10% reduction in the pharmacodynamic marker pSTAT3 inhibition. [46782]

Nafcillin: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are CYP3A4 inducers such as nafcillin, adose adjustment is not necessary, but closely monitor patients and titrate the ruxolitinib dose based on safety and efficacy. TheCmax and AUC of a single 50 mg dose of ruxolitinib was decreased by 32% and 61%, respectively, after rifampin 600 mg oncedaily was administered for 10 days. The relative exposure to ruxolitinib's active metabolites increased by about 100%, which maypartially explain the reported disproportionate 10% reduction in the pharmacodynamic marker pSTAT3 inhibition. [11312] [11313] [46782]

Nefazodone: (Major) Reduce the ruxolitinib dosage during coadministration with nefazodone in patients with myelofibrosis (MF)or polycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur; no dose adjustments are necessary forpatients with graft-versus-host disease. In MF patients, reduce the initial dose to 10 mg PO twice daily for platelet count of100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients, reduce theinitial dose to 5 mg PO twice daily. Avoid the use of nefazodone in MF or PV patients who are stable on a ruxolitinib dose of 5 mgPO once daily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by 50%; in patientsstable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. Additional dose modifications shouldbe made with frequent monitoring of safety and efficacy. Ruxolitinib is a CYP3A4 substrate; nefazodone is a strong CYP3A4inhibitor. [46782] [48645] [54634]

Nelfinavir: (Major) Reduce the ruxolitinib dosage during coadministration with nelfinavir in patients with myelofibrosis (MF) orpolycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur; no dose adjustments are necessary for patientswith graft-versus-host disease. In MF patients, reduce the initial dose to 10 mg PO twice daily for platelet count of 100,000cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients, reduce the initialdose to 5 mg PO twice daily. Avoid the use of nelfinavir in MF or PV patients who are stable on a ruxolitinib dose of 5 mg POonce daily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by 50%; in patientsstable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. Additional dose modifications shouldbe made with frequent monitoring of safety and efficacy. Ruxolitinib is a CYP3A4 substrate; nelfinavir is a strong CYP3A4inhibitor. [28839] [46782]

Netupitant, Fosnetupitant; Palonosetron: (Moderate) Netupitant is a moderate inhibitor of CYP3A4 and should be used withcaution in patients receiving concomitant medications that are primarily metabolized through CYP3A4, such as ruxolitinib. Theplasma concentrations of ruxolitinib can increase when co-administered with netupitant; the inhibitory effect on CYP3A4 can lastfor multiple days. [46782] [58171]

Nevirapine: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are CYP3A4 inducers such as nevirapine, adose adjustment is not necessary, but closely monitor patients and titrate the ruxolitinib dose based on safety and efficacy. TheCmax and AUC of a single 50 mg dose of ruxolitinib was decreased by 32% and 61%, respectively, after rifampin 600 mg oncedaily was administered for 10 days. The relative exposure to ruxolitinib's active metabolites increased by about 100%, which maypartially explain the reported disproportionate 10% reduction in the pharmacodynamic marker pSTAT3 inhibition. [46782] [5222]

Nicardipine: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderate inhibitors ofCYP3A4 such as nicardipine, a dose adjustment is not necessary, but monitoring patients for toxicity may be prudent. There wasan 8% and 27% increase in the Cmax and AUC of a single dose of ruxolitinib 10 mg, respectively, when the dose was given after ashort course of erythromycin 500 mg PO twice daily for 4 days. The change in the pharmacodynamic marker pSTAT3 inhibitionwas consistent with the increase in exposure. [11537] [46782] [50341]

Octreotide: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderate inhibitors of CYP3A4such as octreotide, a dose adjustment is not necessary, but monitoring patients for toxicity may be prudent. There was an 8% and27% increase in the Cmax and AUC of a single dose of ruxolitinib 10 mg, respectively, when the dose was given after a shortcourse of erythromycin 500 mg PO twice daily for 4 days. The change in the pharmacodynamic marker pSTAT3 inhibition wasconsistent with the increase in exposure. [46782] [5850]

