Ruxolitinib (Systemic)
Brand names: Jakafi
Drug class:
Antineoplastic Agents
Usage of Ruxolitinib (Systemic)
Intermediate- or High-Risk Myelofibrosis
Treatment of intermediate- or high-risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis (designated an orphan drug by FDA for this use).
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.
Polycythemia Vera
Treatment of polycythemia vera in adults with a history of inadequate response to or intolerance to hydroxyurea. Designated an orphan drug by FDA for this use.
Some experts recommend use of ruxolitinib as second-line therapy for the treatment of polycythemia vera following failure of first-line therapies.
Acute Graft-Versus-Host Disease
Treatment of acute graft-versus-host disease (GVHD) that is refractory to corticosteroids in adults and pediatric patients ≥12 years of age (designated an orphan drug by the FDA for use in this condition).
Some experts recommend ruxolitinib as a second-line therapy option in patients with acute GVHD who are resistant to or dependent on corticosteroids.
Chronic Graft-Versus-Host Disease
Treatment of chronic GVHD in adults and pediatric patients ≥12 years of age who have failed 1 or 2 prior lines of systemic therapy (designated an orphan drug by the FDA for use in this condition).
Some experts recommend ruxolitinib as a second-line therapy option in patients with chronic GVHD who are already receiving corticosteroids.
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How to use Ruxolitinib (Systemic)
General
Pretreatment Screening
Patient Monitoring
Administration
Oral Administration
Administer orally; take with or without food.
NG TubeDisperse tablet in approximately 40 mL of water, stir for approximately 10 minutes, and administer within 6 hours through an NG tube (8 French or larger) using an appropriate syringe. Following administration, rinse tube with approximately 75 mL of water.
Dosage
Available as ruxolitinib phosphate; dosage expressed in terms of ruxolitinib.
Pediatric Patients
Acute Graft-Versus-Host Disease Oral≥12 years of age: Initially, 5 mg twice daily; may increase dosage 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.
In patients who achieve a response and discontinue therapeutic doses of corticosteroids, consider tapering ruxolitinib after 6 months of therapy; taper dosage should 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). If acute GVHD recurs during or following tapering of the ruxolitinib dosage, consider retreatment with the drug.
When discontinuing ruxolitinib for reasons other than thrombocytopenia, taper dosage gradually (e.g., by 5 mg twice daily on a weekly basis).
Dosage Modification for Toxicity in Pediatric Patients with Acute GVHD OralIf adverse reactions occur during ruxolitinib therapy, temporary interruption of therapy and/or dosage reduction of the drug may be necessary. If dosage reduction is required, reduce dosage as described in Table 1.
Table 1. Recommended Dosage Reduction for Ruxolitinib Toxicity in Pediatric Patients ≥12 Years of Age with Acute GVHD1Current 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 2).
Table 2. Recommended Dosage Modification for Ruxolitinib Toxicity in Pediatric Patients ≥12 Years of Age with Acute GVHD1Laboratory 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 Pediatric Patients ≥12 Years of Age with Acute GVHD OralDosage adjustment is recommended in patients receiving concomitant ruxolitinib with a potent inhibitor of CYP3A4 or fluconazole at dosage of ≤200 mg daily. Avoid concomitant use of ruxolitinib with fluconazole dosage >200 mg daily.
If coadministration with fluconazole ≤200 mg daily is necessary in patients with acute GVHD, reduce the starting dosage of ruxolitinib to 5 mg once daily.
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.
Chronic Graft-Versus-Host Disease Oral≥12 years of age: Initially, 10 mg twice daily.
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). If chronic GVHD recurs during or following tapering of the ruxolitinib dosage, consider retreatment with the drug.
Dosage Modification for Toxicity in Pediatric Patients ≥12 Years of Age with Chronic GVHD OralIf adverse reactions occur during ruxolitinib therapy, temporary interruption of therapy and/or dosage reduction of the drug may be necessary. If dosage reduction is required, reduce dosage as described in Table 3.
Table 3. Recommended Dosage Reduction for Ruxolitinib Toxicity in Pediatric Patients ≥12 Years of Age with Chronic GVHD1Current 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 4).
