Ruxolitinib phosphate, a selective inhibitor of Janus kinase (JAK) 1 and 2, is an antineoplastic agent.1, 2, 3, 6, 9, 10
Intermediate- or High-Risk Myelofibrosis
Ruxolitinib phosphate is used for the treatment of intermediate- or high-risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis in adults.1, 2, 3, 11, 15, 23 Ruxolitinib is designated an orphan drug by the US Food and Drug Administration (FDA) for use in the treatment of these conditions.7 Some experts recommend use of ruxolitinib as second-line therapy after hydroxyurea in patients with low-risk myelofibrosis, and as first-line therapy in patients with intermediate or high-risk myelofibrosis who are not eligible for allogenic stem cell transplantation.3102, 3103
Efficacy and safety of ruxolitinib were established in 2 randomized phase 3 studies (Controlled Myelofibrosis Study with Oral JAK Inhibitor Treatment I and II [COMFORT-I and COMFORT-II]) in patients with myelofibrosis (primary myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocythemia myelofibrosis).1, 2, 3 In these studies, patients had palpable splenomegaly at least 5 cm below the costal margin and a risk category of intermediate-2 (2 prognostic factors) or high risk (3 or more prognostic factors) based on the International Working Group (IWG) consensus criteria.1, 2, 3 The International Prognostic Scoring System (IPSS) includes 5 risk factors for estimating survival from time of diagnosis, including age greater than 65 years, hemoglobin level less than 10 g/dL, leukocyte count greater than 25,000/mm3, circulating myeloblasts of 1% or greater, and presence of constitutional symptoms.3, 4 The presence of 0, 1, 2, or 3 or more risk factors indicate low, intermediate-1, intermediate-2, or high risk, respectively.4
In both clinical studies, ruxolitinib starting dosage was based on platelet count; for initial treatment, patients with platelet counts of 100,000-200,000/mm3 received an initial ruxolitinib dosage of 15 mg twice daily and patients with platelet counts exceeding 200,000/mm3 received ruxolitinib 20 mg twice daily.1, 2, 3 Dosages were then individualized based on tolerability, efficacy, and platelet counts; patients with platelet counts exceeding 100,000 but not exceeding 125,000/mm3 received a maximum dosage of 20 mg twice daily, patients with platelet counts exceeding 75,000 but not exceeding 100,000/mm3 received a maximum dosage of 10 mg twice daily, and those with platelet counts exceeding 50,000 but not exceeding 75,000/mm3 received a maximum dosage of 5 mg twice daily.1
COMFORT-I was a double-blind, randomized, placebo-controlled study in 309 patients with myelofibrosis who were refractory to or not candidates for available therapy.1, 2 The median age was 68 years, and median spleen volume (as measured by magnetic resonance imaging [MRI] or computed tomography [CT]) was 2595 cm3 (upper limit of normal 300 cm3).1 The primary end point of this study was the proportion of patients achieving a 35% or greater reduction from baseline in spleen volume (measured by MRI or CT) at 24 weeks.1, 2 A 35% or greater reduction in spleen volume from baseline was achieved in a substantially larger proportion of patients receiving ruxolitinib compared with those receiving placebo (41.9 versus 0.7%).1, 2
COMFORT-II was an open label, randomized study in 219 patients with myelofibrosis randomized in a 2:1 ratio to receive either ruxolitinib or best available therapy (selected by the investigator on a patient-by-patient basis).1, 3 The median age of patients enrolled in the study was 66 years and median spleen volume (as measured by MRI or CT) was 2381 cm3.1, 3 Among patients receiving best available therapy, the most commonly used drugs were hydroxyurea (47% of patients) and glucocorticoids (16% of patients);1, 3 33% of patients in this treatment arm received no therapy.3 The primary efficacy end point was the proportion of patients achieving 35% or greater reduction from baseline in spleen volume (measured by MRI or CT) at 48 weeks.1, 3 A 35% or greater reduction in spleen volume from baseline was achieved in a substantially larger proportion of patients receiving ruxolitinib compared with those receiving best available therapy (28.5 versus 0%).1, 3
Clinical improvements seen in COMFORT-I and COMFORT-II were generally maintained with continued ruxolitinib therapy for over 5 years.15, 23 After the initial 24-week treatment period in both studies, patients with worsening splenomegaly were unblinded and offered open label ruxolitinib.15, 23 Of the patients randomized to ruxolitinib, 59.4 and 53.4% of patients in COMFORT-I and COMFORT-II, respectively, achieved a 35% or greater reduction in spleen volume at any time during treatment.15, 23 A reduction in spleen volume also was seen in both trials among patients who crossed over from placebo or best available therapy to open-label ruxolitinib.15, 23 Overall survival also was improved among patients treated with ruxolitinib in both trials.15, 23 At 5 years, median overall survival was not reached among patients randomized to ruxolitinib in both trials; however, median overall survival was 108 weeks among patients randomized to placebo in the COMFORT-I study and 2.7 years among patients treated with best available therapy in the COMFORT-II study.15, 23
Myeloproliferative disorders, including myelofibrosis, frequently occur as the result of a driver mutation in the Janus kinase (JAK) 2 signal transducer and activator of transcription (STAT) 5 signaling pathway.3100, 3101 Fedratinib and ruxolitinib are JAK2 inhibitors that target the JAK-STAT pathway.3101 Patients with low- or intermediate-risk myelofibrosis who lack significant symptoms may be managed with observation alone.3103 However, if cytoreductive therapy is indicated in low-to-intermediate risk patients, hydroxyurea is recommended as first-line treatment.3103 Historically, myelofibrosis-associated splenomegaly was treated with hydroxyurea; however, some experts currently recommend ruxolitinib as first-line treatment in patients with intermediate or high-risk disease who are not eligible for allogenic stem cell transplantation and also in those who are unresponsive to or cannot tolerate hydroxyurea.3102, 3103
Ruxolitinib is used for the treatment of polycythemia vera in adults with a history of inadequate response to or intolerance to hydroxyurea.1 Ruxolitinib is designated an orphan drug by the FDA for use in the treatment of this condition.7 The efficacy of ruxolitinib for the treatment of polycythemia vera is principally based on an open-label, phase 3 trial and a supportive open-label randomized phase 3b study.16, 20, 21, 22 Some experts recommend use of ruxolitinib as second-line therapy for the treatment of polycythemia vera following failure of first-line therapies.3102, 3103, 3104
Efficacy and safety of ruxolitinib for the treatment of polycythemia vera were established in a single randomized, open-label, multicenter, active-controlled phase 3 trial (RESPONSE).1, 16 In this study, 222 adult patients with polycythemia vera were enrolled if they required phlebotomy to control hematocrit, had a spleen volume of at least 450 cm3, a history of inadequate response or intolerance to hydroxyurea, and had not received prior therapy with a JAK inhibitor.1, 16 Patients with hematocrit below 40% or above 45% at the time of enrollment were eligible for a hematocrit control period prior to randomization; patients with hematocrit between 40 and 45% within 14 days prior to the start of the trial could proceed directly to randomization to ruxolitinib, best available therapy, or observation.1, 16 Patients were randomized to receive ruxolitinib at an initial dosage of 10 mg orally twice daily or best available therapy as determined by a treating physician (single agent hydroxyurea, interferon, pegylated interferon, anagrelide, lenalidomide, thalidomide, or pipobroman [not commercially available in the US]) or observation only.1, 16 The dosage of ruxolitinib was subsequently individualized based on efficacy, tolerability, and laboratory assessments, including white blood cell (WBC) and platelet counts, up to a maximum dosage of 25 mg twice daily.1, 16