Ombitasvir; Paritaprevir; Ritonavir: (Major) Reduce the ruxolitinib dosage during coadministration with ritonavir in patients withmyelofibrosis (MF) or polycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur; no dose adjustments arenecessary for patients with graft-versus-host disease. In MF patients, reduce the initial dose to 10 mg PO twice daily for plateletcount of 100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients,reduce the initial dose to 5 mg PO twice daily. Avoid the use of ritonavir in MF or PV patients who are stable on a ruxolitinib doseof 5 mg PO once daily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by 50%; inpatients stable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. Additional dose modificationsshould be made with frequent monitoring of safety and efficacy. Ruxolitinib is a CYP3A4 substrate; ritonavir is a strong CYP3A4inhibitor. [46782] [47165]

Oritavancin: (Moderate) Coadministration of oritavancin and ruxolitinib may result in increases or decreases in ruxolitinibexposure and may increase side effects or decrease efficacy of ruxolitinib. Ruxolitinib is primarily metabolized by CYP3A4, but isalso metabolized by CYP2C9. Oritavancin weakly induces CYP3A4, while weakly inhibiting CYP2C9. If these drugs areadministered concurrently, monitor the patient for signs of toxicity or lack of efficacy. [46782] [57741]

Phenobarbital: (Moderate) Monitor patients frequently and adjust the ruxolitinib dose based on safety and efficacy ifcoadministered with phenobarbital; decreased ruxolitinib exposure is possible. Ruxolitinib is a CYP3A4 substrate; phenobarbital isa strong CYP3A4 inducer. Coadministration of another strong CYP3A4 inducer decreased ruxolitinib Cmax and AUC by 32% and61%, respectively. The relative exposure to ruxolitinib's active metabolites increased approximately 100%. [22005] [46782] [55436] [57046] [57048] [57080]

Phenytoin: (Moderate) Monitor patients frequently and adjust the ruxolitinib dose based on safety and efficacy if coadministeredwith phenytoin; decreased ruxolitinib exposure is possible. Ruxolitinib is a CYP3A4 substrate; phenytoin is a strong CYP3A4inducer. 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%. [22005] [46782] [55436] [56579][57046] [57048] [57080] [57105]

Posaconazole: (Major) Reduce the ruxolitinib dosage during coadministration with posaconazole in patients with myelofibrosis(MF) or polycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur; no dose adjustments are necessary forpatients with graft-versus-host disease. In MF patients, reduce the initial dose to 10 mg PO twice daily for platelet count of100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients, reduce theinitial dose to 5 mg PO twice daily. Avoid the use of posaconazole or interrupt ruxolitinib treatment during posaconazole use inMF or PV patients who are stable on a ruxolitinib dose of 5 mg PO once daily. In MF or PV patients stable on ruxolitinib dose of10 mg PO twice daily or more, reduce dose by 50%; in patients stable on ruxolitinib dose of 5 mg PO twice daily, reduceruxolitinib to 5 mg PO once daily. Additional dose modifications should be made with frequent monitoring of safety and efficacy.Ruxolitinib is a CYP3A4 substrate; posaconazole is a strong CYP3A4 inhibitor. [32723] [34464] [46782]

Primidone: (Moderate) Monitor patients frequently and adjust the ruxolitinib dose based on safety and efficacy if coadministeredwith primidone; decreased ruxolitinib exposure is possible. Ruxolitinib is a CYP3A4 substrate; primidone is a strong CYP3A4inducer. 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%. [22005] [46782] [55436] [56579][57046] [57048] [57080]

Ranolazine: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderate inhibitors ofCYP3A4 such as ranolazine, a dose adjustment is not necessary, but monitoring patients for toxicity may be prudent. There was an8% and 27% increase in the Cmax and AUC of a single dose of ruxolitinib 10 mg, respectively, when the dose was given after ashort course of erythromycin 500 mg PO twice daily for 4 days. The change in the pharmacodynamic marker pSTAT3 inhibitionwas consistent with the increase in exposure. [31938] [46782]

