Usual Adult Dose for Myeloproliferative Disorder

Doses should be titrated based on safety and efficacy; CBC (complete blood count) and platelet counts should be performed every 2 to 4 weeks until doses are stabilized and then as clinically indicated

Initial Dose Based on Platelet Count:

• Platelets greater than 200 x 10(9)/L: 20 mg orally twice a day
• Platelets 100 x 10(9)/L to 200 x 10(9)/L: 15 mg orally twice a day
• Platelets 50 x 10(9)/L to less than 100 x 10(9)/L: 5 mg orally twice a day

INSUFFICIENT RESPONSE: Failure to achieve a reduction from baseline in either palpable spleen length of 50% or a 35% reduction in spleen volume as measured by computed tomography (CT) or magnetic resonance imaging (MRI); Platelet count greater than 125 × 10(9)/L at 4 weeks and platelet count never below 100 × 10(9)/L; ANC Levels greater than 0.75 × 10(9)/L
For Patients Starting Treatment with a Platelet Count of 100 × 10(9)/L or greater:

• May increase in 5 mg twice a day increments after the first 4 weeks and then no more frequently than every 2 weeks if response is insufficient and platelet and neutrophil counts are adequate; MAXIMUM DOSE: 25 mg orally twice a day

For Patients Starting Treatment with a Platelet Count of 50 to less than 100 × 10(9)/L or greater:

• May increase in 5 mg once a day increments to a maximum of 5 mg twice a day after the first 4 weeks and then no more frequently than every 2 weeks if response is insufficient and platelet count remains at least 40 × 10(9)/L, platelet count has not fallen by more than 20% in the prior 4 weeks, the ANC is more than 1 × 10(9)/L, and the dose has not been reduced or interrupted for an adverse event or hematological toxicity in the prior 4 weeks

DOSE MODIFICATIONS FOR HEMATOLOGIC TOXICITY: For Patients Starting Treatment with a Platelet Count of 100 × 10(9)/L or greater:
INTERRUPT treatment for PLATELET COUNTS less than 50 x 10(9)/L or ANC (absolute neutrophil count) less than 0.5 x 10(9)/L: RESTART once platelet count is above 50 x 10(9)/L and ANC above 0.75 x 10(9)/L

• When restarting, begin with a dose that is at least 5 mg twice a day below the dose at interruption
• Maximum Restarting Dose after Interruption for Thrombocytopenia:
• Platelet Count: Greater than or equal to 125 × 10(9)/L: Restart at no more than 20 mg twice a day
• Platelet Count 100 to less than 125 × 10(9)/L: Restart at no more than 15 mg twice a day
• Platelet Count 75 to less than 100 × 10(9)/L: Restart at no more than 10 mg twice a day for at least 2 weeks; if stable, may increase to 15 mg twice a day
• Platelet Count 50 to less than 75 × 10(9)/L: Restart at no more than 5 mg twice a day for at least 2 weeks; if stable, may increase to 10 mg twice a day

INTERRUPT treatment for ANC below 0.5 × 10(9)/L, restart once ANC recovers to 0.75 × 10(9)/L or greater: Restart at the higher of 5 mg once a day OR 5 mg twice a day below the largest dose in the week prior to the treatment interruption
DOSE REDUCTIONS: To Avoid Dose Interruptions for Thrombocytopenia Among Patients Starting Treatment with a Platelet Count of 100 x 10(9)/L or greater, consider the following:
If Dose at time of Thrombocytopenia is 25 mg twice a day:

• Reduce dose to 20 mg twice a day for platelet count of 100 to less than 125 x 10(9)/L
• Reduce dose to 10 mg twice a day for platelet count of 75 to less than 100 x 10(9)/L
• Reduce dose to 5 mg twice a day for platelet count of 50 to less than 75 x 10(9)/L

If Dose at time of Thrombocytopenia is 20 mg twice a day:

• Reduce dose to 15 mg twice a day for platelet count of 100 to less than 125 x 10(9)/L
• Reduce dose to 10 mg twice a day for platelet count of 75 to less than 100 x 10(9)/L
• Reduce dose to 5 mg twice a day for platelet count of 50 to less than 75 x 10(9)/L

If Dose at time of Thrombocytopenia is 15 mg twice a day:

• Reduce dose to 10 mg twice a day if platelet count is 75 to less than 100 x 10(9)/L
• Reduce dose to 5 mg twice a day if platelet count is 50 to less than 75 x 10(9)/L