The age of patients enrolled in the study ranged from 33-90 years; 30% of patients were at least 65 years of age, 66% were male, and the median spleen volume (as measured by MRI or CT scan) was 1272 cm3.1 The primary end point was the proportion of patients achieving a response at 32 weeks; a response was defined as achieving both hematocrit control (without phlebotomy between weeks 8-32 and no more than one instance of phlebotomy prior to week 8) and achieving a 35% or greater reduction from baseline in spleen volume.1, 16 Patients were eligible for phlebotomy when hematocrit was greater than 45% and at least 3 percentage points higher than baseline, or when they had a confirmed hematocrit greater than 48%, whichever was lower.1 At week 32, a primary response was achieved in a substantially larger proportion of patients receiving ruxolitinib compared with those receiving best available therapy (23 versus less than 1%).1, 16 Results of a follow-up analysis after approximately 5 years of therapy revealed that the probability of maintaining a primary response was 74% among patients randomized to ruxolitinib who achieved a primary response at week 32.22
A second phase 3b trial was conducted to compare ruxolitinib to best available therapy in 149 adults with polycythemia vera who were phlebotomy-dependent or -resistant or intolerant to hydroxyurea, and did not have evidence of splenomegaly (RESPONSE 2).20 Patients randomized to ruxolitinib received an initial dosage of 10 mg twice daily, which could be titrated in 5 mg increments based on efficacy and safety.20 Hematocrit control at week 28 was achieved in 62% of patients treated with ruxolitinib compared to 19% of patients who received best available therapy; these results also were consistent across various subgroups.20 In an 80-week analysis of RESPONSE 2, the probability of maintaining a hematocrit response was 78% among patients randomized to ruxolitinib who achieved a response at week 28.21
Myeloproliferative disorders, including polycythemia vera, frequently occur as the result of a driver mutation in the JAK2-STAT5 signaling pathway.3100, 3101 Treatment of polycythemia vera is risk-stratified; however, management for all risk groups includes phlebotomy and low-dose aspirin.3102, 3103, 3104 Low-risk patients (e.g., those less than 60 years of age with no other risk factors or history of thrombosis) generally do not require additional therapy unless phlebotomy is not tolerated or the patient has severe disease-related symptoms, cardiovascular risk factors, or progressive disease; such patients may benefit from hydroxyurea or recombinant interferon alfa.3102, 3103, 3104 Patients with high-risk disease (e.g., those 60 years of age or older or history of prior thrombosis) should receive cytoreductive therapy with hydroxyurea or recombinant interferon alfa in the first-line setting.3102, 3103, 3104 Recombinant interferon alfa or ruxolitinib are recommended for high-risk patients with intolerance or resistance to hydroxyurea; however, busulfan may be considered in patients over 70 years of age.3102, 3103, 3104
Acute Graft-Versus-Host Disease
Ruxolitinib is used for the treatment of acute graft-versus-host disease (GVHD) that is refractory to corticosteroids in adults and pediatric patients 12 years of age and older.1, 17 Ruxolitinib is designated an orphan drug by the FDA for use in this condition.7 The efficacy of ruxolitinib for GVHD is based principally on a phase 2, open-label trial and a supportive phase 3 trial.17, 19 Some experts recommend ruxolitinib as a second-line therapy option in patients with acute GVHD who are resistant to or dependent on corticosteroids.3105
The efficacy and safety of ruxolitinib for the treatment of acute corticosteroid-refractory GVHD are based principally on the results of an open label, multicenter, phase 2 study (REACH 1).1, 17 This study was conducted in 71 patients 12 years of age and older who previously underwent hematopoietic stem cell transplantation for the treatment of a hematologic malignancy and had subsequent evidence of myeloid engraftment and development of grade 2-4, corticosteroid-refractory acute GVHD (as defined by the Mount Sinai Acute GVHD International Consortium [MAGIC] criteria).1, 17 Patients were enrolled in this study if they received a maximum of 1 systemic treatment for acute GVHD in addition to corticosteroids.1, 17 Corticosteroid-refractory acute GVHD was defined as progressive GVHD after 3 days of treatment or the absence of improvement of GVHD after 7 days of at least 2 mg/kg per day of methylprednisolone or equivalent, development of GVHD in another organ after treatment with at least 1 mg/kg per day of methylprednisolone or equivalent for skin GVHD or skin plus upper GI GVHD, or if a corticosteroid taper was not tolerated.17 Patients received ruxolitinib at an initial dosage of 5 mg orally twice daily; a dosage increase to 10 mg twice daily after 3 days was permitted if there was no evidence of platelet or absolute neutrophil count (ANC) reductions from day 1 of treatment.17 All patients received methylprednisolone or prednisone on day 1; corticosteroids were tapered according to institutional guidelines.17
Forty-nine patients in the study had acute GVHD that was refractory to corticosteroids alone.1 The median age of patients enrolled in the study was 57 years (range: 18-72 years); 47% were male, 92% were Caucasian, 14% were Hispanic.1 At baseline, 27, 55, and 18% of patients had grade 2, grade 3, and grade 4 infection, respectively.1 The primary end point was overall response rate (as defined by the Center for International Blood and Marrow Transplant Research criteria) on day 28.1, 17 The overall response rate among patients who were refractory to corticosteroids alone was 57.1%; 30.6% of patients receiving the drug achieved a complete response.1 The median duration of response, from day 28 to progression or death, was 16 days, and the median time to death or need for new therapy for acute GVHD was 173 days among day-28 responders.1
The efficacy and safety of ruxolitinib for acute corticosteroid-refractory GVHD was also assessed in a multicenter, randomized, open-label phase 3 trial (REACH 2).19 In this study, 309 patients 12 years of age and older who underwent allogeneic stem cell transplantation and developed grade 2-4 corticosteroid-refractory acute GVHD that required treatment with systemic immunosuppressants were enrolled.19 Corticosteroid-refractory acute GVHD was defined by disease progression after 3 or more days of treatment with high-dose systemic corticosteroids, a lack of response after 7 days, treatment failure during corticosteroid taper, or an inability to taper the dosage of methylprednisolone (or equivalent corticosteroid) to less than 0.5 mg/kg per day for a minimum of 7 days.19 Enrolled patients were randomized to receive ruxolitinib 10 mg orally twice daily or investigator's choice of therapy (antithymocyte globulin, extracorporeal photopheresis, mesenchymal stromal cells, low-dose methotrexate, mycophenolate mofetil, everolimus, sirolimus, etanercept, or infliximab); treatment was administered for up to 24 weeks.19 Patients were permitted to cross over from the control group to ruxolitinib if they did not respond to therapy by day 28 or had a loss of response after day 28 and received additional systemic treatment and did not have evidence of chronic GVHD.19