Ribociclib: (Major) Reduce the ruxolitinib dosage during coadministration with ribociclib in patients with myelofibrosis (MF) orpolycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur; no dose adjustments are necessary for patientswith graft-versus-host disease. In MF patients, reduce the initial dose to 10 mg PO twice daily for platelet count of 100,000cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients, reduce the initialdose to 5 mg PO twice daily. Avoid the use of ribociclib in MF or PV patients who are stable on a ruxolitinib dose of 5 mg POonce daily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by 50%; in patientsstable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. Additional dose modifications shouldbe made with frequent monitoring of safety and efficacy. Ruxolitinib is a CYP3A4 substrate; ribociclib is a strong CYP3A4inhibitor. [46782] [61816]

Ribociclib; Letrozole: (Major) Reduce the ruxolitinib dosage during coadministration with ribociclib in patients with myelofibrosis(MF) or polycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur; no dose adjustments are necessary forpatients with graft-versus-host disease. In MF patients, reduce the initial dose to 10 mg PO twice daily for platelet count of100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients, reduce theinitial dose to 5 mg PO twice daily. Avoid the use of ribociclib in MF or PV patients who are stable on a ruxolitinib dose of 5 mgPO once daily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by 50%; in patientsstable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. Additional dose modifications shouldbe made with frequent monitoring of safety and efficacy. Ruxolitinib is a CYP3A4 substrate; ribociclib is a strong CYP3A4inhibitor. [46782] [61816]

Rifampin: (Moderate) Monitor patients frequently and adjust the ruxolitinib dose based on safety and efficacy if coadministeredwith rifampin; decreased ruxolitinib exposure is possible. Ruxolitinib is a CYP3A4 substrate; rifampin is a strong CYP3A4inducer. Coadministration of rifampin decreased ruxolitinib Cmax and AUC by 32% and 61%, respectively. The relative exposureto ruxolitinib's active metabolites increased approximately 100%. [28840] [29812] [34550] [46782]

Ritonavir: (Major) Reduce the ruxolitinib dosage during coadministration with ritonavir in patients with myelofibrosis (MF) orpolycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur; no dose adjustments are necessary for patientswith graft-versus-host disease. In MF patients, reduce the initial dose to 10 mg PO twice daily for platelet count of 100,000cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients, reduce the initialdose to 5 mg PO twice daily. Avoid the use of ritonavir in MF or PV patients who are stable on a ruxolitinib dose of 5 mg PO oncedaily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by 50%; in patients stable onruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. Additional dose modifications should be madewith frequent monitoring of safety and efficacy. Ruxolitinib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. [46782][47165]

Saquinavir: (Major) Reduce the ruxolitinib dosage during coadministration with saquinavir in patients with myelofibrosis (MF) orpolycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur; no dose adjustments are necessary for patientswith graft-versus-host disease. In MF patients, reduce the initial dose to 10 mg PO twice daily for platelet count of 100,000cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients, reduce the initialdose to 5 mg PO twice daily. Avoid the use of saquinavir in MF or PV patients who are stable on a ruxolitinib dose of 5 mg POonce daily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by 50%; in patientsstable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. Additional dose modifications shouldbe made with frequent monitoring of safety and efficacy. Ruxolitinib is a CYP3A4 substrate; saquinavir is a strong CYP3A4inhibitor. [28995] [39863] [39864] [46782]

Segesterone Acetate; Ethinyl Estradiol: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild ormoderate inhibitors of CYP3A4 such as ethinyl estradiol, a dose adjustment is not necessary, but monitoring patients for toxicitymay 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 thepharmacodynamic marker pSTAT3 inhibition was consistent with the increase in exposure. [46782]

St. John's Wort, Hypericum perforatum: (Moderate) Monitor patients frequently and adjust the ruxolitinib dose based on safety andefficacy 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 andAUC by 32% and 61%, respectively. The relative exposure to ruxolitinib's active metabolites increased approximately 100%. [46782] [57202]