Table 4. Recommended Dosage Modification for Ruxolitinib Toxicity in Pediatric Patients ≥12 Years of Age with Chronic GVHD1Laboratory 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 Pediatric Patients ≥12 Years of Age with Chronic GVHD OralDosage adjustment is recommended in patients receiving concomitant ruxolitinib with a potent inhibitor of CYP3A4 or fluconazole ≤200 mg daily. Avoid concomitant use of ruxolitinib with fluconazole >200 mg daily.
If coadministration with fluconazole ≤200 mg daily is necessary in patients with chronic GVHD, reduce the starting dosage of ruxolitinib to 5 mg twice daily.
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.
Adults
Intermediate- or High-Risk Myelofibrosis OralThe recommended initial dosage of ruxolitinib is based on platelet count.
Platelet count >200,000/mm3: Initially, 20 mg twice daily.
Platelet count 100,000–200,000/mm3: Initially, 15 mg twice daily.
Platelet count of 50,000/mm3 to <100,000/mm3: Initially, 5 mg twice daily.
Individualize dosage to optimize response and manage cytopenias associated with the drug.
When discontinuing ruxolitinib for reasons other than thrombocytopenia, taper dosage gradually (e.g., by 5 mg twice daily on a weekly basis).
Dosage Modification for Hematologic Parameters in Patients with Myelofibrosis OralDosage reductions may be considered based on platelet count without interrupting therapy in patients with a baseline platelet count ≥100,000/mm3 (see Table 5) and in patients with a baseline platelet count of 50,000 to <100,000/mm3 (see Table 6). 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.
Table 5. Recommended Dosage Reduction for Platelet Count in Patients with Baseline Platelet Count ≥100,000/mm31Current 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
Table 6. Recommended Dosage Reduction for Platelet Count in Patients with Baseline Platelet Count 50,000 to <100,000/mm31Current 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. When platelet counts improve to >50,000/mm3 and ANC improves to >750/mm3, ruxolitinib may be resumed. When restarting, begin with a dosage at least 5 mg twice daily below the dosage at interruption and follow the manufacturer's guideline for the maximum allowable dosage that may be used when restarting treatment (see Table 7).
Table 7. Maximum Restarting Dosage of Ruxolitinib Following Interruption of Therapy for Thrombocytopenia in Patients with Baseline Platelet Count ≥100,000/mm31Current 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, resume ruxolitinib 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.
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. When platelet counts improve to >35,000/mm3 and ANC improves to >750/mm3, resume ruxolitinib 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.
Dosage Modification for Insufficient Clinical Response in Patients with Myelofibrosis OralIf clinical response is considered insufficient in patients with a baseline platelet count of ≥100,000/mm3, increase ruxolitinib dosage 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.
Continued long-term use of ruxolitinib at a dosage of 5 mg twice daily should be limited to patients in whom the benefit outweighs the potential risk.
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 >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. Continuation of ruxolitinib for a duration >6 months should be limited to patients in whom the benefit outweighs the potential risk.
Do not increase the ruxolitinib dosage during the first 4 weeks of therapy or more frequently than every 2 weeks.
If spleen size does not reduce or symptoms do not improve following 6 months of therapy with ruxolitinib, discontinue drug.
Dosage Modification for Hemorrhagic Events in Patients with Myelofibrosis OralIf a hemorrhagic event requiring intervention occurs during ruxolitinib therapy in patients with myelofibrosis, interrupt treatment regardless of the current platelet count.
If the hemorrhagic event resolves and the underlying cause of bleeding is controlled, consider resuming ruxolitinib at the dosage used prior to treatment interruption.
If the hemorrhagic event resolves but the underlying cause persists, consider resuming ruxolitinib at a reduced dosage.
Dosage Modification for Concomitant Use with Drugs Affecting Hepatic Microsomal Enzymes in Patients with Myelofibrosis OralDosage adjustment is recommended in patients receiving concomitant ruxolitinib with a potent inhibitor of CYP3A4 or fluconazole ≤200 mg daily. Reduce initial dosage of ruxolitinib based on baseline platelet count. (See Table 8.) Avoid concomitant use of ruxolitinib with fluconazole >200 mg daily.
Table 8. Recommended Initial Dosage of Ruxolitinib in Patients with Myelofibrosis Receiving Concomitant Potent CYP3A4 Inhibitors or Fluconazole1Baseline 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 ≤200 mg daily, the dosage of ruxolitinib should be reduced as described in Table 9.
