JAKAFI (Page 2 of 12)

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:

1. 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);
2. Platelet count greater than 125 x 10⁹ /L at 4 weeks and platelet count never below 100 x 10⁹ /L;
3. 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.

Table 4: Myelofibrosis: Dosing Modifications for Thrombocytopenia for Patients with Starting Platelet Count of 50 x 10⁹ /L to Less Than 100 x 10⁹ /L

Platelet Count	Dosing Recommendations
Less than 25 x 109 /L	Interrupt dosing.
25 x 109 /L to less than 35 x 109 /LAND the platelet count decline is less than 20% during the prior four weeks	Decrease dose by 5 mg once daily. For patients on 5 mg once daily, maintain dose at 5 mg once daily.
25 x 109 /L to less than 35 x 109 /LAND the platelet count decline is 20% or greater during the prior four weeks	Decrease dose by 5 mg twice daily. For patients on 5 mg twice daily, decrease the dose to 5 mg once daily. For patients on 5 mg once daily, maintain dose at 5 mg once daily.

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:

1. the platelet count has remained at least 40 x 10⁹ /L, and
2. the platelet count has not fallen by more than 20% in the prior 4 weeks, and
3. the ANC is more than 1 x 10⁹ /L, and
4. 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.

2.3 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.

Table 5: Polycythemia Vera: Dose Reductions

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	No change required.
Hemoglobin 10 to less than 12 g/dL AND platelet count 75 to less than 100 x 109 /L	Dose reductions should be considered with the goal of avoiding dose interruptions for anemia and thrombocytopenia.
Hemoglobin 8 to less than 10 g/dL OR platelet count 50 to less than 75 x 109 /L	Reduce dose by 5 mg twice daily. For patients on 5 mg twice daily, decrease the dose to 5 mg once daily.
Hemoglobin less than 8 g/dL OR platelet count less than 50 x 109 /L	Interrupt dosing.

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.

* Continue treatment for at least 2 weeks; if stable, may increase dose by 5 mg twice daily.
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 than5 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 than5 mg twice daily less than the dosewhich 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 ORANC greater than or equal to 2 x 109 /L	15 mg twice daily *or no more than5 mg twice daily less than the dosewhich 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.