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Ruxolitinib – Uses, Dosage, Side Effects, Interaction

Dr. Harun Ar Rashid, MD - Arthritis, Bones, Joints Pain, Trauma, and Internal Medicine Specialist Dr. Harun Ar Rashid, MD - Arthritis, Bones, Joints Pain, Trauma, and Internal Medicine Specialist
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Drugs (A - Z)

Ruxolitinib is a small molecule Janus kinase inhibitor that is used in the treatment of intermediate or high-risk myelofibrosis and resistant forms of polycythemia vera and graft-vs-host disease. Ruxolitinib is associated with transient and usually mild elevations in serum aminotransferase during therapy and too rare instances of self-limited, clinically apparent idiosyncratic acute liver injury as well as to cases of reactivation of hepatitis B in susceptible individuals.

Ruxolitinib is an orally bioavailable Janus-associated kinase (JAK) inhibitor with potential antineoplastic and immunomodulating activities. Ruxolitinib specifically binds to and inhibits protein tyrosine kinases JAK 1 and 2, which may lead to a reduction in inflammation and an inhibition of cellular proliferation. The JAK-STAT (signal transducer and activator of transcription) pathway plays a key role in the signaling of many cytokines and growth factors and is involved in cellular proliferation, growth, hematopoiesis, and the immune response; JAK kinases may be upregulated in inflammatory diseases, myeloproliferative disorders, and various malignancies.

Ruxolitinib is a pyrazole substituted at position 1 by a 2-cyano-1-cyclopentyl methyl group and at position 3 by a pyrrolo[2,3-d]pyrimidin-4-yl group. Used as the phosphate salt for the treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis. It has a role as an antineoplastic agent and an EC 2.7.10.2 (non-specific protein-tyrosine kinase) inhibitor. It is a nitrile, a pyrrolopyrimidine, and a member of pyrazoles.

Ruxolitinib Phosphate is the phosphate salt form of ruxolitinib, an orally bioavailable Janus-associated kinase (JAK) inhibitor with potential antineoplastic and immunomodulating activities. Ruxolitinib specifically binds to and inhibits protein tyrosine kinases JAK 1 and 2, which may lead to a reduction in inflammation and an inhibition of cellular proliferation. The JAK-STAT (signal transducer and activator of transcription) pathway plays a key role in the signaling of many cytokines and growth factors and is involved in cellular proliferation, growth, hematopoiesis, and the immune response; JAK kinases may be upregulated in inflammatory diseases, myeloproliferative disorders, and various malignancies.

Ruxolitinib phosphate is a phosphate salt obtained by the reaction of ruxolitinib with one equivalent of phosphoric acid. Used for the treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis. It has a role as an antineoplastic agent and an EC 2.7.10.2 (non-specific protein-tyrosine kinase) inhibitor. It contains ruxolitinib.

Ruxolitinib was first approved for the treatment of adult patients with myelofibrosis by the FDA in 2011, followed by EMA’s approval in 2012. In 2014, it was approved for the treatment of polycythemia vera in adults who have an inadequate response to or are intolerant of hydroxyurea, and in 2019, ruxolitinib was approved for use in steroid-refractory acute graft-versus-host disease in adults, and children.[rx] The topical formulation of ruxolitinib is used to treat atopic dermatitis and vitiligo. It is being investigated for other inflammatory skin conditions.[rx]

