ruxolitinib (Rx)

Brand and Other Names:Jakafi
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

tablet

  • 5mg
  • 10mg
  • 15mg
  • 20mg
  • 25mg
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Myelofibrosis

Kinase inhibitor indicated for treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential thrombocythemia myelofibrosis

Initial doses for myelofibrosis

  • Platelet count >200 x10^9/L: 20 mg PO BID
  • Platelet count 100-200 x10^9/L: 15 mg PO BID
  • Platelet count 50 to <100 x10^9/L: 5 mg PO BID
  • Titrate dose based on response; not to exceed 25 mg PO BID

Dosage Modification (Myelofibrosis)

Dose modification based on response in patients with baseline platelet count >100 X 10^9/L

  • Interrupt treatment for platelet counts <50 x10^9/L
  • Maximum restarting doses after interruption are as follows
    • Platelet count ≥125 x10^9/L: 20 mg BID
    • Platelet count 100 to <125 x10^9/L: 15 mg BID
    • Platelet count 75 to <100 x10^9/L: 10 mg BID for at least 2 weeks; if stable, may increase to 15 mg BID
    • Platelet count 50 to <75 x10^9/L: 5 mg BID for at least 2 weeks; if stable, may increase to 10 mg BID
    • Platelet count <50 x10^9/L: Continue to hold dose
  • When restarting, begin with a dose at least 5 mg PO BID below the dose at interruption

Dose interruptions for ANC

  • Interrupt treatment for ANC <0.5 X 10^9/L
  • After ANC recovers >0.75 X 10^9/L, restart dosing at the higher of 5 mg PO qDay or 5 mg PO BID below the largest dose in the week prior to the treatment interruption

Dose reductions for thrombocytopenia

  • Platelet count 100 to <125 x10^9/L: if taking 25 mg BID, decrease to 20 mg q12hr; if taking 20 mg BID, decrease to 15 mg BID; do not change dose if taking lower doses
  • Platelet count 75 to <100 x10^9/L: 10 mg BID; do not change dose if taking 5 mg BID
  • Platelet count 50 to <75 x10^9/L: 5 mg BID
  • Platelet count <50 x10^9/L: Hold dose

Dosage modification for bleeding (regardless of platelet count)

  • Interrupt treatment until bleeding resolved; may consider resuming at prior dose if underlying cause of bleeding has resolved or at a reduced dose if underlying cause of bleeding persists

Dose modifications based on response

  • If efficacy is considered insufficient and platelet and neutrophil counts are adequate, may increase dose by 5 mg BID increments, not to exceed 25 mg BID
  • Do not increase dose during the first 4 weeks of therapy and not more frequently than q2wk
  • Discontinue treatment after 6 months if there is no spleen size reduction or symptom improvement since initiation of therapy
  • Based on limited clinical data, long-term maintenance at 5 mg q12hr has not shown responses and continued use at this dose should be limited to patients in whom the benefits outweigh the potential risks
  • Consider dose increases in patients with baseline platelet count ≥100 X 10^9/L prior to initial treatment with ruxolitinib who meet all of the following 3 conditions
    • Failure to achieve a reduction from pretreatment baseline in either palpable spleen length of 50% or a 35% reduction in spleen volume as measured by CT or MRI
    • Platelet count >125 x10^9/L at 4 weeks and platelet count never <100 x10^9/L
    • ANC levels >0.75 x10^9/L
  • Consider dose increases in patients with baseline platelet count 50 X 10^9/L to <100 X 10^9/L prior to initial treatment with ruxolitinib who meet all of the following 3 conditions
    • Platelet count remains ≥40 X 109 /L and did not decrease more than 20% in prior 4 weeks
    • ANC >1 X 10^9/L
    • No adverse event or hematological toxicity resulting in dose reduction or interruption occurred in prior 4 weeks

Coadministration with strong CYP3A4 inhibitors or fluconazole

  • Reduce ruxolitinib dose when coadministered with strong CYP3A4 inhibitors or fluconazole (≤200 mg/day)
  • Avoid fluconazole doses >200 mg/day concomitantly with ruxolitinib
  • Starting dose for patients with myelofibrosis based on platelet count
    • Platelet count ≥100 x 10^9/L: 10 mg BID
    • Platelet counts 50 to <100 x 10^9/L: 5 mg BID