Table 9. Recommended Dosage Modification of Ruxolitinib in Patients with Myelofibrosis Receiving Concomitant Potent CYP3A4 Inhibitors or Fluconazole1Current 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
Polycythemia VeraInitially, 10 mg twice daily.
Individualize dosage to optimize response and manage cytopenias associated with the drug.
Dosage Modification for Hematologic Parameters in Patients with Polycythemia Vera OralDosage reduction should be considered for hemoglobin concentration <12 g/dL or platelet count <100,000/mm3 to avoid interruption of therapy (see Table 10).
Table 10. Dosage Reduction For Hematologic Parameters in Patients with Polycythemia Vera1Hemoglobin 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, temporarily interrupt ruxolitinib therapy until hematologic parameters recover to acceptable levels; may then resume ruxolitinib at a reduced dosage as described in Table 11.
The most severe hematologic parameter should be used to determine the corresponding maximum dosage.
Continue therapy for at least 2 weeks; if stable, the dosage of ruxolitinib may be increased by 5 mg twice daily.
Table 11. Maximum Recommended Dosage of Ruxolitinib Following Interruption of Therapy for Hematologic Parameters in Patients with Polycythemia Vera1Hematologic Parameters
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 daily 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 daily 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 daily or no more than 5 mg twice daily less than the dose that resulted in dosage interruption
If dosage interruption is necessary on a reduced dosage of 5 mg twice daily, resume ruxolitinib 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.
Dosage of ruxolitinib may be titrated following treatment interruption; however, maximum total daily dosage should not exceed 5 mg less than the dosage that resulted in the dosage interruption. The manufacturer states that the maximal total daily dosage of ruxolitinib is not limited in patients who required treatment interruption following phlebotomy-associated anemia.
Dosage Modification for Insufficient Clinical Response in Patients with Polycythemia Vera OralIf clinical response is considered insufficient and platelet, hemoglobin, and neutrophil counts are adequate, increase ruxolitinib dosage 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, WBC or platelet count above the ULN, or spleen size reduced by <25% in palpable length from baseline); platelet count ≥140,000/mm3; hemoglobin concentration ≥12 g/dL; ANC ≥1500/mm3.
Do not increase the ruxolitinib dosage during the first 4 weeks of therapy or more frequently than every 2 weeks.
Dosage Modification for Concomitant Use with Drugs Affecting Hepatic Microsomal Enzymes in Patients with Polycythemia Vera OralIn patients receiving concomitant ruxolitinib with a potent inhibitor of CYP3A4 or fluconazole ≤200 mg daily, reduce initial dosage of ruxolitinib to 5 mg twice daily. Avoid concomitant use of ruxolitinib with fluconazole >200 mg daily.
If a stable dosage of ruxolitinib has been achieved in patients with polycythemia vera receiving concomitant potent CYP3A4 inhibitors of fluconazole ≤200 mg daily, reduce dosage of ruxolitinib as described in Table 12.
Table 12. Recommended Dosage Modification of Ruxolitinib in Patients with Polycythemia Vera Receiving Concomitant Potent CYP3A4 Inhibitors or Fluconazole1Current 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 OralInitially, 5 mg twice daily; may increase dosage to 10 mg twice daily after ≥3 days of treatment if ANC and platelet count do not decrease by ≥50% relative to the first ruxolitinib dosage.
In patients who achieve a response and discontinue therapeutic doses of corticosteroids, consider tapering ruxolitinib after 6 months of therapy; taper dosage should 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). If acute GVHD recurs during or following tapering of the ruxolitinib dosage, consider retreatment with the drug.
When discontinuing ruxolitinib for reasons other than thrombocytopenia, taper dosage gradually (e.g., by 5 mg twice daily on a weekly basis).
Dosage Modification for Toxicity in Patients with Acute GVHD OralIf adverse reactions occur during ruxolitinib therapy, temporary interruption of therapy and/or dosage reduction of the drug may be necessary. If dosage reduction is required, reduce dosage as described in Table 13.
Table 13. Recommended Dosage Reduction for Ruxolitinib Toxicity in Patients with Acute GVHD1Current 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 14).