Mechanism of Action

The Janus kinase (JAK) family of protein tyrosine kinases comprises JAK1, JAK2, JAK3, and non-receptor tyrosine kinase 2 (TYK2). JAKs play a pivotal role in intracellular signalling pathways of various cytokines and growth factors essential to hematopoiesis, such as interleukin, erythropoietin, and thrombopoietin. JAKs have diverse functions: JAK1 and JAK3 promote lymphocyte differentiation, survival, and function, while JAK2 promotes signal transduction of erythropoietin and thrombopoietin. JAKs are in close proximity to the cytokine and growth factor receptor’s cytoplasmic region. Upon binding of cytokines and growth factors, JAKs are activated, undergoing cross-phosphorylation and tyrosine phosphorylation. This process also reveals selective binding sites for STATs, which are DNA-binding proteins that also bind to the cytoplasmic region of cytokine or growth factor receptors. Activated JAKs and STATs translocate to the nucleus as transcription factors to regulate gene expression of pro-inflammatory cytokines such as IL-6, IL-10, and nuclear factor κB (NF-κB). They also activate downstream pathways that promote erythroid, myeloid, and megakaryocytic development. The molecular pathogenesis of myeloproliferative neoplasms is not fully understood; however, JAK2 is constitutively activated and the JAK-STAT signaling pathway becomes deregulated and aberrant. Ruxolitinib is a selective and potent inhibitor of JAK2 and JAK1, with some affinity against JAK3 and TYK2. Anticancer effects of ruxolitinib are attributed to its inhibition of JAKs and JAK-mediated phosphorylation of STAT3. By downregulating the JAK-STAT pathway, ruxolitinib inhibits myeloproliferative and suppresses the plasma levels of pro-inflammatory cytokines such as IL-6 and TNF-α. Activated JAKs are also implicated in graft-versus-host-disease (GVHD), which is a severe immune complication of allogeneic hematopoietic cell transplantation GVHD is associated with significant morbidity and mortality, especially for patients who do not respond well to corticosteroid therapy. Activated JAKS stimulate T-effector cell responses, leading to increased proliferation of effector T cells and heightened production of pro-inflammatory cytokines. By blocking JAK1 and JAk2, ruxolitinib inhibits donor T-cell expansion and suppresses pro-inflammatory responses. By directly targeting both JAK1 and JAK2 through small-molecule inhibition, ruxolitinib elicits a reduction in splenomegaly and disease-related symptoms in patients with intermediate- or high-risk myelofibrosis while maintaining an acceptable toxicity profile and a low treatment-discontinuation rate.

or

Ruxolitinib phosphate, a selective inhibitor of Janus kinase (JAK) 1 and 2, is an antineoplastic agent. JAK1 and 2 mediate the signaling of cytokines and growth factors that are important for hematopoiesis and immune function. JAK signaling involves the recruitment of signal transducers and activators of transcription (STAT) to cytokine receptors, activation, and subsequent localization of STATs to the nucleus leading to modulation of gene expression. Myelofibrosis is a myeloproliferative neoplasm known to be associated with dysregulated JAK1 and 2 signalings. Ruxolitinib demonstrated dose- and time-dependent inhibition of cytokine-induced phosphorylated STAT3 with maximal inhibition occurring 1-2 hours after single-dose administration (ranging from 5-200 mg) in healthy individuals at all dosage levels.

Ruxolitinib is an antineoplastic agent that inhibits cell proliferation, induces apoptosis of malignant cells, and reduces pro-inflammatory cytokine plasma levels by inhibiting JAK-induced phosphorylation of signal transducer and activator of transcription (STAT). Inhibition of STAT3 phosphorylation, which is used as a marker of JAK activity, by ruxolitinib is achieved at two hours after dosing which returned to near baseline by 10 hours in patients with myelofibrosis and polycythemia vera. In clinical trials, ruxolitinib reduced splenomegaly and improved symptoms of myelofibrosis. In a mouse model of myeloproliferative neoplasms, administration of ruxolitinib was associated with prolonged survival. Ruxolitinib inhibits both mutant and wild-type JAK2; however, JAK2V617F mutation, which is often seen in approximately 50% of patients with myelofibrosis, was shown to reduce ruxolitinib sensitivity, which may also be associated with possible resistance to JAK inhibitor treatment.