If Dose at time of Thrombocytopenia is 10 mg twice a day:

• Reduce dose to 5 mg twice a day if platelet count is 50 to less than 75 x 10(9)/L

DOSE MODIFICATIONS FOR HEMATOLOGIC TOXICITY: For Patients Starting Treatment with a Platelet Count of 50 to less than 100 × 10(9)/L or greater:
INTERRUPT treatment for PLATELET COUNTS less than 25 x 10(9)/L or ANC less than 0.5 x 10(9)/L
RESTART once platelet count is above 35 x 10(9)/L and ANC above 0.75 x 10(9)/L

• Restart at the higher of 5 mg once a day or 5 mg twice a day below the largest dose in the week prior to the decrease in platelet count below 25 x 10(9)/L or ANC below 0.5 x 10(9)/L that led to dose interruption

REDUCE dose for PLATELET COUNTS less than 35 x 10(9)/L:

• Platelet Count less than 25 x 10(9)/L: Interrupt dosing
• Platelet Count 25 to less than 35 x 10(9)/L AND the platelet count decline is less than 20% during the prior 4 weeks: Decrease by 5 mg once a day; for patients on 5 mg once a day, maintain this dose
• Platelet Count 25 to less than 35 x 10(9)/L AND the platelet count decline is 20% or greater during prior 4 weeks: Decrease by 5 mg twice a day; for patients on 5 mg twice a day, decrease to 5 mg once a day; for patients on 5 mg once a day, maintain this dose

DOSE MODIFICATION FOR BLEEDING:

• Interrupt treatment for bleeding requiring intervention regardless of current platelet count
• Once bleeding event resolves, consider resuming at prior dose if the underlying cause of bleeding has been controlled
• If the bleeding event has resolved but the underlying cause persists, consider resuming treatment with at a lower dose

Comments:

• Based on limited clinical data, long-term maintenance at 5 mg twice a day has not shown benefit; this dose should be limited to patients for whom the benefits outweigh the potential risks.
• Discontinue therapy if there is no spleen size reduction or symptom improvement after 6 months of therapy.

Uses:

• For the treatment of intermediate or high-risk myelofibrosis (MF), including primary MF, post-polycythemia vera MF, and post-essential thrombocythemia MF.

Usual Adult Dose for Graft Versus Host Disease

Monitor complete blood counts (CBC), including platelet count and ANC, and bilirubin prior to
initiating therapy, every 2 to 4 weeks until doses are stabilized, and then as indicated clinically:

Acute Graft-Versus-Host Disease (GVHD): Initial dose: 5 mg orally 2 times a day

• Dose titration: Consider increasing dose to 10 mg orally 2 times a day after at least 3 days if the ANC (absolute neutrophil count) and platelet counts are not decreased by 50% or more relative to the first day of dosing

Duration of therapy: Consider tapering after 6 months for those with response who have stopped therapeutic doses of corticosteroids; taper by 1 dose level every 8 weeks (see comments); if signs or symptoms of GVHD recur during or after taper, consider retreatment

Chronic GVHD: Initial dose: 10 mg orally 2 times a day

• Duration of therapy: Consider tapering after 6 months for those with response who have stopped therapeutic doses of corticosteroids; taper by 1 dose level every 8 weeks (see comments); if signs or symptoms of GVHD recur during or after taper, consider retreatment

Comments:

• Dose level decreases: 10 mg twice a day to 5 mg twice a day to 5 mg once a day.
• See Dose Adjustment section for dose modification guidance for adverse reactions.

Uses: For the treatment of steroid-refractory acute GVHD and treatment of chronic GVHD after failure of 1 or 2 lines of systemic therapy.

Usual Adult Dose for Polycythemia Vera

Doses should be titrated based on safety and efficacy; CBC and platelet counts should be performed every 2 to 4 weeks until doses are stabilized and then as clinically indicated

Initial dose: 10 mg orally twice a day

• Dose may be titrated based on safety and efficacy

INSUFFICIENT RESPONSE: Consider dose increases in patients with inadequate efficacy as demonstrated by one or more of the following: Continued need for phlebotomy; WBC greater than the upper limit of normal range; Platelet count greater than the upper limit of normal range; Palpable spleen that is reduced by less than 25% from baseline; Platelet count greater than or equal to 140 × 10(9)/L;. Hb (hemoglobin) greater than or equal to 12 g/dL; ANC greater than or equal to 1.5 × 10(9)/L
DOSE INCREASES: Increased dose in 5 mg twice a day increments to a MAXIMUM of 25 mg twice a day; doses should not be increased during the first 4 weeks of therapy and not more frequently than every two weeks