The median age of patients was 54 years (range: 12-73 years); 59% were male, 3% were adolescents, and 34, 44, and 20% of patients had grade 2, 3, and 4 acute GVHD, respectively.19 The primary end point of overall response at day 28 was 62% in patients treated with ruxolitinib compared with 39% of patients receiving investigator's choice of therapy.19 A complete response was achieved in 34% of patients treated with ruxolitinib and 19% of patients in the control group at day 28.19
Chronic Graft-Versus-Host Disease
Ruxolitinib is used for the treatment of chronic GVHD in adults and pediatric patients 12 years of age and older who have failed 1 or 2 prior lines of systemic therapy.1, 18 Ruxolitinib is designated an orphan drug by the FDA for use in this condition.7 Some experts recommend ruxolitinib as a second-line therapy option in patients with chronic GVHD who are already receiving corticosteroids.3105
The efficacy of ruxolitinib for the treatment of chronic GVHD refractory to corticosteroids is based principally on the results of an open-label, multicenter, phase 3 study (REACH 3).1, 18 In this study, 329 patients 12 years of age and older who underwent allogeneic stem cell transplantation and developed moderate or severe chronic GVHD (as defined by the National Institutes of Health [NIH] Consensus Criteria), had treatment failure with corticosteroids, and received a maximum of 1 additional salvage therapy were enrolled.1, 18 Patients were randomized to receive ruxolitinib 10 mg orally twice daily or best available therapy (i.e., extracorporeal photopheresis, low-dose methotrexate, mycophenolate mofetil, everolimus, sirolimus, infliximab, rituximab, pentostatin, imatinib, ibrutinib).1, 18 Patients receiving best available therapy who experienced disease progression, mixed or unchanged response, flare of chronic GVHD, or toxicity to treatment on or after the first day of cycle 7 were permitted to cross over to ruxolitinib treatment.1, 18
The median age of patients enrolled in the study was 49 years (range: 12-76 years); 61.1% were male, 42.9% of patients had moderate chronic GVHD, 56.5% had severe chronic GVHD, 71.4% had corticosteroid-refractory GVHD, and 28.6% were dependent on corticosteroids.18 The most commonly used control therapies included extracorporeal photopheresis, mycophenolate mofetil, and ibrutinib, which were reported in 34.8, 22.2, and 17.1% of patients, respectively.18 The primary end point was overall response at week 24 (cycle 7 day 1), which was defined as a complete or partial response according to the 2014 NIH consensus criteria.1, 18
By week 24, the overall response rate was 70% among patients treated with ruxolitinib and 57% among patients who received best available therapy.1 Complete response at week 24 was achieved in 8 or 5% of patients receiving ruxolitinib or best available therapy, respectively, and partial response at week 24 was achieved in 62 or 52%, respectively.1 Responses were higher in patients receiving ruxolitinib regardless of the organ involved.18 The median duration of response was 4.2 months for patients treated with ruxolitinib and 2.1 months for patients treated with best available therapy.1
Acute Graft-Versus-Host Disease
Clinical signs should be used to determine whether systemic treatment should be initiated for treatment of acute GVHD.3105 Some experts recommend systemic therapy for grade 2 or greater acute GVHD; first-line treatment includes methylprednisolone or prednisone.3105, 3106 Steroids are often administered IV initially, then transitioned to oral, and gradually tapered over several weeks.3105, 3106 In patients who develop resistance or dependence on corticosteroids, some experts recommend second-line therapy with one of the following options: alemtuzumab, basiliximab, cellular therapies (e.g., mesenchymal cells), daclizumab, extracorporeal photopheresis, fecal microbiota transplantation, ruxolitinib, mycophenolate mofetil, methotrexate, pentostatin, recombinant anti-thymocyte globulin, sirolimus, or vedolizumab.3105
While specific guidance does not exist for management of acute GVHD in pediatric patients, treatment options are generally similar to those available for adult patients.3105
Chronic Graft-Versus-Host Disease
Multiple factors, including symptom type, severity, and risk of disease progression, should be considered when deciding to start systemic treatment for chronic GVHD.3105 Some experts recommend first-line treatment of newly diagnosed chronic GVHD with prednisone; however, an immunosuppressant may also be necessary to reduce the corticosteroid dosage in patients with severe disease.3105 In the second-line setting, calcineurin inhibitors, extracorporeal photopheresis, ibrutinib, JAK inhibitors, mycophenolate mofetil, rituximab, mammalian target of rapamycin (mTOR) inhibitors, pentostatin, proteasome inhibitors, and tyrosine kinase inhibitors may be used as add-on therapy to corticosteroid therapy.3105
While specific guidance does not exist for management of chronic GVHD in pediatric patients, treatment options are generally similar to those available for adult patients.3105
Ruxolitinib is administered orally and can be taken with or without food.1, 5 If a dose is missed, the patient should not take an additional dose, but should take the next scheduled dose.1
For patients unable to swallow tablets, a ruxolitinib tablet can be dispersed in a glass of water containing approximately 40 mL and administered through a nasogastric tube (8 French or larger).1 The water should be stirred for approximately 10 minutes; once the tablet has dispersed, the suspension should be administered within 6 hours through a nasogastric tube using an appropriate syringe.1 Following administration, the tube should be rinsed with approximately 75 mL of water.1
Store ruxolitinib at room temperature (20-25°C).1 Excursions are permitted between 15-30ºC.1
Dosage of ruxolitinib phosphate is expressed in terms of ruxolitinib.1
Intermediate- or High-Risk Myelofibrosis
The recommended initial dosage of ruxolitinib is based on platelet count.1 In patients with platelet counts exceeding 200,000/mm3, the recommended initial adult dosage of ruxolitinib for the treatment of intermediate- or high-risk myelofibrosis is 20 mg twice daily.1 In patients with platelet counts of 100,000-200,000/mm3, the recommended initial adult dosage is 15 mg twice daily.1 In patients with platelet counts of 50,000/mm3 to <100,000/mm3, the recommended initial adult dosage is 5 mg twice daily.1 The manufacturer states that appropriate and individualized dose management of ruxolitinib is essential to optimize response and manage cytopenias associated with the drug.1, 24
When ruxolitinib is discontinued for reasons other than thrombocytopenia, the dosage of ruxolitinib should be tapered gradually (e.g., by 5 mg twice daily on a weekly basis).1
Dosage Modification for Hematologic Parameters in Patients with Myelofibrosis
Dosage reductions may be considered based on platelet count without interrupting therapy in patients with a baseline platelet count ≥100,000/mm3 (see Table 1) and in patients with a baseline platelet count of 50,000 to <100,000/mm3 (see Table 2).1 However, temporary interruption of therapy is necessary in patients with a baseline platelet count of 100,000/mm3 if platelet count decreases to <50,000/mm3 or ANC decreases to <500/mm3.1
Current Platelet Count and Ruxolitinib Dosage | Recommended Ruxolitinib Dosage |
|---|---|
100,000 to <125,000/mm3 on a ruxolitinib dosage of 25 mg twice daily | 20 mg twice daily |
100,000 to <125,000/mm3 on a ruxolitinib dosage of 20 mg twice daily | 15 mg twice daily |
100,000 to <125,000/mm3 on a ruxolitinib dosage of 5, 10, or 15 mg twice daily | No dosage adjustment |
75,000 to <100,000/mm3 on a ruxolitinib dosage of 15, 20, or 25 mg twice daily | 10 mg twice daily |
75,000 to <100,000/mm3 on a ruxolitinib dosage of 5 or 10 mg twice daily | No dosage adjustment |
50,000 to <75,000/mm3 on a ruxolitinib dosage of 10, 15, 20, or 25 mg twice daily | 5 mg twice daily |