Telaprevir: (Major) Avoid coadministration of ruxolitinib and telaprevir in patients with platelet counts < 100 x 10^9/L. In patientswith platelet counts >= 100 x 10^9/L, ruxolitinib may be administered concurrently with telaprevir if the initial ruxolitinib dose isreduced to 10 mg PO twice daily. Additional dose modification should be made only after close monitoring of ruxolitinib's safetyand efficacy. Predictions about the interaction can be made based on the metabolic pathway of ruxolitinib. Ruxolitinib is primarilymetabolized by CYP3A4; telaprevir is a potent inhibitor of this isoenzyme. Coadministration may result in a large increase inruxolitinib serum concentrations, which could cause adverse events such as thrombocytopenia, anemia, neutropenia, or infection. [44393] [46782]

Telithromycin: (Major) Reduce the ruxolitinib dosage during coadministration with telithromycin in patients with myelofibrosis(MF) or polycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur; no dose adjustments are necessary forpatients with graft-versus-host disease. In MF patients, reduce the initial dose to 10 mg PO twice daily for platelet count of100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients, reduce theinitial dose to 5 mg PO twice daily. Avoid the use of telithromycin or interrupt ruxolitinib treatment during telithromycin use inMF or PV patients who are stable on a ruxolitinib dose of 5 mg PO once daily. In MF or PV patients stable on ruxolitinib dose of10 mg PO twice daily or more, reduce dose by 50%; in patients stable on ruxolitinib dose of 5 mg PO twice daily, reduceruxolitinib to 5 mg PO once daily. Additional dose modifications should be made with frequent monitoring of safety and efficacy.Ruxolitinib is a CYP3A4 substrate; telithromycin is a strong CYP3A4 inhibitor. [28156] [46782]

Telotristat Ethyl: (Moderate) Use caution if coadministration of telotristat ethyl and ruxolitinib is necessary, as the systemicexposure of ruxolitinib may be decreased resulting in reduced efficacy. If these drugs are used together, monitor patients forsuboptimal efficacy of ruxolitinib; consider increasing the dose of ruxolitinib if necessary. Ruxolitinib is a CYP3A4 substrate. Themean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministeredwith telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of theCYP3A4 substrate. [46782] [61795]

Tipranavir: (Major) Reduce the ruxolitinib dosage during coadministration with tipranavir in patients with myelofibrosis (MF) orpolycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur; no dose adjustments are necessary for patientswith graft-versus-host disease. In MF patients, reduce the initial dose to 10 mg PO twice daily for platelet count of 100,000cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients, reduce the initialdose to 5 mg PO twice daily. Avoid the use of tipranavir in MF or PV patients who are stable on a ruxolitinib dose of 5 mg POonce daily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by 50%; in patients

stable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. Additional dose modifications shouldbe made with frequent monitoring of safety and efficacy. Ruxolitinib is a CYP3A4 substrate; tipranavir is a strong CYP3A4inhibitor. [31320] [46782]

Trandolapril; Verapamil: (Minor) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderate inhibitors ofCYP3A4 such as verapamil, a dose adjustment is not necessary, but monitoring patients for toxicity may be prudent. There was an8% and 27% increase in the Cmax and AUC of a single dose of ruxolitinib 10 mg, respectively, when the dose was given after ashort course of erythromycin 500 mg PO twice daily for 4 days. The change in the pharmacodynamic marker pSTAT3 inhibitionwas consistent with the increase in exposure. [46782] [6446]

Tucatinib: (Major) Reduce the ruxolitinib dosage during coadministration with tucatinib in patients with myelofibrosis (MF) orpolycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur; no dose adjustments are necessary for patientswith graft-versus-host disease. In MF patients, reduce the initial dose to 10 mg PO twice daily for platelet count of 100,000cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients, reduce the initialdose to 5 mg PO twice daily. Avoid the use of tucatinib in MF or PV patients who are stable on a ruxolitinib dose of 5 mg PO oncedaily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by 50%; in patients stable onruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. Additional dose modifications should be madewith frequent monitoring of safety and efficacy. Ruxolitinib is a CYP3A4 substrate; tucatinib is a strong CYP3A4 inhibitor. [46782][65295]

