JAKAFI (Page 3 of 12)

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:

1. Inadequate efficacy as demonstrated by one or more of the following:
   1. Continued need for phlebotomy
   2. WBC greater than the upper limit of normal range
   3. Platelet count greater than the upper limit of normal range
   4. Palpable spleen that is reduced by less than 25% from Baseline
2. Platelet count greater than or equal to 140 x 10⁹ /L
3. Hemoglobin greater than or equal to 12 g/dL
4. ANC greater than or equal to 1.5 x 10⁹ /L

2.4 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.

Table 7: Dose Modifications for Adverse Reactions in Patients with Acute GVHD

Laboratory Parameter	Dosing Recommendations
Clinically significantthrombocytopenia after supportivemeasures	Reduce dose by 1 dose level.When platelets recover to previous values, dosing mayreturn to prior dose level.
ANC less than 1 x 109 /Lconsidered related to Jakafi	Hold Jakafi for up to 14 days; resume at 1 dose levellower upon recovery.
Total Bilirubin elevation, no liverGVHD	3.0−5.0 x ULN: Continue Jakafi at 1 dose level loweruntil recovery. > 5.0−10.0 x ULN: Hold Jakafi for up to 14 days untilbilirubin ≤ 1.5 x ULN; resume at current dose uponrecovery. Total bilirubin > 10.0 x ULN: Hold Jakafi for up to14 days until bilirubin ≤ 1.5 x ULN; resume at 1 doselevel lower upon recovery.
Total Bilirubin elevation, liverGVHD	> 3.0 × ULN: Continue Jakafi at 1 dose level loweruntil recovery.

2.5 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.

Table 8: Dose Modifications for Adverse Reactions in Patients with Chronic GVHD

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.

2.6 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.

Table 9: Dose Modifications for Concomitant Use with Strong CYP3A4 Inhibitors or Fluconazole

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:
Greater than or equal to 100 x 109 /L	10 mg twice daily
50 x 109 /L to less than 100 x 109 /L	5 mg once daily
Starting dose for patients with PV:	5 mg twice daily
If on stable dose for patients with MF or PV:
Greater than or equal to 10 mg twice daily	Decrease dose by 50% (round up to the closest available tablet strength)
5 mg twice daily	5 mg once daily
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 dose for patients with aGVHD or cGVHD:
Fluconazole doses of less than or equal to 200 mg	5 mg once daily for patients with aGVHD;5 mg twice daily for patients with cGVHD
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 ) ].