50,000 to <75,000/mm3 on a ruxolitinib dosage of 5 mg twice daily | No dosage adjustment |
Current Platelet Count | Recommended Ruxolitinib Dosage Reduction |
|---|---|
25,000 to <35,000/mm3 AND decline in platelet count is <20% during the prior 4 weeks | Reduce ruxolitinib dosage by 5 mg once daily |
| For patients currently receiving 5 mg once daily, maintain dosage |
25,000 to <35,000/mm3 AND decline in platelet count is ≥20% during the prior 4 weeks | Reduce dosage by 5 mg twice daily |
| For patients currently receiving 5 mg twice daily, decrease dosage to 5 mg once daily |
| For patients receiving 5 mg once daily, maintain dosage |
In patients with a baseline platelet count of 100,000/mm3 , temporarily interrupt ruxolitinib therapy if platelet count decreases to <50,000/mm3 or ANC decreases to <500/mm3.1 When platelet counts improve to >50,000/mm3 and ANC improves to >750/mm3, ruxolitinib may be resumed.1 When restarting, begin with a dosage at least 5 mg twice daily below the dosage at interruption and follow the manufacturer's guidelines for the maximum allowable dosage that may be used when restarting treatment (see Table 3).1
Current Platelet Count | Maximum Recommended Dosage Following Interruption of Therapy |
|---|---|
≥125,000/mm3 | Maximum dosage of 20 mg twice daily |
100,000 to <125,000/mm3 | Maximum dosage of 15 mg twice daily |
75,000 to <100,000/mm3 | Maximum dosage of 10 mg twice daily for at least 2 weeks; if stable, may increase to 15 mg twice daily |
50,000 to <75,000/mm3 | Maximum dosage of 5 mg twice daily for at least 2 weeks; if stable, may increase to 10 mg twice daily |
<50,000/mm3 | Continue to withhold therapy |
If ANC <500/mm3 occurs, temporarily interrupt ruxolitinib therapy; when ANC improves to ≥750/mm3, ruxolitinib may be resumed at the higher of the following dosages: 5 mg once daily; or 5 mg twice daily below the highest dosage in the week prior to the treatment interruption.1
In patients with a baseline platelet count of 50,000/mm3 to 100,000/mm3 , temporarily interrupt ruxolitinib therapy if platelet count decreases to <25,000/mm3 or ANC decreases to <500/mm3.1 When platelet counts improve to >35,000/mm3 and ANC improves to >750/mm3, ruxolitinib may be resumed at the higher of the following dosages: 5 mg once daily; or 5 mg twice daily below the highest dosage during the week prior to the treatment interruption.1
Dosage Modification for Insufficient Clinical Response in Patients with Myelofibrosis
If clinical response is considered insufficient in patients with a baseline platelet count of 100,000/mm3 , the dosage of ruxolitinib may be increased in increments of 5 mg twice daily up to a maximum of 25 mg twice daily if all the following conditions have been met: failure to achieve a reduction from pretreatment baseline spleen size of either 50% in palpable length or 35% in volume as measured by CT or MRI; platelet count >125,000/mm3 at 4 weeks; platelet count never reduced to <100,000/mm3; ANC >750/mm3.1
Based on limited clinical data, long-term maintenance with ruxolitinib at a dosage of 5 mg twice daily has not shown response; therefore, continued long-term use of the drug at a dosage of 5 mg twice daily should be limited to patients in whom benefits outweigh the potential risks.1
If clinical response is considered insufficient in patients with a baseline platelet count of 50,000/mm3 to 100,000/mm3 , the dosage of ruxolitinib may be increased in increments of 5 mg daily up to a maximum of 10 mg twice daily if the following conditions have been met: platelet count has remained ≥40,000/mm3 and has not decreased by more than 20% in the prior 4 weeks; ANC is >1000/mm3; and the dosage of ruxolitinib has not been reduced or withheld due to an adverse event or hematologic toxicity in the prior 4 weeks.1 Continuation of ruxolitinib beyond a duration of 6 months should be limited to patients in whom the benefits outweigh the potential risks.1
Do not increase the ruxolitinib dosage during the first 4 weeks of therapy or more frequently than every 2 weeks.1
If the size of the spleen does not reduce or symptoms do not improve following 6 months of therapy with ruxolitinib, the drug should be discontinued.1
Dosage Modification for Hemorrhagic Events in Patients with Myelofibrosis
If a hemorrhagic event requiring intervention occurs during ruxolitinib therapy in patients with myelofibrosis, interrupt treatment regardless of the current platelet count.1 If the hemorrhagic event resolves and the underlying cause of bleeding is controlled, consider resuming ruxolitinib at the dosage used prior to treatment interruption.1 If the hemorrhagic event resolves but the underlying cause persists, consider resuming ruxolitinib at a reduced dosage.1
Dosage Modification for Concomitant Use with Drugs Affecting Hepatic Microsomal Enzymes in Patients with Myelofibrosis
Dosage adjustment is recommended in patients receiving concomitant ruxolitinib with a potent inhibitor of cytochrome P-450 (CYP) isoenzyme 3A4 or fluconazole at dosage of ≤200 mg daily.1 The initial dosage of ruxolitinib should be reduced based on baseline platelet count.1 (See Table 4.) Avoid concomitant use of ruxolitinib with fluconazole at a dosage >200 mg daily.1
Baseline Platelet Count | Recommended Initial Ruxolitinib Dosage |
|---|---|
≥100,000/mm3 | 10 mg twice daily |
50,000 to <100,000/mm3 | 5 mg twice daily |
If a stable dosage of ruxolitinib has been achieved in patients with myelofibrosis receiving concomitant potent CYP3A4 inhibitors or fluconazole at a dosage of ≤200 mg daily, the dosage of ruxolitinib should be reduced as described in Table 5.1
Current Stable Dosage of Ruxolitinib | Recommended Ruxolitinib Dosage Modification |
|---|---|
≥10 mg twice daily | Decrease ruxolitinib dosage by 50% (round up to the next available tablet strength) |
5 mg twice daily | 5 mg once daily |
5 mg once daily | Avoid potent CYP3A4 inhibitor or fluconazole therapy or temporarily withhold ruxolitinib therapy for the duration of CYP3A4 inhibitor or fluconazole use |
For the treatment of polycythemia vera in adults, the recommended initial dosage of ruxolitinib is 10 mg twice daily.1 The manufacturer states that appropriate and individualized dose management of ruxolitinib is essential to optimize response and manage cytopenias associated with the drug.1, 24
Dosage Modification for Hematologic Parameters in Patients with Polycythemia Vera
Dosage reduction should be considered for hemoglobin concentration <12 g/dL or platelet count <100,000/mm3 to avoid interruption of therapy (see Table 6).1
Hemoglobin and/or Platelet Count | Recommended Ruxolitinib Dosage Reduction |
|---|---|
Hemoglobin ≥12 g/dL AND platelet count ≥100,000/mm3 | No dosage adjustment |
Hemoglobin 10 to <12 g/dL AND platelet count 75,000 to <100,000/mm3 | Consider reducing the dosage to avoid interruption of therapy |
Hemoglobin 8 to <10 g/dL OR platelet count 50,000 to <75,000/mm3 | Reduce dosage by 5 mg twice daily |
| For patients currently receiving 5 mg twice daily, decrease ruxolitinib dosage to 5 mg once daily |
If hemoglobin <8 g/dL, platelet count <50,000/mm3, or ANC <1000/mm3 occurs, ruxolitinib should be withheld until hematologic parameters recover to acceptable levels; ruxolitinib therapy may then be resumed at a reduced dosage as described in Table 7.1
Hematologic Parametersa | Maximum Recommended Dosage Following Interruption of Therapy |
|---|---|
Hemoglobin 8 to <10 g/dL OR platelet count 50,000 to <75,000/mm3 OR ANC 1000 to <1500/mm3 | Resume at maximum dosage of 5 mg twice dailyb or no more than 5 mg twice daily less than the dose that resulted in dosage interruption |
Hemoglobin 10 to <12 g/dL OR platelet count 75,000 to <100,000/mm3 OR ANC 1500 to <2000/mm3 | Resume at maximum dosage of 10 mg twice dailyb or no more than 5 mg twice daily less than the dose that resulted in dosage interruption |