Indications

  • Ruxolitinib is indicated for the treatment of the following conditions: – intermediate or high-risk myelofibrosis (MF), including prima1y MF, post-polycythemia vera MF and post-essential thrombocythemia MF in adults. It is also used to treat disease-related splenomegaly or symptoms in adult patients with these conditions. – polycythemia vera (PV) in adults who have had an inadequate response to or are intolerant of hydroxyurea. – steroid-refracto1y acute graft-versus-host disease (GVHD) in adult and pediatric patients 12 years and older. – chronic GVHD in patients aged 12 years and older who have failed one or two lines of systemic therapy. Topical ruxolitinib is indicated for: – the short-term and non-continuous chronic treatment of mild to moderate atopic dermatitis in non-immunocompromised patients 12 years of age and older whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable. – the treatment of nonsegmental vitiligo in adult and pediatric patients 12 years of age and older.
  • Myelofibrosis (MF): Jakavi is indicated for the treatment of disease-related splenomegaly or symptoms in adult patients with primary myelofibrosis (also known as chronic idiopathic myelofibrosis), post polycythemia vera myelofibrosis or post essential thrombocythaemia myelofibrosis.
  • Polycythaemia vera (PV): Jakavi is indicated for the treatment of adult patients with polycythemia vera who are resistant to or intolerant of hydroxyurea.
  • Graft versus host disease (GvHD): Jakavi is indicated for the treatment of patients aged 12 years and older with acute graft versus host disease or chronic graft versus host disease who have an inadequate response to corticosteroids or other systemic therapies.
  • Ruxolitinib is a small molecule Janus kinase inhibitor that is used in the treatment of intermediate or high-risk myelofibrosis and resistant forms of polycythemia vera and graft-vs-host disease.
  • Treatment of vitiligo.
  • Ruxolitinib is a kinase inhibitor used to treat various types of myelofibrosis, and polycythemia vera in patients who have not responded to or cannot tolerate hydroxyurea, and to treat graft-versus-host disease in cases that are refractory to steroid treatment.
  • Acute Graft-Versus-Host Disease (GVHD)
  • Chronic Graft Versus Host Disease
  • Non-segmental Vitiligo
  • Post Polycythemia Vera Myelofibrosis
  • Post-essential Thrombocythemia Myelofibrosis (Post-ET MF)
  • Primary Myelofibrosis (PMF)
  • High-risk Myelofibrosis
  • Intermediate risk Myelofibrosis
  • Mild Atopic dermatitis
  • Moderate Atopic dermatitis
  • Refractory Polycythemia vera

Use in Cancer

Ruxolitinib phosphate is approved for use in adults to treat:

Ruxolitinib phosphate is also being studied in the treatment of some types of cancer.

Contraindications

  • active tuberculosis
  • a bad infection
  • cancer or malignancy
  • squamous cell carcinoma
  • anemia
  • decreased blood platelets
  • low levels of a type of white blood cell called neutrophils
  • hardening of the arteries due to plaque buildup
  • obstruction of a blood vessel by a blood clot
  • a blood clot
  • a patient who is producing milk and breastfeeding
  • basal cell carcinoma of the skin
  • malignant lymphoma
  • progressive multifocal leukoencephalopathy, a type of brain infection
  • a type of skin cancer called Merkel cell carcinoma
  • chronic kidney disease stage 3A (moderate)
  • chronic kidney disease stage 3B (moderate)
  • chronic kidney disease stage 4 (severe)
  • chronic kidney disease stage 5 (failure)
  • kidney disease with likely reduction in kidney function
  • Child-Pugh class A liver impairment
  • Child-Pugh class B liver impairment
  • Child-Pugh class C liver impairment

Dosage

Strengths: 5 mg; 10 mg; 15 mg; 20 mg; 25 mg

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 the 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 the 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 the 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 the Dose at the time of Thrombocytopenia is 25 mg twice a day:

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

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

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

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

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

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

  • Reduce the dose to 5 mg twice a day if the 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
  • 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.
  • For the treatment of intermediate or high-risk myelofibrosis (MF), including primary MF, post-polycythemia vera MF, and post-essential thrombocythemia MF.

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 the 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 the 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 the taper, consider retreatment
  • The dose level decreases from 10 mg twice a day to 5 mg once a day.
  • See the Dose Adjustment section for dose modification guidance for adverse reactions.
  • For the treatment of steroid-refractory acute GVHD and treatment of chronic GVHD after the failure of 1 or 2 lines of systemic therapy.

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
  • The 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 the 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
  • Dose should be continued for at least 2 weeks, if stable may increase dose by 5 mg twice a day
  • For treatment of polycythemia vera (PV) in adults who have had an inadequate response to or are intolerant of hydroxyurea.

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 the 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 the 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 the taper, consider retreatment
  • The dose level decreases from 10 mg twice a day to 5 mg once a day.
  • See the Dose Adjustment section for dose modification guidance for adverse reactions.
  • For the treatment of steroid-refractory acute GVHD and treatment of chronic GVHD after the 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 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 the 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 is 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 is 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 the 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):

  • A 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 the 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 once daily). If GVHD signs or symptoms recur during or after the taper, consider retreatment

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
  • 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
  • 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
  • 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.

