Drug Detail:Jakafi (Ruxolitinib [ rux-oh-li-ti-nib ])
Generic Name: RUXOLITINIB 5.0mg
Dosage Form: tablet
Drug Class: Multikinase inhibitors
2.1 Monitoring to Assess Safety
Prior to Jakafi treatment:
- Perform a complete blood count [see Warnings and Precautions (5.1)].
- Inquire about past infections, including tuberculosis, herpes simplex, herpes zoster, and hepatitis B [see Warnings and Precautions (5.2)].
During treatment with Jakafi:
- Perform a complete blood count every 2 to 4 weeks until doses are stabilized, and then as clinically indicated [see Warnings and Precautions (5.1)].
- Assess lipid parameters approximately 8-12 weeks following initiation of Jakafi therapy [see Warnings and Precautions (5.5)].
Recommended Dosage for Myelofibrosis
The recommended starting dose of Jakafi is based on platelet count (Table 1). Doses may be titrated based on safety and efficacy.
Platelet Count | Starting Dose |
Greater than 200 x 109/L | 20 mg orally twice daily |
100 x 109/L to 200 x 109/L | 15 mg orally twice daily |
50 x 109/L to less than 100 x 109/L | 5 mg orally twice daily |
Dose Modification Guidelines for Hematologic Toxicity for Patients with Myelofibrosis Starting Treatment with a Platelet Count of 100 x 109/L or Greater
Treatment Interruption and Restarting Dosing
Interrupt treatment for platelet counts less than 50 x 109/L or absolute neutrophil count (ANC) less than 0.5 x 109/L.
After recovery of platelet counts above 50 x 109/L and ANC above 0.75 x 109/L, dosing may be restarted. Table 2 illustrates the maximum allowable dose that may be used in restarting Jakafi after a previous interruption.
|
|
Current Platelet Count | Maximum Dose When Restarting Jakafi Treatment* |
Greater than or equal to 125 x 109/L | 20 mg twice daily |
100 to less than 125 x 109/L | 15 mg twice daily |
75 to less than 100 x 109/L | 10 mg twice daily for at least 2 weeks; if stable, may increase to 15 mg twice daily |
50 to less than 75 x 109/L | 5 mg twice daily for at least 2 weeks; if stable, may increase to 10 mg twice daily |
Less than 50 x 109/L | Continue hold |
Following treatment interruption for ANC below 0.5 x 109/L, after ANC recovers to 0.75 x 109/L or greater, restart dosing at the higher of 5 mg once daily or 5 mg twice daily below the largest dose in the week prior to the treatment interruption.
Dose Reductions
Dose reductions should be considered if the platelet counts decrease as outlined in Table 3 with the goal of avoiding dose interruptions for thrombocytopenia.
Dose at Time of Platelet Decline | |||||
Platelet Count | 25 mg twice daily |
20 mg twice daily |
15 mg twice daily |
10 mg twice daily |
5 mg twice daily |
New Dose |
New Dose |
New Dose |
New Dose |
New Dose |
|
100 to less than 125 x 109/L |
20 mg twice daily |
15 mg twice daily |
No Change |
No Change |
No Change |
75 to less than 100 x 109/L |
10 mg twice daily |
10 mg twice daily |
10 mg twice daily |
No Change |
No Change |
50 to less than 75 x 109/L |
5 mg twice daily |
5 mg twice daily |
5 mg twice daily |
5 mg twice daily |
No Change |
Less than 50 x 109/L | Hold | Hold | Hold | Hold | Hold |
Dose Modification Based on Insufficient Response for Patients with Myelofibrosis Starting Treatment with a Platelet Count of 100 x 109/L or Greater
If the response is insufficient and platelet and neutrophil counts are adequate, doses may be increased in 5 mg twice daily increments to a maximum of 25 mg twice daily. Doses should not be increased during the first 4 weeks of therapy and not more frequently than every 2 weeks.
Consider dose increases in patients who meet all of the following conditions:
- Failure to achieve a reduction from pretreatment baseline in either palpable spleen length of 50% or a 35% reduction in spleen volume as measured by computed tomography (CT) or magnetic resonance imaging (MRI);
- Platelet count greater than 125 x 109/L at 4 weeks and platelet count never below 100 x 109/L;
- ANC Levels greater than 0.75 x 109/L.