Hemoglobin ≥12 g/dL OR platelet count ≥100,000/mm3 OR ANC ≥2000/mm3 | Resume at maximum dosage of 15 mg twice dailyb or no more than 5 mg twice daily less than the dose that resulted in dosage interruption |
a The most severe hematologic parameter should be used to determine the corresponding maximum dosage.1
bContinue therapy for at least 2 weeks; if stable, the dosage of ruxolitinib may be increased by 5 mg twice daily.1
If dosage interruption is necessary on a reduced dosage of 5 mg twice daily, ruxolitinib may be resumed at a dosage of 5 mg twice daily or 5 mg once daily, but not higher, once hemoglobin concentration improves to ≥10 g/dL, platelet count improves to ≥75,000/mm3, and ANC improves to ≥1500/mm3.1
The dosage of ruxolitinib may be titrated following treatment interruption; however, the maximum total daily dosage should not exceed 5 mg less than the dosage that resulted in the dosage interruption.1 The manufacturer states that the maximal total daily dosage of ruxolitinib is not limited in patients who required treatment interruption following phlebotomy-associated anemia.1
Dosage Modification for Insufficient Clinical Response in Patients with Polycythemia Vera
If clinical response is considered insufficient and platelet, hemoglobin, and neutrophil counts are adequate, the dosage of ruxolitinib may be increased in increments of 5 mg twice daily up to a maximum of 25 mg twice daily if all the following conditions have been met: inadequate efficacy (demonstrated by one or more of the following: continued need for phlebotomy, white blood cell [WBC] or platelet count above the upper limit of normal [ULN], or spleen size that is reduced by <25% in palpable length from baseline); platelet count ≥140,000/mm3; hemoglobin concentration ≥12 g/dL; ANC ≥1500/mm3.1
Do not increase the ruxolitinib dosage during the first 4 weeks of therapy or more frequently than every 2 weeks.1
Dosage Modification for Concomitant Use with Drugs Affecting Hepatic Microsomal Enzymes in Patients with Polycythemia Vera
Dosage adjustment is recommended in patients receiving concomitant ruxolitinib with a potent inhibitor of cytochrome P-450 (CYP) isoenzyme 3A4 or fluconazole at dosage of ≤200 mg daily.1 The initial dosage of ruxolitinib should be reduced to 5 mg twice daily.1 Avoid concomitant use of ruxolitinib with fluconazole at a dosage >200 mg daily.1
If a stable dosage of ruxolitinib has been achieved in patients with polycythemia vera receiving concomitant potent CYP3A4 inhibitors of fluconazole at a dosage of ≤200 mg daily, the dosage of ruxolitinib should be reduced as described in Table 8.1
Current Stable Dosage of Ruxolitinib | Recommended Ruxolitinib Dosage Modification |
|---|---|
≥10 mg twice daily | Decrease ruxolitinib dosage by 50% (round up to the next available tablet strength) |
5 mg twice daily | 5 mg once daily |
5 mg once daily | Avoid potent CYP3A4 inhibitor or fluconazole therapy or temporarily withhold ruxolitinib therapy for the duration of CYP3A4 inhibitor or fluconazole use |
Acute Graft-Versus-Host Disease
For the treatment of corticosteroid-refractory acute graft-versus-host disease (GVHD) in adults and pediatric patients ≥12 years of age, the recommended initial dosage of ruxolitinib is 5 mg twice daily.1 The dosage may be increased to 10 mg twice daily after at least 3 days of treatment if ANC and platelet count do not decrease by ≥50% relative to the first ruxolitinib dosage.1
In patients who achieve a response and discontinue therapeutic doses of corticosteroids, consider tapering ruxolitinib after 6 months of therapy; the dosage should be tapered by one dose level approximately every 8 weeks (e.g., 10 mg twice daily to 5 mg twice daily; 5 mg twice daily to 5 mg once daily).1 If acute GVHD recurs during or following tapering of the ruxolitinib dosage, consider retreatment with the drug.1
Dosage Modification for Toxicity in Patients with Acute GVHD
If adverse reactions occur during ruxolitinib therapy, temporary interruption of therapy and/or dosage reduction of the drug may be necessary.1 If dosage reduction is required, reduce dosage as described in Table 9.1
Current Ruxolitinib Dosage | Recommended Dosage Reduction |
|---|---|
10 mg twice daily | Reduce dosage to 5 mg twice daily |
5 mg twice daily | Reduce dosage to 5 mg once daily |
5 mg once daily | Interrupt therapy until clinical and/or laboratory parameters recover |
If an adverse reaction occurs, modify dosage accordingly (see Table 10).
Laboratory Parameter | Recommended Dosage Modification |
|---|---|
Clinically significant thrombocytopenia despite supportive measures | Reduce ruxolitinib dosage by 1 dose level; when platelet count recovers to previous values, return dosage to previous dosage |
ANC <1000/mm3 considered related to ruxolitinib therapy | Temporarily interrupt therapy for up to 14 days, then resume ruxolitinib at a dosage reduced by 1 dose level |
Total bilirubin concentration 3-5 times the ULN in patients without liver GVHD | Reduce ruxolitinib dosage by 1 dose level until recovery of total bilirubin concentrations |
Total bilirubin concentration >5 to 10 times the ULN in patients without liver GVHD | Temporarily withhold ruxolitinib therapy for up to 14 days until total bilirubin concentrations improve to ≤1.5 times the ULN, then resume ruxolitinib at same dosage |
Total bilirubin concentration >10 times the ULN in patients without liver GVHD | Temporarily withhold ruxolitinib therapy for up to 14 days until total bilirubin concentration improves to ≤1.5 times the ULN, then resume ruxolitinib at a dosage reduced by 1 dose level |
Total bilirubin concentration >3 times the ULN in patients with liver GVHD | Reduce ruxolitinib dosage by 1 dose level until recovery of total bilirubin concentrations |
Dosage Modification for Concomitant Use with Drugs Affecting Hepatic Microsomal Enzymes in Patients with Acute GVHD
Dosage adjustment is recommended in patients receiving concomitant ruxolitinib with a potent inhibitor of cytochrome P-450 (CYP) isoenzyme 3A4 or fluconazole at dosage of ≤200 mg daily.1 Avoid concomitant use of ruxolitinib with fluconazole at a dosage >200 mg daily.1
If coadministration with fluconazole at dosages of up to 200 mg per day is necessary in patients with acute GVHD, reduce the starting dosage of ruxolitinib to 5 mg once daily.1
If coadministration with a potent CYP3A4 inhibitor (other than fluconazole) is necessary in patients with acute GVHD, monitor CBCs more frequently and adjust ruxolitinib dosage for adverse effects, if necessary.1
Chronic Graft-Versus-Host Disease
For the treatment of chronic GVHD following failure of 1 or 2 prior systemic therapies in adults and pediatric patients ≥12 years of age, the recommended initial dosage of ruxolitinib is 10 mg twice daily.1
In patients who achieve a response and discontinue therapeutic doses of corticosteroids, consider tapering ruxolitinib after 6 months of therapy; the dosage should be tapered by one dose level approximately every 8 weeks (e.g., 10 mg twice daily to 5 mg twice daily; 5 mg twice daily to 5 mg once daily).1 If chronic GVHD recurs during or following tapering of the ruxolitinib dosage, consider retreatment with the drug.1
Dosage Modification for Toxicity in Patients with Chronic GVHD
If adverse reactions occur during ruxolitinib therapy, temporary interruption of therapy and/or dosage reduction of the drug may be necessary.1 If dosage reduction is required, reduce dosage as described in Table 11.1
Current Ruxolitinib Dosage | Recommended Dosage Reduction |
|---|---|
10 mg twice daily | Reduce dosage to 5 mg twice daily |
5 mg twice daily | Reduce dosage to 5 mg once daily |
5 mg once daily | Interrupt therapy until clinical and/or laboratory parameters recover |
If an adverse reaction occurs, modify dosage accordingly (see Table 12).
