Incyte Corporation

Incyte Corporation Drugs

• Jakafi
  

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  Jakafi

  

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  2.1 Myelofibrosis

  The recommended starting dose of Jakafi is based on platelet count (Table 1). A complete blood count (CBC) and platelet count must be performed before initiating therapy, every 2 to 4 weeks until doses are stabilized, and then as clinically indicated [see Warnings and Precautions (5.1)]. Doses may be titrated based on safety and efficacy.

  Table 1: Jakafi Starting Doses for Myelofibrosis 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

  2.1.1 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.

  Table 2: Myelofibrosis: Maximum Restarting Doses for Jakafi after Safety Interruption for Thrombocytopenia for Patients Starting Treatment with a Platelet Count of 100 X 109/L or Greater

  *Maximum doses are displayed. When restarting, begin with a dose at least 5 mg twice daily below the dose at 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.

  Table 3: Myelofibrosis: Dosing Recommendations for Thrombocytopenia for Patients Starting Treatment with a Platelet Count of 100 X 109/L or Greater   Dose at Time of Platelet Decline Platelet Count 25 mg twicedaily 20 mg twicedaily 15 mg twicedaily 10 mg twicedaily 5 mg twicedaily NewDose NewDose NewDose NewDose NewDose 100 to less than 125 X 109/L 20 mg twicedaily 15 mg twicedaily NoChange NoChange NoChange 75 to less than 100 X 109/L 10 mg twicedaily 10 mg twicedaily 10 mg twicedaily NoChange NoChange 50 to less than 75 X 109/L 5 mg twicedaily 5 mg twicedaily 5 mg twicedaily 5 mg twicedaily NoChange Less than 50 X 109/L Hold Hold Hold Hold Hold

  2.1.2 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:

  a. 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); b. Platelet count greater than 125 X 10 9/L at 4 weeks and platelet count never below 100 X 10 9/L; c. ANC Levels greater than 0.75 X 10 9/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.

  2.1.3 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 ruxolitinib. See Section 2.1.1 for dose modifications for hematological toxicity in patients whose platelet counts were 100 X 109/L or more prior to starting treatment with ruxolitinib.

  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 ruxolitinib 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/L     AND 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/L     AND 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.

  2.1.4 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 2.1.2, doses may be increased by increments of 5 mg daily to a maximum of 10 mg twice daily if:

  a) the platelet count has remained at least 40 X 10 9/L, and b) the platelet count has not fallen by more than 20% in the prior 4 weeks, and c) the ANC is more than 1 X 10 9/L, and d) 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.

  2.1.5 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.

  2.2 Polycythemia Vera

  The recommended starting dose of Jakafi is 10 mg twice daily. Doses may be titrated based on safety and efficacy.

  2.2.1 Dose Modification Guidelines for Patients with Polycythemia Vera

  A complete blood count (CBC) and platelet count must be performed before initiating therapy, every 2 to 4 weeks until doses are stabilized, and then as clinically indicated [see Warnings and Precautions (5.1)].

  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.

  aContinue 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 dailya 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 dailya 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 dailya 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.

  2.2.2 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

  2.3 Dose Modification for Drug Interactions

  Concomitant Use with Strong CYP3A4 Inhibitors or Fluconazole

  Modify the dose of Jakafi when given concomitantly with strong CYP3A4 inhibitors (such as but not limited to boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole) and fluconazole doses of less than or equal to 200 mg as follows [see Drug Interactions (7.1)], according to Table 7.

  Table 7: Dose Modification for Drug Interactions   Patients on concomitant strong CYP3A4  inhibitors or fluconazole doses of less than or  equal to 200 mg Recommended Dose Modification   Starting Dose for Myelofibrosis Patients 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 Polycythemia Vera Patients 5 mg twice daily   All Patients on a Stable Dose of: 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

  Avoid the use of fluconazole doses of greater than 200 mg daily concomitantly with Jakafi.

  Additional dose modifications should be made with careful monitoring of safety and efficacy.

  2.4 Organ Impairment

  Renal Impairment

  Modify the dose of Jakafi accordingly in patients with moderate or severe renal impairment.

  Table 8: Dosing for Renal Impairment   Renal Impairment Status   Platelet Count   Recommended Starting Dosage   Myelofibrosis Patients   Moderate (CrCl 30–59 mL/min) or  Severe (CrCl 15–29 mL/min)   Greater than 150 X 109/L   No dose modification needed   100 X 109/L - 150 X 109/L   10 mg twice daily   50 - less than 100 X 109/L   5 mg daily   Less than 50 X 109/L   Avoid use [see Use in Specific  Populations (8.6)]   Polycythemia Vera Patients   Moderate (CrCl 30-59 mL/min) or  Severe (CrCl 15-29 mL/min)   Any   5 mg twice daily

  Patients on Dialysis

  The recommended starting dose for myelofibrosis patients with end stage renal disease on dialysis is 15 mg once after a dialysis session for patients with a platelet count between 100 X 109/L and 200 X 109/L or 20 mg for patients with a platelet count of greater than 200 X 109/L. The recommended starting dose for polycythemia vera patients with end stage renal disease on dialysis is 10 mg. Additional dose modifications should be made with frequent monitoring of safety and efficacy. Avoid use of Jakafi in patients with end stage renal disease (CrCl less than 15 mL/min) not requiring dialysis [see Use in Specific Populations (8.6)].

  Hepatic Impairment

  The dose of Jakafi should be reduced in patients with hepatic impairment.

  Table 9: Dosing for Hepatic Impairment   Hepatic Impairment Status   Platelet Count   Recommended Starting Dosage   Myelofibrosis Patients   Mild, Moderate, or Severe (Child-  Pugh categories A, B, C)   Greater than 150 X 109/L   No dose modification needed   100 X 109/L - 150 X 109/L   10 mg twice daily   50 - less than 100 X 109/L   5 mg daily   Less than 50 X 109/L   Avoid use [see Use in Specific  Populations (8.6)]   Polycythemia Vera Patients   Mild, Moderate, or Severe (Child-  Pugh categories A, B, C)   Any   5 mg twice daily

  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.

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