Based on limited clinical data, long-term maintenance at a 5 mg twice daily dose has not shown responses and continued use at this dose should be limited to patients in whom the benefits outweigh the potential risks. Discontinue Jakafi if there is no spleen size reduction or symptom improvement after 6 months of therapy.
Dose Modifications for Hematologic Toxicity for Patients with Myelofibrosis Starting Treatment with Platelet Counts of 50 x 109/L to Less Than 100 x 109/L
This section applies only to patients with platelet counts of 50 x 109/L to less than 100 x 109/L prior to any treatment with Jakafi. See dose modifications in Section 2.2 (Dose Modification Guidelines for Hematological Toxicity for Patients with Myelofibrosis Starting Treatment with a Platelet Count of 100 x 109/L or Greater) for hematological toxicity in patients whose platelet counts were 100 x 109/L or more prior to starting treatment with Jakafi.
Treatment Interruption and Restarting Dosing
Interrupt treatment for platelet counts less than 25 x 109/L or ANC less than 0.5 x 109/L.
After recovery of platelet counts above 35 x 109/L and ANC above 0.75 x 109/L, dosing may be restarted. Restart dosing at the higher of 5 mg once daily or 5 mg twice daily below the largest dose in the week prior to the decrease in platelet count below 25 x 109/L or ANC below 0.5 x 109/L that led to dose interruption.
Dose Reductions
Reduce the dose of Jakafi for platelet counts less than 35 x 109/L as described in Table 4.
Platelet Count | Dosing Recommendations |
Less than 25 x 109/L |
|
25 x 109/L to less than 35 x 109/L |
|
25 x 109/L to less than 35 x 109/L |
|
Dose Modifications Based on Insufficient Response for Patients with Myelofibrosis and Starting Platelet Count of 50 x 109/L to Less Than 100 x 109/L
Do not increase doses during the first 4 weeks of therapy, and do not increase the dose more frequently than every 2 weeks.
If the response is insufficient as defined in Section 2.2 (see Dose Modification Based on Insufficient Response with Myelofibrosis Starting Treatment with a platelet count of 100 x 109/L or Greater), doses may be increased by increments of 5 mg daily to a maximum of 10 mg twice daily if:
- the platelet count has remained at least 40 x 109/L, and
- the platelet count has not fallen by more than 20% in the prior 4 weeks, and
- the ANC is more than 1 x 109/L, and
- the dose has not been reduced or interrupted for an adverse event or hematological toxicity in the prior 4 weeks.
Continuation of treatment for more than 6 months should be limited to patients in whom the benefits outweigh the potential risks. Discontinue Jakafi if there is no spleen size reduction or symptom improvement after 6 months of therapy.
Dose Modification for Bleeding
Interrupt treatment for bleeding requiring intervention regardless of current platelet count. Once the bleeding event has resolved, consider resuming treatment at the prior dose if the underlying cause of bleeding has been controlled. If the bleeding event has resolved but the underlying cause persists, consider resuming treatment with Jakafi at a lower dose.
Recommended Dosage for Polycythemia Vera
The recommended starting dose of Jakafi is 10 mg twice daily. Doses may be titrated based on safety and efficacy.
Dose Modification Guidelines for Patients with Polycythemia Vera
Dose Reductions
Dose reductions should be considered for hemoglobin and platelet count decreases as described in Table 5.
Hemoglobin and/or Platelet Count | Dosing Recommendations |
Hemoglobin greater than or equal to 12 g/dL AND platelet count greater than or equal to 100 x 109/L |
|
Hemoglobin 10 to less than 12 g/dL AND platelet count 75 to less than 100 x 109/L |
|
Hemoglobin 8 to less than 10 g/dL OR platelet count 50 to less than 75 x 109/L |
|
Hemoglobin less than 8 g/dL OR platelet count less than 50 x 109/L |
|
Treatment Interruption and Restarting Dosing
Interrupt treatment for hemoglobin less than 8 g/dL, platelet counts less than 50 x 109/L or ANC less than 1.0 x 109/L.
After recovery of the hematologic parameter(s) to acceptable levels, dosing may be restarted.