Laboratory Parameter | Recommended Dosage Modification |
|---|---|
Platelet count <20,000/mm3 | Continue ruxolitinib at a dosage reduced by 1 dose level |
| If thrombocytopenia resolves within 7 days, return dosage to initial dosage |
| If thrombocytopenia does not resolve within 7 days, maintain the reduced dosage of ruxolitinib |
ANC <750/mm3 considered related to ruxolitinib therapy | Continue ruxolitinib at a dosage reduced by 1 dose level; when neutropenia resolves, dosage may be returned to initial dosage |
ANC <500/mm3 considered related to ruxolitinib therapy | Temporarily withhold ruxolitinib therapy for up to 14 days until neutropenia resolves, then resume ruxolitinib at a dosage reduced by 1 dose level |
| When ANC improves to >1000/mm3, may return to initial dosage level |
Total bilirubin concentration 3-5 times the ULN | Continue ruxolitinib at a dosage reduced by 1 dose level until elevated total bilirubin concentrations resolve |
| If elevated total bilirubin concentrations resolve within 14 days, increase the dosage by 1 dose level |
| If elevated total bilirubin concentrations do not resolve within 14 days, maintain the reduced dosage of ruxolitinib |
Total bilirubin concentration >5 to 10 times the ULN | Temporarily withhold ruxolitinib therapy for up to 14 days until elevated total bilirubin concentrations resolve, then resume ruxolitinib at same dosage |
| If elevated total bilirubin concentrations do not resolve within 14 days, resume ruxolitinib at a dosage reduced by 1 dose level upon recovery |
Total bilirubin concentration >10 times the ULN | Temporarily withhold ruxolitinib therapy for up to 14 days until elevated total bilirubin concentrations resolve, then resume ruxolitinib at a dosage reduced by 1 dose level |
| If elevated total bilirubin concentrations do not resolve within 14 days, discontinue drug |
Other toxicity of grade 3 severity | Reduce ruxolitinib dosage by 1 dose level until toxicity resolves |
Other toxicity of grade 4 severity | Discontinue drug |
Dosage Modification for Concomitant Use with Drugs Affecting Hepatic Microsomal Enzymes in Patients with Chronic GVHD
Dosage adjustment is recommended in patients receiving concomitant ruxolitinib with a potent inhibitor of cytochrome P-450 (CYP) isoenzyme 3A4 or fluconazole at dosage of ≤200 mg daily.1 Avoid concomitant use of ruxolitinib with fluconazole at a dosage >200 mg daily.1
If coadministration with fluconazole at dosages of up to 200 mg per day is necessary in patients with chronic GVHD, reduce the starting dosage of ruxolitinib to 5 mg twice daily.1
If coadministration with a potent CYP3A4 inhibitor (other than fluconazole) is necessary in patients with chronic GVHD, CBCs should be monitored more frequently for toxicity and the dosage of ruxolitinib should be modified for adverse effects, if they occur.1
Intermediate- or High-Risk Myelofibrosis
In patients with myelofibrosis and preexisting mild, moderate, or severe hepatic impairment (Child-Pugh class A, B, or C), dosage adjustment of the initial dosage of ruxolitinib is determined by the patient's baseline platelet count.1
In patients with a baseline platelet count >150,000/mm3, no dosage adjustment necessary.1
In patients with a baseline platelet count 100,000-150,000/mm3, reduce initial ruxolitinib dosage to 10 mg twice daily.1
In patients with a baseline platelet count 50,000 to <100,000/mm3, reduce initial ruxolitinib dosage to 5 mg once daily.1
The manufacturer states that ruxolitinib should be avoided in patients with a baseline platelet count <50,000/mm3 and hepatic impairment.1
In patients with polycythemia vera and preexisting mild, moderate, or severe hepatic impairment (Child-Pugh class A, B, or C), reduce initial ruxolitinib dosage to 5 mg twice daily.1
In patients with acute GVHD (not of the liver) and preexisting mild, moderate, or severe hepatic impairment (based on National Cancer Institute [NCI] criteria), no dosage adjustment necessary.1
In patients with grade 1, 2, or 3 acute GVHD of the liver, no dosage adjustment necessary.1
In patients with grade 4 acute GVHD of the liver, reduce ruxolitinib dosage to 5 mg once daily.1
In patients with chronic GVHD (not of the liver) and preexisting mild, moderate, or severe hepatic impairment (based on NCI criteria), no dosage adjustment necessary.1
In patients with grade 1 or 2 chronic GVHD of the liver, no dosage adjustment necessary.1
In patients with grade 3 chronic GVHD of the liver, monitor CBCs more frequently and adjust ruxolitinib dosage for adverse effects, if necessary.1
Intermediate- or High-Risk Myelofibrosis
In patients with myelofibrosis and preexisting mild, moderate, or severe renal impairment, dosage adjustment of the initial dosage of ruxolitinib is determined by the patient's baseline platelet count.1 (See Table 13.)
Severity of Renal Impairment | Recommended Dosage Reduction |
|---|---|
Moderate to severe renal impairment (Clcr15-59 mL/minute) | Baseline platelet count >150,000/mm3: No dosage adjustment |
| Baseline platelet count 100,000-150,000/mm3: Reduce ruxolitinib dosage to 10 mg twice daily |
| Baseline platelet count 50,000 to <100,000/mm3: Reduce ruxolitinib dosage to 5 mg once daily |
| Baseline platelet count <50,000/mm3: Avoid use |
End-stage renal disease on dialysis | Baseline platelet count 100,000-200,000/mm3: Administer ruxolitinib 15 mg once after dialysis session only on days when hemodialysis is scheduled |
| Baseline platelet count >200,000/mm3: Administer ruxolitinib 20 mg once after dialysis session only on days when hemodialysis is scheduled |
In patients with polycythemia vera and moderate to severe renal impairment (Clcr15-59 mL/minute), reduce initial ruxolitinib dosage to 5 mg twice daily.1
In patients with polycythemia vera and end-stage renal disease who are receiving dialysis, administer ruxolitinib 10 mg once after dialysis session only on days when hemodialysis is scheduled.1
In patients with acute GVHD and moderate to severe renal impairment (Clcr15-59 mL/minute), reduce initial ruxolitinib dosage to 5 mg once daily.1
In patients with acute GVHD and end-stage renal disease who are receiving dialysis, administer ruxolitinib 5 mg once after dialysis session only on days when hemodialysis is scheduled.1
In patients with chronic GVHD and moderate to severe renal impairment (Clcr15-59 mL/minute), reduce initial ruxolitinib dosage to 5 mg twice daily.1
In patients with chronic GVHD and end-stage renal disease who are receiving dialysis, administer ruxolitinib 10 mg once after dialysis session only on days when hemodialysis is scheduled.1
The manufacturer makes no specific dosage recommendations for geriatric patients.1
Thrombocytopenia, Anemia, and Neutropenia
Ruxolitinib can cause adverse hematologic reactions, including thrombocytopenia, anemia, and neutropenia.1, 2, 3, 11 A complete blood cell count (CBC) must be performed before initiating therapy with ruxolitinib and every 2 to 4 weeks until a stable dosage of the drug is reached.1 Once a stable dosage has been reached, monitor CBCs as clinically indicated.1
In clinical trials of patients receiving ruxolitinib for treatment of myelofibrosis, grade 3 or 4 thrombocytopenia occurred in 9 or 4%, respectively, of patients treated with ruxolitinib compared to 1 or 0% of patients treated with placebo, respectively.1 The median time to onset of grade 3 or 4 thrombocytopenia was approximately 8 weeks.1 Patients with platelet counts of 100,000-200,000/mm3 prior to initiation of ruxolitinib had a higher incidence of grade 3 or 4 thrombocytopenia compared with patients with platelet counts exceeding 200,000/mm3 (17 versus 7%).1 In an open-label, active-controlled study of patients who received ruxolitinib for the treatment of polycythemia vera, grade 3 or 4 thrombocytopenia occurred in 5 or less than 1%, respectively, of patients who received ruxolitinib compared with 3 or less than 1% of patients, respectively, who received best available therapy.1 In an open-label, single cohort of patients who received ruxolitinib for the treatment of acute graft-versus-host disease (GVHD), 61% of patients developed grade 3 or 4 thrombocytopenia.1 In an open-label study comparing ruxolitinib to best available therapy for the treatment of chronic GVHD, 20% of patients receiving ruxolitinib developed grade 3 or higher thrombocytopenia compared to 17% of patients receiving best available therapy.1
Thrombocytopenia usually was managed by reducing the dosage or temporarily withholding ruxolitinib.1, 2, 3, 11 If clinically indicated, platelet transfusions may be administered.1