Side Effects

The Most Common

  • dizziness
  • headache
  • tiredness
  • shortness of breath
  • weight gain
  • gas
  • diarrhea
  • constipation
  • nausea
  • rash
  • muscle or joint pain
  • swelling of the arms, legs or other parts of the body
  • unusual or heavy bleeding or bruising
  • fever, sore throat, chills, cough, chest pain, night sweats, frequent, painful, urgent urination, and other signs of infection
  • burning, tingling, itching, or skin sensitivity on one side of the body or face with painful rash or blisters appearing several days later.
  • new sores, bumps, or discoloration or other changes to the skin
  • pale skin, tiredness, or shortness of breath (especially while exercising)
  • difficulty moving or keeping your balance, weakness of the legs or arms that keeps getting worse, difficulty understanding or speaking, loss of memory, vision problems, or changes in personality
  • swelling, pain, tenderness, warmth or redness in one or both legs
  • shortness of breath
  • difficulty breathing
  • pain in the chest, arms, back, neck, jaw, or stomach
  • breaking out in cold sweat
  • nausea or vomiting
  • lightheadedness
  • slow or difficult speech
  • numbness or weakness of the face, arm, or leg on one side of your body

More common

  • Black, tarry stools
  • bladder pain
  • bleeding gums
  • blood in the urine or stools
  • blurred vision
  • bruising
  • chest tightness
  • chills
  • cloudy urine
  • collection of blood under the skin
  • cough
  • coughing up blood
  • deep, dark purple bruise
  • difficult, burning, or painful urination
  • difficulty in breathing or swallowing
  • dizziness
  • fever
  • frequent urge to urinate
  • headache
  • hoarseness
  • increased menstrual flow or vaginal bleeding
  • itching, pain, redness, or swelling
  • large, flat, blue or purplish patches in the skin
  • lower back or side pain
  • nervousness
  • nosebleeds
  • painful or difficult urination
  • pale skin
  • paralysis
  • pinpoint red spots on the skin
  • pounding in the ears
  • prolonged bleeding from cuts
  • pus in the urine
  • red or dark brown urine
  • small, red or purple spots on the skin
  • slow or fast heartbeat
  • sore throat
  • swelling
  • tenderness, pain, swelling, warmth, skin discoloration, and prominent superficial veins over the affected area
  • trouble breathing
  • ulcers, sores, or white spots in the mouth
  • unusual bleeding or bruising
  • unusual tiredness or weakness

Rare

  • Painful blisters on the trunk of the body
  • Anxiety
  • chest pain
  • fainting
  • pain, redness, or swelling in the arm or leg
  • pains in the chest, groin, or legs, especially calves of the legs
  • persistent non-healing sore
  • pink growth
  • reddish patch or irritated area
  • severe headaches of sudden onset
  • sudden loss of coordination
  • sudden onset of slurred speech
  • sudden vision changes
  • shiny bump
  • a white, yellow, or waxy scar-like area

Drug Interaction

Pregnancy and Lactation

AU TGA pregnancy category: C
US FDA pregnancy category: N

Pregnancy

When pregnant rats and rabbits were administered ruxolitinib during the period of organogenesis adverse developmental outcomes occurred at doses associated with maternal toxicity (see Data). There are no studies on the use of Jakafi in pregnant women to inform drug-associated risks. The background risk of major birth defects and miscarriage for the indicated populations is unknown. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. The background risk in the U.S. general population of major birth defects is 2% to 4% and miscarriage is 15% to 20% of clinically recognized pregnancies.

Lactation

No information is available on the clinical use of ruxolitinib during breastfeeding. Because ruxolitinib is 97% bound to plasma proteins, the amount in milk is likely to be low. The manufacturer recommends that breastfeeding be discontinued during ruxolitinib therapy and for 2 weeks after the last dose.

Why is this medication prescribed?