Upadacitinib: (Severe) Concomitant use of ruxolitinib with upadacitinib is not recommended because of the duplication of themechanism of action (both are Janus kinase inhibitors, also known as JAK inhibitors) and the possibility of increasedimmunosuppression and increased infection risk. Both drugs are known to cause elevations in hepatic enzymes and gastrointestinalperforation, and a possibility for increased thrombotic risk. [64572]

Verapamil: (Minor) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderate inhibitors of CYP3A4such as verapamil, a dose adjustment is not necessary, but monitoring patients for toxicity may be prudent. There was an 8% and27% increase in the Cmax and AUC of a single dose of ruxolitinib 10 mg, respectively, when the dose was given after a shortcourse of erythromycin 500 mg PO twice daily for 4 days. The change in the pharmacodynamic marker pSTAT3 inhibition wasconsistent with the increase in exposure. [46782] [6446]

Voriconazole: (Major) Reduce the ruxolitinib dosage during coadministration with voriconazole in patients with myelofibrosis(MF) or polycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur; no dose adjustments are necessary forpatients with graft-versus-host disease. In MF patients, reduce the initial dose to 10 mg PO twice daily for platelet count of100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients, reduce theinitial dose to 5 mg PO twice daily. Avoid the use of voriconazole or interrupt ruxolitinib treatment during voriconazole use in MFor PV patients who are stable on a ruxolitinib dose of 5 mg PO once daily. In MF or PV patients stable on ruxolitinib dose of 10mg PO twice daily or more, reduce dose by 50%; in patients stable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinibto 5 mg PO once daily. Additional dose modifications should be made with frequent monitoring of safety and efficacy. Ruxolitinibis a CYP3A4 substrate; voriconazole is a strong CYP3A4 inhibitor. [28158] [46782]

Zafirlukast: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderate inhibitors of CYP3A4such as zafirlukast, a dose adjustment is not necessary, but monitoring patients for toxicity may be prudent. There was an 8% and27% increase in the Cmax and AUC of a single dose of ruxolitinib 10 mg, respectively, when the dose was given after a shortcourse of erythromycin 500 mg PO twice daily for 4 days. The change in the pharmacodynamic marker pSTAT3 inhibition wasconsistent with the increase in exposure. [2129] [46782] [4948] [7806] [9700]

Revision Date: 05/02/2020 02:31:00 AM

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Monitoring Parameters

CBC with differentialLFTsplatelet countserum creatinine/BUNserum lipid profileserum triglyceridesskin cancer screening exam

US Drug Names

Jakafi

Global Drug names

Argentina

Jakavi - (Novartis)

Australia

Jakavi - (Novartis)

Austria

Jakavi - (Novartis)

Belgium

Jakavi - (Novartis)

Brazil

Jakavi - (Novartis)

Canada

Jakavi - (Novartis)

Chile

Jakavi - (Novartis)

China

Jakavi - (Novartis)

Czech Republic

Jakavi - (Novartis)

Denmark

Jakavi - (Novartis)

Finland

Jakavi - (Novartis)

France

Jakavi - (Novartis)

Germany

Jakavi - (Novartis)

Greece

Jakavi - (Novartis)

Hong Kong

Jakavi - (Novartis)

Hungary

Jakavi - (Novartis)

Ireland

Jakavi - (Novartis)

Israel

Jakavi - (Novartis)

Japan

Jakavi - (Novartis)

Netherlands

Jakavi - (Novartis)

New Zealand

Jakavi - (Novartis)

Norway

Jakavi - (Novartis)

Poland

Jakavi - (Novartis)

Portugal

Jakavi - (Novartis)

Russian Federation

Jakavi - (Novartis)

Singapore

Jakavi - (Novartis)

Spain

Jakavi - (Novartis)

Sweden

Jakavi - (Novartis)

Switzerland

Jakavi - (Novartis)

Thailand

Jakavi - (Novartis)

Turkey

Jakavi - (Novartis)

Ukraine

Jakavi - (Novartis)

United Kingdom

Jakavi - (Novartis)

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