In clinical trials of ruxolitinib for treatment of myelofibrosis, grade 3 or 4 anemia occurred in 34 or 11%, respectively, of patients receiving ruxolitinib compared with 16 or 3%, respectively, of patients receiving placebo. 1, 2 In clinical trials evaluating ruxolitinib in patients with polycythemia vera, grade 3 or 4 anemia occurred in less than 1% of patients receiving ruxolitinib compared with 0% of patients receiving best available therapy.1 In clinical trials in patients with GVHD, grade 3 or 4 anemia occurred in 45% of patients with acute GVHD receiving ruxolitinib and in 13% of patients with chronic GVHD receiving ruxolitinib.1 Patients who develop anemia may require blood transfusions; dosage modification of ruxolitinib also may be considered in such patients.1
In clinical trials evaluating the use of ruxolitinib in patients with myelofibrosis, grade 3 or 4 neutropenia occurred in 5 or 2%, respectively, of patients receiving ruxolitinib compared with less than 1 or 1%, respectively, of patients receiving placebo. 1 In an open-label trial comparing ruxolitinib with best available therapy for treatment of polycythemia vera, grade 3 or 4 neutropenia occurred in 0 or less than 1% of patients receiving ruxolitinib, respectively, compared to less than 1 or 0% of patients receiving best available therapy.1 In clinical trials in patients with GVHD, grade 3 or 4 neutropenia occurred in 40% of patients with acute GVHD receiving ruxolitinib and in 12% of patients with chronic GVHD receiving ruxolitinib.1 Neutropenia (absolute neutrophil count [ANC] less than 500/mm3) generally was reversible and managed by temporarily withholding ruxolitinib.1
Patients should be assessed for the risk of developing serious bacterial, mycobacterial, fungal, and viral infections.1 Active serious infections should have resolved prior to initiating therapy with ruxolitinib.1 Clinicians should carefully observe patients receiving ruxolitinib for signs and symptoms of infection and should promptly initiate appropriate treatment.1
Tuberculosis infection has been reported in patients during treatment with ruxolitinib.1 Patients should be evaluated for tuberculosis prior to initiating therapy with the drug and patients at high risk for tuberculosis should be tested for latent infection.1 Risk factors for tuberculosis include a history of residence in or travel to an area with high tuberculosis prevalence, close contact with someone with active tuberculosis, or a history of latent or active tuberculosis without an ability to verify that adequate treatment was administered.1 Consultation with a tuberculosis specialist is recommended when deciding whether antimycobacterial therapy should be initiated in patients with active or latent tuberculosis.1
Progressive multifocal leukoencephalopathy has been reported in patients treated with ruxolitinib.1 If progressive multifocal leukoencephalopathy is suspected, discontinue treatment with ruxolitinib and evaluate the patient.1
In clinical studies, herpes zoster infection occurred in 2% of ruxolitinib-treated patients with myelofibrosis, and in 6% of patients with polycythemia vera.1 Clinicians should inform patients about the early signs and symptoms of herpes zoster and advise patients to seek treatment as soon as possible for this condition.1
Herpes simplex virus reactivation and/or dissemination has also been reported with ruxolitinib therapy.1 Clinicians should monitor patients for signs and symptoms of herpes simplex infection and, if a patient develops evidence of herpes simplex dissemination, consider therapy interruption and prompt treatment according to clinical guidelines.1
Increases in hepatitis B viral load, both with and without concomitant elevations in alanine and aspartate aminotransferases, have been reported during ruxolitinib therapy in patients with chronic hepatitis B virus infection,1 The effect of ruxolitinib on viral replication in patients with chronic hepatitis B virus infection is unknown.1 Patients with chronic hepatitis B virus infection should be treated and monitored according to current clinical guidelines.1
Following interruption or discontinuance of ruxolitinib therapy, symptoms of myeloproliferative neoplasms may return to pretreatment levels within approximately 1 week.1 Some patients with myelofibrosis have reported adverse effects including fever, respiratory distress, hypotension, disseminated intravascular coagulation, and multiorgan failure following discontinuance of ruxolitinib.1 Evaluate for adverse effects during tapering or discontinuance of ruxolitinib and consider restarting or increasing the dosage if any of these adverse effects occur.1 Instruct patients to contact their physician before interrupting or discontinuing therapy with ruxolitinib.1 Consider gradual tapering of the dosage when ruxolitinib is discontinued for reasons other than thrombocytopenia or neutropenia.1
Withdrawal manifestations, characterized by acute relapse of disease symptoms, accelerated splenomegaly, worsening of cytopenias, and occasional hemodynamic decompensation (including septic shock-like syndrome with severe hypoxia, hypotension, fever, and confusion), have been reported in some patients following discontinuance of ruxolitinib.10, 12 Some experts recommend that ruxolitinib dosage be tapered gradually over a 2-week period under close medical supervision.10, 13
Malignancies and Lymphoproliferative Disorders
Nonmelanoma skin cancers, including basal cell, squamous cell, and Merkel cell carcinoma, have been reported in patients receiving ruxolitinib.1 Lymphoma and other malignancies have been reported in patients receiving other Janus kinase (JAK) inhibitors for the treatment of rheumatoid arthritis.1
The risks and benefits of ruxolitinib should be considered prior to initiating therapy or when considering whether to continue ruxolitinib, particularly in patients with a known malignancy (other than successfully treated nonmelanoma skin cancer), in those who develop a malignancy, and those who are current or past smokers.1
Because nonmelanoma skin cancers have been reported in patients receiving ruxolitinib, periodic dermatologic examinations are recommended during therapy.1
Increases in total cholesterol, low-density lipoprotein (LDL)-cholesterol, and triglyceride concentrations have been observed in patients receiving ruxolitinib.1 The potential effects of these elevations on cardiovascular morbidity and mortality have not been determined.1
Lipid concentrations should be monitored 8-12 weeks after initiation of ruxolitinib therapy.1 Hyperlipidemia should be managed according to current standards of care.1
Major Adverse Cardiovascular Events
Increased risk of major adverse cardiovascular events (MACE), including cardiovascular death, myocardial infarction, and stroke, has been reported in patients receiving other JAK inhibitors for the treatment of rheumatoid arthritis.1
The risks and benefits of ruxolitinib should be considered prior to initiating therapy, particularly in patients who are current or past smokers and in those with other cardiovascular risk factors.1 Patients receiving ruxolitinib should be advised to seek immediate medical attention if symptoms of serious cardiovascular events occur.1
Serious and sometimes fatal thromboembolic events, including deep-vein thrombosis, pulmonary embolism, and arterial thrombosis in the extremities, have been reported in patients receiving other JAK inhibitors for the treatment of rheumatoid arthritis.1 In clinical trials evaluating ruxolitinib in patients with myelofibrosis and polycythemia vera, no difference in thromboembolic events was observed between patients receiving ruxolitinib and patients assigned to control.1
Promptly evaluate and treat any patients who develop symptoms of thrombosis during treatment with ruxolitinib.1
Adverse developmental outcomes, including decreased fetal weight, have been observed in animal studies when ruxolitinib was administered to pregnant rabbits and rats at dosages associated with maternal toxicity.1
There are no studies of ruxolitinib in pregnant women to inform a drug-associated risk.1
Ruxolitinib and/or its metabolites are distributed into milk in rats; it is not known whether ruxolitinib is distributed into human milk.1 Because of the potential for adverse reactions (i.e., thrombocytopenia, anemia) to ruxolitinib in the breastfed infant, and because many drugs are present in human milk, discontinue breast-feeding during ruxolitinib therapy and for 2 weeks after the final dose of the drug.1
Safety and efficacy of ruxolitinib have not been established in pediatric patients younger than 12 years of age with acute or chronic GVHD or in pediatric patients for the treatment of myelofibrosis and polycythemia vera.1
In clinical studies of ruxolitinib, approximately 52% of patients with myelofibrosis were 65 years of age or older and 15% of patients were 75 years of age or older.1 In clinical studies of ruxolitinib in patients with chronic GVHD, approximately 11% were 65 years of age or older.1 No overall differences in safety or efficacy relative to younger adults were observed in clinical trials.1 Clinical studies of patients with acute GVHD did not include sufficient numbers of subjects 65 years of age and older to determine whether they respond differently than younger adults.1