Table 14. Recommended Dosage Modification for Ruxolitinib Toxicity1Laboratory 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 OralDosage adjustment is recommended in patients receiving concomitant ruxolitinib with a potent inhibitor of CYP3A4 or fluconazole ≤200 mg daily. Avoid concomitant use of ruxolitinib with fluconazole >200 mg daily.
If coadministration with fluconazole at dosages of up to 200 mg per day is necessary in patients with acute GVHD, reduce starting dosage of ruxolitinib to 5 mg once daily.
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.
Chronic Graft-Versus-Host Disease OralInitially, 10 mg twice daily.
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). If chronic GVHD recurs during or following tapering of the ruxolitinib dosage, consider retreatment with the drug.
Dosage Modification for Toxicity in Patients with Chronic GVHD OralIf adverse reactions occur during ruxolitinib therapy, temporary interruption of therapy and/or dosage reduction of the drug may be necessary. If dosage reduction is required, reduce dosage as described in Table 15.
Table 15. Recommended Dosage Reduction for Ruxolitinib Toxicity in Patients with Chronic GVHD1Current 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 16).
Table 16. Recommended Dosage Modification for Ruxolitinib Toxicity1Laboratory 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 OralDosage adjustment is recommended in patients receiving concomitant ruxolitinib with a potent inhibitor of CYP3A4 or fluconazole ≤200 mg daily. Avoid concomitant use of ruxolitinib with fluconazole >200 mg daily.
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.
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.
Prescribing Limits
Adults
Intermediate- or High-Risk Myelofibrosis OralMaximum recommended dosage is based on baseline platelet count and other parameters. (See Intermediate- or High-Risk Myelofibrosis under Dosage and Administration.)
Polycythemia Vera OralMaximum recommended dosage is based on baseline platelet count and other parameters. (See Polycythemia Vera under Dosage and Administration.)
Special Populations
Hepatic Impairment
Intermediate- or High-Risk MyelofibrosisIn 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.
In patients with a baseline platelet count >150,000/mm3, no dosage adjustment necessary.
In patients with a baseline platelet count 100,000–150,000/mm3, reduce initial ruxolitinib dosage to 10 mg twice daily.
In patients with a baseline platelet count 50,000 to <100,000/mm3, reduce initial ruxolitinib dosage to 5 mg once daily.
The manufacturer states that ruxolitinib should be avoided in patients with a baseline platelet count <50,000/mm3 and hepatic impairment.
Polycythemia VeraIn 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.
Acute GVHDIn 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.
In patients with grade 1, 2, or 3 acute GVHD of the liver, no dosage adjustment necessary.
In patients with grade 4 acute GVHD of the liver, reduce ruxolitinib dosage to 5 mg once daily.
Chronic GVHDIn patients with chronic GVHD (not of the liver) and preexisting mild, moderate, or severe hepatic impairment (based on NCI criteria), no dosage adjustment necessary.
In patients with grade 1 or 2 chronic GVHD of the liver, no dosage adjustment necessary.
In patients with grade 3 chronic GVHD of the liver, monitor CBCs more frequently and adjust ruxolitinib dosage for adverse effects, if necessary.
Renal Impairment
Intermediate- or High-Risk MyelofibrosisIn 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. (See Table 17.)
Table 17. Recommended Initial Ruxolitinib Dosage in Patients with Myelofibrosis and Renal Impairment1Severity 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
Polycythemia VeraIn patients with polycythemia vera and moderate to severe renal impairment (ClCr15–59 mL/minute), reduce initial ruxolitinib dosage to 5 mg twice daily.
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.
Acute GVHDIn patients with acute GVHD and moderate to severe renal impairment (ClCr15–59 mL/minute), reduce initial ruxolitinib dosage to 5 mg once daily.
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.
Chronic GVHDIn patients with chronic GVHD and moderate to severe renal impairment (ClCr15–59 mL/minute), reduce initial ruxolitinib dosage to 5 mg twice daily.
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.
Geriatric Patients
Manufacturer makes no specific dosage recommendations in patients ≥65 years of age.
Warnings
Contraindications
Warnings/Precautions
Thrombocytopenia, Anemia, and Neutropenia
Can cause adverse hematologic reactions (e.g., thrombocytopenia, anemia, neutropenia). Perform CBCs before initiating therapy and every 2 to 4 weeks until a stable dosage of the drug is reached. Once a stable dosage has been reached, monitor CBCs as clinically indicated.