DOSE REDUCTIONS: Dose reductions should be considered for Hb and platelet count decreases:

• Hb greater than or equal to 12 g/dL AND platelet count greater than or equal to 100 × 10(9)/L: No change needed
• Hb 10 to less than 12 g/dL AND platelet count 75 to less than 100 × 10(9)/L: Dose reductions should be considered with the goal of avoiding dose interruptions for anemia and thrombocytopenia
• Hb 8 to less than 10 g/dL OR platelet count 50 to less than 75 × 10(9)/L: Reduce dose by 5 mg twice a day; for patients on 5 mg twice a day, decrease the dose to 5 mg once a day
• Hb less than 8 g/dL OR platelet count less than 50 × 10(9)/L OR ANC less than 1 x 10(9)/L: Interrupt dosing

RESTARTING THERAPY: After recovery of hematologic parameter(s) to acceptable levels, dosing may be restarted: Restarted doses may be titrated, but the maximum total daily dose should not exceed 5 mg less than the dose that resulted in the dose interruption (One exception: following phlebotomy-associated anemia, the maximal total daily dose allowed would not be limited). Use the most severe category of a patient's Hb, platelet count, or ANC abnormality to determine the corresponding MAXIMUM restarting dose:

• Hb 8 to less than 10 g/dL OR platelet count 50 to less than 75 × 10(9)/L OR ANC 1 to less than 1.5 × 10(9)/L: MAXIMUM restarting dose: 5 mg twice a day or no more than 5 mg twice a day less than the dose which resulted in dose interruption
• Hb 10 to less than 12 g/dL OR platelet count 75 to less than 100 × 10(9)/L OR ANC 1.5 to less than 2 × 10(9)/L: MAXIMUM restarting dose: 10 mg twice day or no more than 5 mg twice a day less than the dose which resulted in dose interruption
• Hb greater than or equal to 12 g/dL OR platelet count greater than or equal to 100 × 10(9)/L OR ANC greater than or equal to 2 × 10(9)/L: MAXIMUM restarting dose: 15 mg twice a day or no more than 5 mg twice a day less than the dose which resulted in dose interruption

TITRATION: Dose should be continued for at least 2 weeks, if stable may increase dose by 5 mg twice a day

Use: For treatment of polycythemia vera (PV) in adults who have had an inadequate response to or are intolerant of hydroxyurea.

Usual Pediatric Dose for Graft Versus Host Disease

12 years or older:

Monitor complete blood counts (CBC), including platelet count and ANC, and bilirubin prior to
initiating therapy, every 2 to 4 weeks until doses are stabilized, and then as indicated clinically:

Acute Graft-Versus-Host Disease (GVHD): Initial dose: 5 mg orally 2 times a day

• Dose titration: Consider increasing dose to 10 mg orally 2 times a day after at least 3 days if the ANC (absolute neutrophil count) and platelet counts are not decreased by 50% or more relative to the first day of dosing

Duration of therapy: Consider tapering after 6 months for those with response who have stopped therapeutic doses of corticosteroids; taper by 1 dose level every 8 weeks (see comments); if signs or symptoms of GVHD recur during or after taper, consider retreatment

Chronic GVHD: Initial dose: 10 mg orally 2 times a day

• Duration of therapy: Consider tapering after 6 months for those with response who have stopped therapeutic doses of corticosteroids; taper by 1 dose level every 8 weeks (see comments); if signs or symptoms of GVHD recur during or after taper, consider retreatment

Comments:

• Dose level decreases: 10 mg twice a day to 5 mg twice a day to 5 mg once a day.
• See Dose Adjustment section for dose modification guidance for adverse reactions.

Uses: For the treatment of steroid-refractory acute GVHD and treatment of chronic GVHD after failure of 1 or 2 lines of systemic therapy in pediatric patients 12 years or older.