Following administration of ruxolitinib in patients with acute or chronic GVHD, no clinically significant effects on pharmacokinetics were observed in patients with mild to severe hepatic impairment as defined by National Cancer Institute (NCI) criteria.1 In patients with mild to severe hepatic impairment according to Child-Pugh criteria, mean area under the plasma concentration-time curve (AUC) for the drug was increased by 1.9-, 1.3-, or 1.7-fold in patients with mild (Child-Pugh class A), moderate (Child-Pugh class B), or severe (Child-Pugh class C) hepatic impairment, respectively, compared with patients with normal hepatic function.1 In patients with GVHD of the liver, no clinically significant effects on pharmacokinetics of ruxolitinib were observed in patients with grade 1, 2, or 3 acute GVHD or grade 1 or 2 chronic GVHD; however, clearance of the drug was reduced in patients with grade 4 acute GVHD of the liver compared with patients without acute GVHD of the liver.1 The effect of grade 3 chronic GVHD on the pharmacokinetics of ruxolitinib is not known.1
Dosage adjustment in patients with hepatic impairment may be necessary.1
After administration of ruxolitinib in patients with renal impairment, total AUC of ruxolitinib and its active metabolites was increased by 1.3-, 1.5-, or 1.9-fold in patients with mild, moderate, or severe renal impairment, respectively, compared with patients with normal renal function; total AUC increased by 1.6-fold in patients with end-stage renal disease after dialysis.1
Dosage reduction of ruxolitinib is recommended in patients with end-stage renal disease requiring dialysis and in patients with moderate or severe renal impairment (creatinine clearance of 15-59 mL/minute).1
In patients with myelofibrosis and polycythemia vera treated with ruxolitinib, the most common adverse hematologic reactions (reported in >20%) include thrombocytopenia and anemia.1 The most common nonhematologic adverse reactions (reported in ≥15%) include bruising, dizziness, headache, and diarrhea.1
In patients with acute GVHD treated with ruxolitinib, the most common adverse hematologic reactions (reported in >50%) include anemia, thrombocytopenia, and neutropenia.1 The most common nonhematologic adverse reactions (reported in >50%) include infections and edema.1
In patients with chronic GVHD treated with ruxolitinib, the most common adverse hematologic reactions (reported in >35%) include anemia and thrombocytopenia.1 The most common nonhematologic adverse reactions (reported in ≥20%) include infections and viral infections.1
Ruxolitinib is metabolized mainly by cytochrome P-450 (CYP) isoenzyme 3A4.1, 6
Ruxolitinib and its M18 metabolite do not inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4 in vitro.1 Ruxolitinib also does not induce CYP1A2, 2B6, or 3A4 at clinically relevant concentrations.1
In vitro data indicate that neither ruxolitinib nor its M18 metabolite is an inhibitor of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion-transporting polypeptides (OATP) 1B1 and 1B3, organic cation transporters (OCT) 1 and 2, and organic anion transporters (OAT) 1 and 3 at clinically relevant concentrations.1 Ruxolitinib also is not a substrate for P-gp.1, 6
Drugs Affecting Hepatic Microsomal Enzymes
Because ruxolitinib is mainly metabolized by CYP3A4, potent inhibitors or inducers of this isoenzyme are expected to alter the drug's pharmacokinetics.1, 6
Concomitant use of ruxolitinib with potent inhibitors of CYP3A4 has resulted in increased peak plasma concentrations and area under the serum concentration-time curve (AUC) of ruxolitinib.1, 6 Dosage reduction of ruxolitinib may be necessary when the drug is used concomitantly with potent CYP3A4 inhibitors.1, 6
Concomitant use of ruxolitinib with weak or moderate CYP3A4 inhibitors (e.g., erythromycin) also has resulted in increased peak plasma concentrations and AUC of ruxolitinib, but does not appear to be a clinically important interaction.1, 6 Dosage adjustment of ruxolitinib is not recommended when used concomitantly with weak or moderate CYP3A4 inhibitors.1, 6
Concomitant use of ruxolitinib with potent CYP3A4 inducers (e.g., rifampin) has resulted in decreased peak plasma concentrations and AUC of ruxolitinib.1, 6 However, no dosage adjustment is recommended when the drug is used concomitantly with CYP3A4 inducers.1, 6 The manufacturer states that patients should be monitored closely during concomitant therapy and dosage should be titrated based on safety and efficacy.1
Concomitant use of ruxolitinib with fluconazole may result in increased systemic exposure of ruxolitinib, and increased risk of toxicities.1
When ruxolitinib was used concomitantly with fluconazole (100 to 400 mg once daily), steady state AUC of ruxolitinib increased by 100-300%.1
Avoid concomitant use of ruxolitinib with fluconazole (at dosages >200 mg daily).1 If ruxolitinib is used concomitantly with fluconazole at a dosage of 200 mg or less, the dosage of ruxolitinib should be reduced.1
Concomitant administration of ruxolitinib (single 10-mg dose) with ketoconazole (200 mg twice daily for 4 days) increased peak plasma concentrations and AUC of ruxolitinib by 33 and 91%, respectively.1, 6 Half-life of ruxolitinib also was prolonged from 3.7 to 6 hours with concomitant use of ketoconazole.1 Dosage reduction is recommended when ruxolitinib is administered with potent CYP3A4 inhibitors (e.g., ketoconazole).1, 6
Concomitant administration of ruxolitinib (single 10-mg dose) with erythromycin (500 mg twice daily for 4 days) increased ruxolitinib peak plasma concentrations and AUC by 8 and 27%, respectively.1, 6 No dosage adjustment is recommended when ruxolitinib is administered with weak or moderate CYP3A4 inhibitors (e.g., erythromycin).1, 6 In patients receiving a stable dosage of ruxolitinib, clinicians should use caution when initiating treatment with a moderate CYP3A4 inhibitor, especially in patients with low platelet counts.6
Concomitant administration of ruxolitinib (single 50-mg dose) with rifampin (600 mg once daily for 10 days) decreased ruxolitinib peak plasma concentrations and AUC by 32 and 61%, respectively.1 No dosage adjustment is recommended when ruxolitinib is administered with a CYP3A4 inducer.1, 6 Patients should be closely monitored and the dosage titrated based on safety and efficacy.1
Ruxolitinib phosphate, a selective inhibitor of Janus kinase (JAK) 1 and 2, is an antineoplastic agent.1, 2, 3, 6, 9, 10 JAK1 and 2 mediate the signaling of cytokines and growth factors that are important for hematopoiesis and immune function.1 JAK signaling involves 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.1 Myelofibrosis and polycythemia vera are myeloproliferative neoplasms known to be associated with dysregulated JAK1 and 2 signaling.1 JAK-STAT signaling pathways play a role in regulating the development, proliferation, and activation of several immune cell types important for pathogenesis of graft-versus-host disease (GVHD).1 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.5
Following oral administration, absorption of ruxolitinib is approximately 95%,1, 9 and mean systemic bioavailability is estimated to be about 80%.5 Following oral administration of ruxolitinib, peak plasma concentrations are achieved within 1-2 hours.1, 5 The mean half-life of ruxolitinib following a single oral dose is approximately 3 hours, and the mean half-life of ruxolitinib and its metabolites is approximately 5.8 hours.1, 5 Cytochrome P-450 (CYP) isoenzyme 3A4 is the major enzyme responsible for metabolism of ruxolitinib.1 Two major active metabolites were identified in the plasma of healthy individuals; all active metabolites contribute 18% of the overall pharmacodynamic activity of ruxolitinib.1 Following administration of a single oral dose of radiolabeled ruxolitinib in healthy individuals, elimination was predominantly through metabolism with 74 and 22% of radioactivity excreted in urine and feces, respectively.1, 9 Unchanged drug accounted for less than 1% of the excreted total radioactivity.1, 9
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Distribution of ruxolitinib is restricted.8 Patients must obtain ruxolitinib through the Incyte® Connecting to Access, Reimbursement, Education, and Support (IncyteCARES) program.8
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets | 5 mg (of ruxolitinib) | ||
10 mg (of ruxolitinib) | Jakafi® | Incyte Corporation | ||
15 mg (of ruxolitinib) | Jakafi® | Incyte Corporation | ||
20 mg (of ruxolitinib) | Jakafi® | Incyte Corporation | ||
25 mg (of ruxolitinib) | Jakafi® | Incyte Corporation |
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions July 10, 2024. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
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