Coadministration with CYP3A4 inducers

  • No dose adjustment recommended; however, closely monitor and titrate dose based on safety and efficacy

Renal & Hepatic Impairment (Myelofibrosis)

Renal impairment

  • Moderate-to-severe (CrCl 15-59 mL/min)
    • Platelet count >150 x10^9/L: No dose modification needed
    • Platelet count 100-150 x10^9/L: Starting dose is 10 mg BID
    • Platelet count 50 to <100 x10^9/L: Starting dose is 5 mg qDay
    • Platelet count <50 x10^9/L: Avoid use
  • ESRD (CrCl <15 mL/min)
    • On dialysis and platelet count 100-200 x10^9/L: Starting dose is 15 mg once following dialysis session
    • On dialysis and platelet count >200 x10^9/L: Starting dose is 20 mg once following dialysis session
    • Not on dialysis: Avoid use

Hepatic impairment (any severity)

  • Platelet count >150 x10^9/L: No dose modification needed
  • Platelet count 100-150 x10^9/L: Starting dose is 10 mg BID
  • Platelet count 50 to <100 x10^9/L: Starting dose is 5 mg qDay
  • Platelet count <50 x10^9/L: Avoid use

Polycythemia Vera

Indicated for polycythemia vera in patients who have had an inadequate response to or are intolerant of hydroxyurea

Initial: 10 mg PO BID

Obtain CBC and platelet count before initiating and q2-4wk until doses are stabilized, and then as clinically indicated

Dosage Modification (Polycythemia Vera)

Dose reductions

  • Hgb ≥12 g/dL AND platelet count ≥100 x10^9/L: No change required
  • Hgb 10 to <12 g/dL AND platelet count 75 to <100 x10^9/L: Consider dose reduction with the goal of avoiding dose interruptions for anemia and thrombocytopenia
  • Hgb 8 to <10 g/dL OR platelet count 50 to < 75 x10^9/L: Reduce dose by 5 mg BID; if already on 5 mg BID, then reduce dose to 5 mg qDay
  • Hgb <8 g/dL OR platelet count <50 x10^9/L: Interrupt dosing

Treatment interruption and restarting dosing

  • Interrupt treatment for hgb <8 g/dL, platelet counts <50 x10^9/L, or ANC <1.0 x10^9/L
  • After recovery to acceptable levels, dosing may be restarted
    • Use most severe category for individual parameters
    • Hgb <8 g/dL OR platelet count <50 x10^9/L OR ANC <1 x10^9/L: Continue to hold dosing
    • Hgb 8 to <10 g/dL OR platelet count 50 to <75 x10^9/L OR ANC 1 to <1.5 x10^9/L: 5 mg BID, or not to exceed 5 mg BID less than the dose which resulted in dose interruption
    • Hgb 10 to <12 g/dL OR platelet count 75 to <100 x10^9/L OR ANC 1.5 to <2 x10^9/L: 10 mg BID or not to exceed 5 mg BID less than the dose which resulted in dose interruption
    • Hgb ≥12 g/dL OR platelet count ≥100 x 10^9/L OR ANC ≥2 x10^9/L: 15 mg BID or not to exceed 5 mg BID less than the dose which resulted in dose interruption
  • Reinitiated doses: Continue dose for at least 2 weeks; if stable, may increase dose 5 mg BID
  • Patients who had required dose interruption while receiving a dose of 5 mg BID, may restart at a dose of 5 mg BID or 5 mg qDay, but not higher

Increasing dose for insufficient response

  • If the response is insufficient and platelet, hemoglobin, and neutrophil counts are adequate, doses may be increased in 5 mg BID increments to a maximum of 25 mg BID
  • Doses should not be increased during the first 4 weeks of therapy and not more frequently than q2wk
  • Consider dose increases in patients who meet all of the following criteria:
  • Inadequate efficacy as demonstrated by ≥1 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 <25% from baseline
  • Platelet count ≥140 x10^9/L
  • Hemoglobin ≥2 g/dL
  • ANC ≥1.5 X 10^9/L