Renal Dose Adjustments

Mild Renal Impairment (CrCl 60 mL/min or greater): No adjustment recommended

Moderate or Severe Renal Impairment (CrCl 15 to less than 60 mL/min):

• MF: Platelet Count greater than 150 x 10(9)/L: No adjustment recommended
• MF: Platelet Count: 100 to 150 x 10(9)/L: Initial dose: 10 mg twice a day
• MF: Platelet Count: 50 to less than 100 x 10(9)/L: Initial dose: 5 mg once a day
• MF: Platelets less than 50 x 10(9)/L: Avoid use
• MF: ESRD (CrCl less than 15 mL/min) not on dialysis: Avoid use
• MF: ESRD on dialysis: See Dialysis

Moderate or Severe Renal Impairment (CrCl 15 to less than 60 mL/min):

• PV: Initial dose: 5 mg twice a day
• PV: ESRD (CrCl less than 15 mL/min) not on dialysis: Avoid use
• PV: ESRD on dialysis: See Dialysis

Moderate or Severe Renal Impairment (CrCl 15 to less than 60 mL/min):

• Acute GVHD: Initial dose: 5 mg mg once a day
• Chronic GVHD: Initial dose: 5 mg twice a day
• GVHD (acute or chronic) (CrCl less than 15 mL/min) not on dialysis: Avoid use
• GVHD (acute or chronic): ESRD on dialysis: See Dialysis

Liver Dose Adjustments

Mild, Moderate or Severe Hepatic Impairment (Child Pugh Class A, B, C):

• MF: Platelet Count greater than 150 x 10(9)/L: No adjustment recommended
• MF: Platelet Count: 100 to 150 x 10(9)/L: Initial dose: 10 mg twice a day
• MF: Platelet Count: 50 to less than 100 x 10(9)/L: Initial dose: 5 mg once a day
• MF: Platelets less than 50 x 10(9)/L: Avoid use

Mild, Moderate or Severe Hepatic Impairment (Child Pugh Class A, B, C):

• PV: Initial dose: 5 mg twice a day

Acute GVHD:

• Mild, Moderate or Severe Hepatic Impairment (based on NCI criteria without liver GVHD): No adjustment recommended
• Stage 1, 2 or 3 Liver Acute GVHD: No adjustment recommended
• Stage 4 Liver Acute GVHD: Initial dose: 5 mg once a day

Chronic GVHD:

• Mild, Moderate or Severe Hepatic Impairment (based on NCI criteria without liver GVHD): No adjustment recommended
• Score 1 or 2 Liver Chronic GVHD: No adjustment recommended
• Score 3 Liver Chronic GVHD: Monitor blood counts more frequently for toxicity and modify dosage for adverse reactions if they occur

Dose Adjustments

DRUG INTERACTIONS:

• Avoid concomitant use of Ruxolitinib with Fluconazole at doses greater than 200 mg/day
• Modify dose of Ruxolitinib when used with Strong CYP450 3A4 Inhibitors or Fluconazole less than 200 mg/day
• MF: Initial dose with platelets 100 x 10(9)/L or greater: 10 mg twice a day
• MF: Initial dose with platelets 50 to less than 100 x 10(9)/L: 5 mg once a day
• PV: Initial dose: 5 mg twice a day

MF OR PV ON STABLE RUXOLITINIB (adding strong CYP450 3A4 inhibitor or fluconazole dose less than 200 mg/day):

• Dose greater than or equal to 10 mg twice a day: Decrease dose by 50% (rounded to closest tablet strength)
• Stable on 5 mg twice a day: Reduce to 5 mg once a day
• Stable on 5 mg once a day: Avoid use of strong CYP450 3A4 inhibitor or fluconazole or interrupt ruxolitinib for the duration of strong CYP450 3A4 inhibitor or fluconazole use

ACUTE GVHD: With fluconazole 200 mg/day or less: Initial dose: 5 mg once a day
CHRONIC GVHD: With fluconazole 200 mg/day or less: Initial dose: 5 mg twice a day
ACUTE OR CHRONIC GVHD: With CYP450 3A4 Inhibitors: Monitor blood counts more frequently for toxicity and modify the ruxolitinib dosage for adverse reactions if they occur

GVHD: DOSE MODIFICATIONS for ADVERSE REACTIONS
Dose Level Reductions for Patients with GVHD:

• A dose of 10 mg twice a day should be reduced to 5 mg twice a day
• A dose of 5 mg twice a day should be reduced to 5 mg once a day
• Patients unable to tolerate 5 mg once a day should have treatment interrupted until their clinical and/or laboratory parameters recover

DOSE MODIFICATION for Patients with ACUTE GVHD:

• Clinically significant thrombocytopenia after supportive measures: Reduce dose by 1 level; when platelets recover to previous values, dosing may return to prior dose level
• ANC less than 1 × 10(9) considered related to therapy: Hold for up to 14 days; resume at 1 dose level lower upon recovery
• Total Bilirubin Elevation, no liver GVHD:
• Total bilirubin elevated 3 to 5 × ULN (times upper limit of normal), continue at 1 dose level lower until recovery
• Total bilirubin elevated greater than 5 to less than 10 × ULN, hold for up to 14 days until bilirubin is 1.5 or less than ULN, resume at current dose upon recovery
• Total bilirubin greater than 10 × ULN, hold for up to 14 days until bilirubin is 1.5 or less than ULN, resume at 1 dose level lower upon recovery
• Total Bilirubin Elevation, liver GVHD: Total bilirubin greater than 3 × ULN, continue at 1 dose level lower until recovery

DOSE MODIFICATION for Patients with CHRONIC GVHD:

• Platelet count less than 20 × 10(9)/L: Reduce by 1 dose level; if resolved within 7 days, may return to initial dose level, if not resolved within 7 days, maintain at 1 dose level lower
• ANC less than 0.75 × 10(9)/L (considered related to therapy): Reduce by 1 dose level, resume at initial dose level upon recovery
• ANC less than 0.5 × 10(9)/L (considered related to therapy): Hold for up to 14 days, resume at 1 dose level lower upon recovery; may resume initial dose level when ANC greater than 1 × 10(9)/L
• Total bilirubin elevated 3 to 5 × ULN: Continue at 1 dose level lower until recovery; if resolved within 14 days, then increase by 1 dose level, if not resolved within 14 days, then maintain the decreased dose level
• Total bilirubin elevated greater than 5 to less than 10 × ULN: Hold for up to 14 days until resolved; resume at current dose upon recovery, if not resolved within 14 days, resume at 1 dose level lower upon recovery
• Total bilirubin greater than 10 × ULN: Hold for up to 14 days until resolved, resume at 1 dose level lower upon recovery, if not resolved within 14 days, discontinue
• Other Adverse Reactions: Grade 3: Continue at 1 dose level lower until recovery
• Other Adverse Reactions: Grade 4: Discontinue

Therapy Discontinuation:

• MF or PV: When discontinuing therapy for reasons other than thrombocytopenia, a gradual tapering should be considered, for example by 5 mg twice daily each week.
• Acute or Chronic GVHD: Consider tapering therapy after 6 months in patients with response who have discontinued therapeutic doses of corticosteroids; taper by 1 dose level approximately every 8 weeks (10 mg twice daily to 5 mg twice daily to 5 mg once daily). If GVHD signs or symptoms recur during or after the taper, consider retreatment

Precautions

CONTRAINDICATIONS: None

Safety and efficacy have not been established in patients younger than 18 years.

Consult WARNINGS section for additional precautions.

Dialysis

Hemodialysis:

• MF: Platelet Count: 100 to 200 × 10(9)/L: Initial dose: 15 mg once after dialysis session
• MF: Platelet Count: Greater than 200 × 10(9)/L: Initial dose: 20 mg once after dialysis session
• PV: Initial dose: 10 mg once after dialysis session
• Acute GVHD: Initial dose: 5 mg once after dialysis session
• Chronic ESRD: Initial dose: 10 mg once after dialysis session

Peritoneal Dialysis: Data not available

Other Comments

Administration advice:

• Take orally without regard to meals
• For a missed dose, the patient should not take an additional dose, but should take the next usual scheduled dose

Reconstitution/preparation techniques:
May be administered through a nasogastric tube (8 French or greater):

• Suspend 1 table in approximately 40 mL of water; stir for approximately 10 minutes
• Administer suspension using an appropriate syringe within 6 hours of the tablet being dispersed; rinse with 75 mL of water after administration
• The effect of tube feeding preparations on drug exposure has not been evaluated

Monitoring:

• Perform pretreatment complete blood count (CBC) and monitor CBCs every 2 to 4 weeks until doses are stabilized, and then as clinically indicated
• Perform periodic skin examinations
• Assess lipid parameters approximately 8¬ to 12 weeks following initiation of therapy; monitor accordingly

Patient advice:

• Patients should be advised to read the FDA-approved patient labeling (Patient Information).
• Patients should be aware of potential adverse events including thrombocytopenia, anemia, neutropenia, infections, and increased cholesterol.
• Patients should be advised to continue therapy as prescribed and talk with their healthcare provider prior to discontinuation.
• Patients should be aware that drug interactions may require dose modifications and they should discuss all medication use with their healthcare provider.

Frequently asked questions

• What are the most common skin conditions? (with photos)