Table 6 illustrates the dose that may be used in restarting Jakafi after a previous interruption.
Table 6: Polycythemia Vera: Restarting Doses for Jakafi after Safety Interruption for Hematologic Parameter(s)
Use the most severe category of a patient’s hemoglobin, platelet count, or ANC abnormality to determine the corresponding maximum restarting dose.
|
|
Hemoglobin, Platelet Count, or ANC | Maximum Restarting Dose |
Hemoglobin less than 8 g/dL OR platelet count less than 50 x 109/L OR ANC less than 1 x 109/L |
Continue hold |
Hemoglobin 8 to less than 10 g/dL OR platelet count 50 to less than 75 x 109/L OR ANC 1 to less than 1.5 x 109/L |
5 mg twice daily*or no more than 5 mg twice daily less than the dose which resulted in dose interruption |
Hemoglobin 10 to less than 12 g/dL OR platelet count 75 to less than 100 x 109/L OR ANC 1.5 to less than 2 x 109/L |
10 mg twice daily*or no more than 5 mg twice daily less than the dose which resulted in dose interruption |
Hemoglobin greater than or equal to 12 g/dL OR platelet count greater than or equal to 100 x 109/L OR ANC greater than or equal to 2 x 109/L |
15 mg twice daily*or no more than 5 mg twice daily less than the dose which resulted in dose interruption |
Patients who had required dose interruption while receiving a dose of 5 mg twice daily, may restart at a dose of 5 mg twice daily or 5 mg once daily, but not higher, once hemoglobin is greater than or equal to 10 g/dL, platelet count is greater than or equal to 75 x 109/L, and ANC is greater than or equal to 1.5 x 109/L.
Dose Management after Restarting Treatment
After restarting Jakafi following treatment interruption, doses may be titrated, but the maximum total daily dose should not exceed 5 mg less than the dose that resulted in the dose interruption. An exception to this is dose interruption following phlebotomy-associated anemia, in which case the maximal total daily dose allowed after restarting Jakafi would not be limited.
Dose Modifications Based on Insufficient Response for Patients with Polycythemia Vera
If the response is insufficient and platelet, hemoglobin, and neutrophil counts are adequate, doses may be increased in 5 mg twice daily increments to a maximum of 25 mg twice daily. Doses should not be increased during the first 4 weeks of therapy and not more frequently than every two weeks.
Consider dose increases in patients who meet all of the following conditions:
- Inadequate efficacy as demonstrated by one or more of the following:
- Continued need for phlebotomy
- WBC greater than the upper limit of normal range
- Platelet count greater than the upper limit of normal range
- Palpable spleen that is reduced by less than 25% from Baseline
- Platelet count greater than or equal to 140 x 109/L
- Hemoglobin greater than or equal to 12 g/dL
- ANC greater than or equal to 1.5 x 109/L
Recommended Dosage for Acute Graft-Versus-Host Disease
The recommended starting dose of Jakafi is 5 mg given orally twice daily. Consider increasing the dose to 10 mg twice daily after at least 3 days of treatment if the ANC and platelet counts are not decreased by 50% or more relative to the first day of dosing with Jakafi.
Consider tapering Jakafi after 6 months of treatment in patients with response who have discontinued therapeutic doses of corticosteroids. Taper Jakafi by one dose level approximately every 8 weeks (10 mg twice daily to 5 mg twice daily to 5 mg once daily). If aGVHD signs or symptoms recur during or after the taper of Jakafi, consider retreatment.
Dose Modification Guidelines for Patients with Acute Graft-Versus-Host Disease
Monitor complete blood counts (CBC), including platelet count and ANC, and bilirubin prior to initiating therapy, every 2 to 4 weeks until doses are stabilized, and then as indicated clinically.
Modify the dose of Jakafi for adverse reactions as described in Table 7. For dose reductions, patients who are currently receiving Jakafi 10 mg twice daily may have their dose reduced to 5 mg twice daily; patients receiving 5 mg twice daily may have their dose reduced to 5 mg once daily. Patients who are unable to tolerate Jakafi at a dose of 5 mg once daily should have treatment interrupted until their clinical and/or laboratory parameters recover.