Concomitant use with strong CYP3A4 inhibitors

  • Dose reductions for patients with polycythemia vera on concomitant strong CYP3A4 inhibitors or fluconazole doses of ≤200 mg
  • Avoid fluconazole doses >200 mg/day concomitantly with ruxolitinib
  • Starting dose for patients with polycythemia vera
    • Stable on ruxolitinib dose ≥10 mg BID: Reduce dose by 50% (rounded up to the closest available tablet strength)
    • Stable on ruxolitinib dose of 5 mg BID: Reduce to 5 mg once daily
    • Stable on ruxolitinib dose of 5 mg PO qDay: Avoid coadministration with strong CYP3A4 inhibitors or fluconazole treatment or interrupt ruxolitinib treatment for the duration of strong CYP3A4 inhibitor or fluconazole use

Coadministration with CYP3A4 inducers

  • No dose adjustment recommended; however, closely monitor and titrate dose based on safety and efficacy

Renal & Hepatic Impairment (Polycythemia Vera)

Renal impairment

  • Moderate-to-severe (CrCl 15-59 mL/min) with any platelet count: Starting dose is 5 BID
  • ESRD (CrCl <15 mL/min) on dialysis: Starting dose is 10 mg BID; monitor and make additional dose adjustments as needed
  • ESRD (CrCl <15 mL/min) not on dialysis: Avoid use

Hepatic impairment

  • Mild, moderate, or severe (Child-Pugh A, B, C) with any platelet count: Starting dose is 5 BID

Dosing Considerations

Perform complete blood count before initiating therapy

Monitor complete blood counts q2-4 weeks until doses are stabilized, and then as clinically indicated

Modify dose for thrombocytopenia

Orphan Designations

Pancreatic cancer

Graft vs host disease

Orphan sponsor

  • Incyte Corporation; 1801 Augustine Cut-Off; Wilmington, Delaware 19803

Safety and efficacy not established

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Interactions

Interaction Checker

and ruxolitinib

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     activity indicator 
    No Interactions Found
    Interactions Found

    Contraindicated

      Serious - Use Alternative

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            Adverse Effects

            >10%

            Anemia (96.1%)

            Thrombocytopenia (69.7%)

            Increased ALT, grade 1 (25.2%)

            Bruising (23.2%)

            Neutropenia (18.7%)

            Dizziness (18.1%)

            Increased AST, grade 1 (17.1%)

            Increased cholesterol, grade 1 (16.8%)

            Headache (14.8%)

            1-10%

            Urinary tract infection (9%)

            Weight gain (7.1%)

            Flatulence (5.2%)

            Herpes zoster (1.9%)

            Increased ALT, grade 2 (1.9%)

            Increased ALT, grade 3 (1.3%)

            <1%

            Increased AST, grade 2 (0.6%)

            Increased cholesterol, grade 2 (0.6%)

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            Warnings

            Contraindications

            Hypersensitivity

            Cautions

            Nonmelanoma skin cancers reporrted including basal cell, squamous cell, and Merkel cell carcinoma

            Thrombocytopenia, anemia, & neutropenia

            • CBC must be performed before initiating therapy and should be monitored as clinically indicated and dosing adjusted as required
            • Patients with platelet counts <200 x10^9/L at the start of therapy are more likely to develop thrombocytopenia during treatment
            • Thrombocytopenia was generally reversible and was usually managed by reducing the dose or temporarily withholding dose (see Adult Dosing); if clinically indicated, platelet transfusions may be administered
            • Anemia may require blood transfusions; dose modifications may also be considered
            • Neutropenia (ANC <0.5 x10^9/L) was generally reversible and was managed by temporarily withholding dose

            Infections

            • Patients should be assessed for the risk of developing serious bacterial, mycobacterial, fungal, and viral infections
            • Active serious infections should have resolved before starting therapy
            • Tuberculosis (TB) infection has been reported; before initiating, evaluate patients for TB risk factors, and those at higher risk should be tested for latent infection
            • Carefully observe patients for signs and symptoms of infection and initiate appropriate treatment promptly
            • Herpes zoster: Inform patients about early signs and symptoms of herpes zoster and advise to seek treatment as early as possible
            • Progressive multifocal leukoencephalopathy (PML): Reported with ruxolitinib treatment for myelofibrosis; if suspected, discontinue drug and evaluate
            • Hepatitis B viral load (HBV-DNA titer) increases, with or without associated elevations in alanine aminotransferase and aspartate aminotransferase, reported in patients with chronic HBV infection; effect of ruxolitinib on viral replication unknown; treat and monitor patients with chronic HBV infection according to clinical guidelines