Thrombocytopenia usually managed by reducing dosage or temporarily withholding therapy. Administer platelet transfusions if clinically indicated.
Patients who develop anemia may require blood transfusions; consider dosage modification in such patients.
Neutropenia (ANC <500/mm3) generally reversible; managed by temporarily withholding ruxolitinib.
Infectious Complications
Assess patients for risk of developing serious bacterial, mycobacterial, fungal, and viral infections. Resolve active serious infections prior to initiating ruxolitinib. Carefully observe patients for signs and/or symptoms of infection and promptly initiate appropriate treatment.
Tuberculosis infection reported. Evaluate patients for tuberculosis prior to initiating therapy and test patients at high risk for tuberculosis for latent infection. 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. Consult a tuberculosis specialist when deciding whether antimycobacterial therapy should be initiated in patients with active or latent tuberculosis.
Progressive multifocal leukoencephalopathy reported. If progressive multifocal leukoencephalopathy is suspected, discontinue treatment with ruxolitinib and evaluate patient.
Herpes zoster infection reported. Inform patients about the early signs and symptoms of herpes zoster and advise patients to seek treatment as soon as possible for this condition.
Herpes simplex virus reactivation and/or dissemination reported. Monitor patients for signs and symptoms of herpes simplex infection. If confirmed, consider therapy interruption and prompt treatment according to clinical guidelines.
Increases in hepatitis B viral load, both with and without concomitant elevations in alanine and aspartate aminotransferases, reported in patients with chronic hepatitis B virus infection. Effect of ruxolitinib on viral replication in patients with chronic hepatitis B virus infection is unknown. Treat patients with chronic hepatitis B virus infection and monitor according to current clinical guidelines.
Withdrawal of Therapy
Following interruption or discontinuance of therapy, symptoms of myeloproliferative neoplasms may return to pretreatment levels within approximately 1 week.
Some patients with myelofibrosis have reported adverse effects including fever, respiratory distress, hypotension, disseminated intravascular coagulation, and multiorgan failure following discontinuance of ruxolitinib.
Evaluate for adverse effects during tapering or discontinuance of ruxolitinib and consider restarting or increasing dosage if any of adverse effects associated with withdrawal occur. Consider gradual tapering of the dosage when ruxolitinib is discontinued for reasons other than thrombocytopenia or neutropenia.
Malignancies and Lymphoproliferative Disorders
Nonmelanoma skin cancers, including basal cell, squamous cell, and Merkel cell carcinoma, reported. Lymphoma and other malignancies reported in patients receiving other Janus kinase (JAK) inhibitors for the treatment of rheumatoid arthritis.
Consider risks and benefits of ruxolitinib 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.
Periodically perform dermatologic examinations during therapy.
Metabolic Effects
Increases in total cholesterol, low-density lipoprotein (LDL)-cholesterol, and triglyceride concentrations observed. Potential effects of these elevations on cardiovascular morbidity and mortality not determined.
Monitor lipid concentrations 8–12 weeks after initiation of ruxolitinib therapy. Manage hyperlipidemia according to current standards of care.
Major Adverse Cardiovascular Events
Increased risk of major adverse cardiovascular events (MACE), including cardiovascular death, myocardial infarction, and stroke, reported in patients receiving other JAK inhibitors for the treatment of rheumatoid arthritis.
Consider risks and benefits of ruxolitinib prior to initiating therapy, particularly in patients who are current or past smokers and in those with other cardiovascular risk factors. Advise patient to seek immediate medical attention if symptoms of serious cardiovascular events occur.
Thromboembolic Events
Serious and sometimes fatal thromboembolic events, including DVT, pulmonary embolism, and arterial thrombosis in the extremities, reported in patients receiving other JAK inhibitors for the treatment of rheumatoid arthritis.
Promptly evaluate and treat any patients who develop symptoms of thrombosis during treatment with ruxolitinib.
Specific Populations
PregnancyAdverse developmental outcomes, including decreased fetal weight, observed in animal studies.
No studies of ruxolitinib in pregnant women exist to inform a drug-associated risk.