Ruxolitinib is used to treat myelofibrosis (a cancer of the bone marrow in which the bone marrow is replaced by scar tissue and causes decreased blood cell production). It is also used to treat polycythemia vera (PV; a slow growing cancer of the blood in which the bone marrow makes too many red blood cells) in people who were not able to be treated successfully with hydroxyurea. Ruxolitinib is also used to treat acute graft versus host disease (aGVHD; a complication of hematopoietic stem-cell transplant [HSCT; a procedure that replaces diseased bone marrow with healthy bone marrow] that usually develops within the first months after HSCT) in adults and children 12 years of age and older who were treated unsuccessfully with steroid medications. It is also used to treat chronic GVHD (cGVHD; a complication of HSCT that usually develops at least 3 months after HSCT) in adults and children 12 years of age and older who were treated unsuccessfully with 1 or 2 other treatments. Ruxolitinib is in a class of medications called kinase inhibitors. It works to treat myelofibrosis and PV by blocking the signals that cause cancer cells to multiply. This helps to stop the spread of cancer cells. It works to treat GVHD by blocking the signals of the cells that cause GVHD.

How should this medicine be used?

Ruxolitinib comes as a tablet to take by mouth. It is usually taken with or without food two times a day. Take ruxolitinib at around the same times every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take ruxolitinib exactly as directed. Do not take more or less of it, or take it more often than prescribed by your doctor.

If you are being treated for myelofibrosis or PV your doctor may start you on a low dose of ruxolitinib for the first four weeks of treatment, and gradually increase your dose after that time, not more than once every 2 weeks. If you are being treated for acute GVHD your doctor may start you on a low dose of ruxolitinib and may increase your dose after at least 3 days of therapy. If you are being treated for acute or chronic GVHD your doctor may gradually lower your dose of ruxolitinib after at least 6 months of therapy.

Swallow the tablets whole; do not chew or crush them.

If you can not have food by mouth and have a nasogastric (NG) tube, your doctor may tell you to take ruxolitinib through the nasogastric (NG) tube. Your doctor or pharmacist will explain how to prepare ruxolitinib to give through an NG tube.

Your doctor will order blood tests before and during your treatment to see how you are affected by this medication. Your doctor may increase or decrease your dose of ruxolitinib during your treatment, or may tell you to stop taking ruxolitinib for awhile. This depends on how well the medication works for you, your lab test results, and if you experience side effects. Talk to your doctor about how you are feeling during your treatment. Continue to take ruxolitinib even if you feel well. Do not stop taking ruxolitinib without talking to your doctor. If your doctor decides to stop your treatment with ruxolitinib, your doctor may decrease your dose gradually. Ask your pharmacist or doctor for a copy of the manufacturer’s information for the patient.

What special precautions should I follow?

Before taking ruxolitinib,

  • tell your doctor and pharmacist if you are allergic to ruxolitinib, any other medications, or any of the ingredients in ruxolitinib. Ask your pharmacist for a list of the ingredients.
  • tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention any of the following: antifungal medications including itraconazole (Sporanox), ketoconazole, and voriconazole (Vfend); carbamazepine (Carbatrol, Equetro, Tegretol, others); clarithromycin; efavirenz (Sustiva, in Atripla, Symfi); erythromycin (E.E.S, Eryc, Ery-tab); fluconazole (Diflucan); HIV protease inhibitors including indinavir (Crixivan), nelfinavir (Viracept), ritonavir (Norvir, in Kaletra, Viekira Pak), and saquinavir (Invirase); nefazodone; nevirapine (Viramune); phenytoin (Dilantin, Phenytek); pioglitazone (Actos, in Oseni, Duetact); rifabutin (Mycobutin); rifampin (Rifadin, Rimactane, in Rifamate, Rifater); and telaprevir (Incivik). Your doctor may need to change the doses of your medications or monitor you carefully for side effects. Many other medications may also interact with ruxolitinib, so be sure to tell your doctor about all the medications you are taking, even those that do not appear on this list.
  • tell your doctor what herbal products you are taking, especially St. John’s wort.
  • tell your doctor if you have anemia, an infection, if you are on dialysis, or if you were recently around someone who has tuberculosis (TB, a severe lung infection) or visited or lived where TB is common. Also tell your doctor if you are a current or past smoker; if you have or have ever had TB; high cholesterol or triglycerides; a blood clot, heart attack, stroke, or other heart problems; skin cancer; herpes zoster (shingles); hepatitis B or other liver disease; or kidney disease.
  • tell your doctor if you are pregnant, plan to become pregnant, or are breastfeeding. If you become pregnant while taking ruxolitinib, call your doctor. You should not breast-feed while taking ruxolitinib and for 2 weeks after your final dose.

What special dietary instructions should I follow?

Unless your doctor tells you otherwise, continue your normal diet.

What should I do if I forget a dose?

Skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.

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