Laboratory Parameter | Dosing Recommendations |
Clinically significant thrombocytopenia after supportive measures |
Reduce dose by 1 dose level. |
ANC less than 1 x 109/L considered related to Jakafi |
Hold Jakafi for up to 14 days; resume at 1 dose level lower upon recovery. |
Total Bilirubin elevation, no liver GVHD |
3.0−5.0 x ULN: Continue Jakafi at 1 dose level lower until recovery. > 5.0−10.0 x ULN: Hold Jakafi for up to 14 days until Total bilirubin > 10.0 x ULN: Hold Jakafi for up to |
Total Bilirubin elevation, liver GVHD |
> 3.0 × ULN: Continue Jakafi at 1 dose level lower until recovery. |
Recommended Dosage for Chronic Graft-Versus-Host Disease
The recommended starting dose of Jakafi is 10 mg given orally twice daily.
Consider tapering Jakafi after 6 months of treatment in patients with response who have discontinued therapeutic doses of corticosteroids. Taper Jakafi by one dose level approximately every 8 weeks (10 mg twice daily to 5 mg twice daily to 5 mg once daily). If GVHD signs or symptoms recur during or after the taper of Jakafi, consider retreatment.
Dose Modification Guidelines for Patients with Chronic Graft-Versus-Host Disease
Monitor complete blood counts (CBC), including platelet count and ANC, and bilirubin prior to initiating therapy, every 2 to 4 weeks until doses are stabilized, and then as indicated clinically.
Modify the dose of Jakafi for adverse reactions as described in Table 8. For dose reductions, patients who are currently receiving Jakafi 10 mg twice daily may have their dose reduced to 5 mg twice daily; patients receiving 5 mg twice daily may have their dose reduced to 5 mg once daily. Patients who are unable to tolerate Jakafi at a dose of 5 mg once daily should have treatment interrupted until their clinical and/or laboratory parameters recover.
Parameter | Dosing Recommendations |
Platelet count less than 20 × 109/L | Reduce Jakafi by 1 dose level. If resolved within 7 days, dosing may return to initial dose level. If not resolved within 7 days, then maintain at 1 dose level lower. |
ANC less than 0.75 × 109/L considered related to Jakafi |
Reduce Jakafi by 1 dose level; resume at initial dose level upon recovery. |
ANC less than 0.5 × 109/L considered related to Jakafi |
Hold Jakafi for up to 14 days; resume at 1 dose level lower upon recovery. May resume initial dose level when ANC greater than 1.0 × 109/L. |
Total Bilirubin: 3.0-5.0 × ULN |
Continue Jakafi at 1 dose level lower until recovery. If resolved within 14 days, then increase by one dose level. If not resolved within 14 days, then maintain the decreased dose level. |
Total Bilirubin: > 5.0-10.0 × ULN |
Hold Jakafi for up to 14 days until resolved; resume at current dose upon recovery. If not resolved within 14 days, then resume at 1 dose level lower upon recovery. |
Total Bilirubin: > 10.0 × ULN |
Hold Jakafi for up to 14 days until resolved; resume at 1 dose level lower upon recovery. If not resolved within 14 days, discontinue. |
Other Adverse Reactions: Grade 3 | Continue Jakafi at 1 dose level lower until recovery. |
Other Adverse Reactions: Grade 4 |
Discontinue Jakafi. |
Dose Modifications for Concomitant Use with Strong CYP3A4 Inhibitors or Fluconazole
Modify the Jakafi dosage when coadministered with strong CYP3A4 inhibitors or doses of less than or equal to 200 mg of fluconazole [see Drug Interactions (7)], according to Table 9. Avoid concomitant use of Jakafi with fluconazole doses of greater than 200 mg daily.