LactationRuxolitinib and/or its metabolites distributed into milk in rats; not known whether distributed into human milk. Discontinue breast-feeding during ruxolitinib therapy and for 2 weeks after the final dose of the drug.
Pediatric UseSafety and efficacy not established in pediatric patients <12 years of age with acute or chronic GVHD or in pediatric patients <18 years of age for the treatment of myelofibrosis and polycythemia vera.
Geriatric UseNo overall differences in safety or efficacy relative to younger adults.
Clinical studies of patients with acute GVHD did not include sufficient numbers of subjects ≥65 years of age to determine whether they respond different relative to younger adults.
Hepatic ImpairmentAcute or chronic GVHD: No clinically significant effects on pharmacokinetics observed in patients with mild to severe hepatic impairment as defined by National Cancer Institute (NCI) criteria. 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 in patients with mild (Child-Pugh class A), moderate (Child-Pugh class B), or severe (Child-Pugh class C) hepatic impairment compared with patients with normal hepatic function. In patients with GVHD of the liver, no clinically significant effects on pharmacokinetics of ruxolitinib 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. The effect of grade 3 chronic GVHD on the pharmacokinetics of ruxolitinib is not known.
Dosage adjustment in patients with hepatic impairment may be necessary.
Renal ImpairmentTotal AUC of ruxolitinib and its active metabolites increased in patients with mild, moderate, or severe renal impairment compared with patients with normal renal function.
Total AUC increased in patients with end-stage renal disease after dialysis.
Dosage reduction of ruxolitinib recommended in patients with end-stage renal disease requiring dialysis and in patients with moderate or severe renal impairment (Clcr 15–59 mL/minute).
Common Adverse Effects
Myelofibrosis and polycythemia vera: Most common adverse hematologic reactions (reported in >20%) include thrombocytopenia and anemia. Most common nonhematologic adverse reactions (reported in ≥15%) include bruising, dizziness, headache, and diarrhea.
Acute GVHD: Most common adverse hematologic reactions (reported in >50%) include anemia, thrombocytopenia, and neutropenia. Most common nonhematologic adverse reactions (reported in >50%) include infections and edema.
Chronic GVHD: Most common adverse hematologic reactions (reported in >35%) include anemia and thrombocytopenia. Most common nonhematologic adverse reactions (reported in ≥20%) include infections and viral infections.
What other drugs will affect Ruxolitinib (Systemic)
Metabolized mainly by CYP3A4.
Ruxolitinib and its M18 metabolite do not inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4 in vitro.
Ruxolitinib does not induce CYP1A2, 2B6, or 3A4 at clinically relevant concentrations.
Not a substrate for P-glycoprotein (P-gp).
Ruxolitinib and its M18 metabolite do not inhibit 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 in vitro at clinically relevant concentrations.
Drugs Affecting Hepatic Microsomal Enzymes
Potent CYP3A4 inhibitors: Pharmacokinetic interaction (increased ruxolitinib peak plasma concentrations and AUC). Dosage modification of ruxolitinib may be necessary.
Weak or moderate CYP3A4 inhibitors: Pharmacokinetic interaction (increased ruxolitinib peak plasma concentrations and AUC). Not clinically important; dosage adjustment not recommended.
Potent CYP3A4 inducers: Pharmacokinetic interaction (decreased ruxolitinib peak plasma concentrations and AUC). Dosage adjustment not recommended. Monitor patients closely; titrate dosage based on safety and efficacy.
Specific Drugs
Drug
Interaction
Comments
Antifungals, azole (e.g., fluconazole, ketoconazole)
Fluconazole: Increased ruxolitinib AUC (by up to 300%)
Ketoconazole: Increased ruxolitinib peak plasma concentration (by 33%), AUC (by 91%), and half-life
Potent CYP3A4 inhibitors or fluconazole ≤200 mg daily: Dosage adjustment necessary; varies by indication. See specific information under Dosage.
Avoid concomitant use with fluconazole >200 mg daily
Erythromycin
Increased ruxolitinib peak plasma concentration (by 8%) and AUC (by 27%)
No dosage adjustment recommended
Rifampin
Decreased ruxolitinib peak plasma concentration (by 32%) and AUC (by 61%)
No dosage adjustment recommended
Closely monitor patients; titrate dosage based on safety and efficacy
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