            CYP3A4 inhibitors

            • Ruxolitinib is predominantly metabolized by CYP3A4
            • Strong CYP3A4 inhibitors increase ruxolitinib Cmax and AUC 33% and 91%, respectively
            • Dose modification recommended when coadministered with strong CYP3A4 inhibitors (such as but not limited to boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole); see Adult Dosing

            Symptoms with dose interruption, dose tapering, or discontinuing

            • Following discontinuation/interruption, myelofibrosis symptoms may be exacerbated and general return to pretreatment levels after 1 week
            • Other adverse effects reported include fever, respiratory distress, hypotension, DIC, or multiorgan failure
            • If these symptoms occur after discontinuation or dose tapering, evaluate and treat any intercurrent illness and consider restarting ruxolitinib or increase the dose
            • Instruct patients not to interrupt or discontinue ruxolitinib without consulting their physician
            • When discontinuing or interrupting therapy for reasons other than thrombocytopenia or neutropenia, consider tapering the dose gradually rather than discontinuing abruptly

            Hyperlipidemia

            • Treatment has been associated with increases in lipid parameters including total cholesterol, low density lipoprotein, and triglycerides; assess lipid parameters approximately 8-12 weeks following initiation of therapy; monitor according to clinical guidelines for management of hyperlipidemia
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            Pregnancy & Lactation

            Pregnancy

            When pregnant rats and rabbits were administered ruxolitinib during period of organogenesis adverse developmental outcomes occurred at doses associated with maternal toxicity; there are no studies with use in pregnant women to inform drug-associated risks; the background risk of major birth defects and miscarriage for indicated populations is unknown; adverse outcomes in pregnancy occur regardless of health of mother or use of medications

            Lactation

            No data are available regarding presence of ruxolitinib in human milk, effects on breast fed infant, or on milk production; the drug and/or its metabolites were present in milk of lactating rats; because many drugs are present in human milk and because of potential for thrombocytopenia and anemia shown in human studies, discontinue breastfeeding during treatment and for two weeks after final dose

            Pregnancy Categories

            A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA:Information not available.

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            Pharmacology

            Mechanism of Action

            Kinase inhibitor; inhibits Janus Associated Kinases (JAKs) JAK1 and JAK2 which mediate the signaling of a number of cytokines and growth factors that are important for hematopoiesis and immune function

            JAK signaling involves recruitment of STATs (signal transducers and activators of transcription) to cytokine receptors, activation and subsequent localization of STATs to the nucleus leading to modulation of gene expression

            Myelofibrosis (MF) is a myeloproliferative neoplasm (MPN) known to be associated with dysregulated JAK1 and JAK2 signaling

            Absorption

            Bioavailability: 95%

            Peak plasma time: 1-2 hr

            Distribution

            Protein bound: 97% (mostly albumin)

            Vd: 53-65 L

            Metabolism

            Ruxolitinib is the predominant entity in humans representing approximately 60% of the drug-related material in circulation

            Metabolized by CYP3A4 (major)

            Metabolites: 2 major active metabolites identified representing 25% and 11% of parent AUC; these 2 metabolites have 20% and 50% of ruxolitinib’s pharmacological activity, respectively; the sum total of all active metabolites contributes 18% of the overall pharmacodynamics of ruxolitinib

            Elimination

            Half-life: 2.8- 3 hr (ruxolitinib); 5.8 hr (ruxolitinib plus metabolites); 5 hr (hepatic impairment)

            Excretion: feces (22%), urine (74%); unchanged drug accounted for <1%

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            Administration

            Oral Administration

            May administer with or without food

            If a dose is missed, patients should not take an additional dose, but take the next usual prescribed dose

            When discontinuing for reasons other than thrombocytopenia, consider gradual tapering the dose (eg, by 5 mg q12hr per week)

            NG tube administration

            • If unable to ingest tablets, can be administered through a nasogastric tube (8 French or greater) as follows
              • Suspend 1 tablet in approximately 40 mL of water with stirring for approximately 10 minutes
              • Administer suspension within 6 hr after the tablet has dispersed through NG using an appropriate syringe
              • Rinse NG tube with ~75 mL of water
              • Effect of tube feeding preparations on ruxolitinib exposure during administration through NG has not been evaluated

            Storage

            Store at room temperature 20-25°C (68-77°F); excursions permitted between 15-30°C (59-86°F)

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            Formulary

            FormularyPatient Discounts

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            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
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