For patients coadministered strong CYP3A4 inhibitors or doses of less than or equal to 200 mg of fluconazole | Recommended Jakafi Dose Modification |
Starting dose for patients with MF with a platelet count: | |
|
10 mg twice daily |
|
5 mg once daily |
Starting dose for patients with PV: | 5 mg twice daily |
If on stable dose for patients with MF or PV: | |
|
Decrease dose by 50% (round up to the closest available tablet strength) |
|
5 mg once daily |
|
Avoid strong CYP3A4 inhibitor or fluconazole treatment or interrupt Jakafi treatment for the duration of strong CYP3A4 inhibitor or fluconazole use |
Starting dosefor patients with aGVHD or cGVHD: | |
Fluconazole doses of less than or equal to 200 mg |
5 mg once daily for patients with aGVHD; |
Other CYP3A4 inhibitors | Monitor blood counts more frequently for toxicity and modify the Jakafi dosage for adverse reactions if they occur [see Dosage and Administration (2.4, 2.5)]. |
Dose Modifications for Renal or Hepatic Impairment
Moderate to Severe Renal Impairment or End Stage Renal Disease on Dialysis
Modify the Jakafi dosage for patients with moderate (CLcr 30 to 59 mL/min) to severe (CLcr 15 to 29 mL/min) renal impairment or end stage renal disease (ESRD) on dialysis according to Table 10. Avoid use of Jakafi in patients with ESRD (CLcr less than 15 mL/min) not requiring dialysis [see Use in Specific Populations (8.6)].
ESRD = end stage renal disease, and CLcr = creatinine clearance | ||
Renal Impairment Status | Platelet Count | Recommended Starting Dosage |
Patients with MF |
||
Moderate or Severe |
Greater than 150 x 109/L | No dose adjustment |
100 to 150 x 109/L | 10 mg twice daily | |
50 to less than 100 x 109/L | 5 mg daily | |
Less than 50 x 109/L |
Avoid use [see Use in Specific |
|
ESRD on dialysis |
100 to 200 x 109/L | 15 mg once after dialysis session |
Greater than 200 x 109/L |
20 mg once after dialysis session | |
Patients with PV | ||
Moderate or Severe | Any | 5 mg twice daily |
ESRD on dialysis | Any | 10 mg once after dialysis session |
Patients with aGVHD | ||
Moderate or Severe | Any | 5 mg once daily |
ESRD on dialysis | Any | 5 mg once after dialysis session |
Patients with cGVHD |
||
Moderate or Severe |
Any |
5 mg twice daily |
ESRD on dialysis | Any |
10 mg once after dialysis session |
Hepatic Impairment
Modify the Jakafi dosage for patients with hepatic impairment according to Table 11.
Hepatic Impairment Status | Platelet Count | Recommended Starting Dosage |
Patients with MF |
Greater than 150 x 109/L | No dose adjustment |
100 x 109/L to 150 x 109/L | 10 mg twice daily | |
50 to less than 100 x 109/L | 5 mg daily | |
Less than 50 x 109/L | Avoid use [see Use in Specific Populations (8.7)] |
|
Patients with PV Mild, Moderate, or Severe (Child-Pugh Class A, B, C) |
Any | 5 mg twice daily |
Patients with aGVHD | ||
Mild, Moderate, or Severe based on NCI criteria without liver GVHD |
Any | No dose adjustment |
Stage 1, 2 or 3 Liver aGVHD |
Any |
No dose adjustment |
Stage 4 Liver aGVHD |
Any | 5 mg once daily |
Patients with cGVHD |
||
Mild, Moderate, or Severe based on NCI criteria without liver GVHD |
Any | No dose adjustment |
Score 1 or 2 Liver cGVHD |
Any | No dose adjustment |
Score 3 Liver cGVHD |
Any | Monitor blood counts more frequently for toxicity and modify the Jakafi dosage for adverse reactions if they occur [see Dosage and Administration (2.4, 2.5)]. |
Method of Administration
Jakafi is dosed orally and can be administered with or without food.
If a dose is missed, the patient should not take an additional dose, but should take the next usual prescribed dose.
When discontinuing Jakafi therapy for reasons other than thrombocytopenia, gradual tapering of the dose of Jakafi may be considered, for example by 5 mg twice daily each week.
For patients unable to ingest tablets, Jakafi can be administered through a nasogastric tube (8 French or greater) as follows:
- Suspend one tablet in approximately 40 mL of water with stirring for approximately 10 minutes.
- Within 6 hours after the tablet has dispersed, the suspension can be administered through a nasogastric tube using an appropriate syringe.
The tube should be rinsed with approximately 75 mL of water. The effect of tube feeding preparations on Jakafi exposure during administration through a nasogastric tube has not been evaluated.