Ruxolitinib phosphate is a kinase inhibitor with the chemical name ( R )-3-(4-(7 H -pyrrolo[2,3- d ]pyrimidin-4-yl)-1 H -pyrazol-1-yl)-3-cyclopentylpropanenitrile phosphate and a molecular weight of 404.36. Ruxolitinib phosphate has the following structural formula: Ruxolitinib phosphate is a white to off-white to light pink powder and is soluble in aqueous buffers across a pH range of 1 to 8. JAKAFI (ruxolitinib) tablets are for oral administration. Each tablet contains 5 mg, 10 mg, 15 mg, 20 mg, or 25 mg of ruxolitinib free base, equivalent to 6.6 mg, 13.2 mg, 19.8 mg, 26.4 mg, or 33 mg of ruxolitinib phosphate, respectively, and the following inactive ingredients: colloidal silicon dioxide, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone and sodium starch glycolate. JAKAFI XR (ruxolitinib) extended-release tablets are for oral administration. Each tablet contains 11 mg, 22 mg, 33 mg, 44 mg, or 55 mg of ruxolitinib free base equivalent to 14.5 mg, 29 mg, 43.6 mg, 58.1 mg, or 72.6 mg of ruxolitinib phosphate, respectively, and the following inactive ingredients: colloidal silicon dioxide, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium stearyl fumarate. In addition, the film coating contains the following inactive ingredients: colorants (black iron oxide, red iron oxide, and yellow iron oxide), copovidone, hypromellose, polydextrose, polyethylene glycol, titanium dioxide, and triglycerides. Ruxolitinib phosphate structure

JAKAFI/JAKAFI XR is a kinase inhibitor indicated for treatment of: intermediate or high-risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis in adults. polycythemia vera in adults who have had an inadequate response to or are intolerant of hydroxyurea. steroid-refractory acute graft-versus-host disease in adult and pediatric patients 12 years and older. chronic graft-versus-host disease after failure of one or two lines of systemic therapy in adult and pediatric patients 12 years and older

Myelofibrosis JAKAFI/JAKAFI XR is indicated for treatment of intermediate or high-risk myelofibrosis (MF), including primary MF, post-polycythemia vera MF, and post-essential thrombocythemia MF in adults

Polycythemia Vera JAKAFI/JAKAFI XR is indicated for treatment of polycythemia vera (PV) in adults who have had an inadequate response to or are intolerant of hydroxyurea

Acute Graft-Versus-Host Disease JAKAFI/JAKAFI XR is indicated for treatment of steroid-refractory acute graft-versus-host disease (aGVHD) in adult and pediatric patients 12 years and older

Chronic Graft-Versus-Host Disease JAKAFI/JAKAFI XR is indicated for treatment of chronic graft-versus-host disease (cGVHD) after failure of one or two lines of systemic therapy in adult and pediatric patients 12 years and older.

JAKAFI : 5 mg tablets - round and white with "INCY" on one side and "5" on the other. 10 mg tablets - round and white with "INCY" on one side and "10" on the other. 15 mg tablets - oval and white with "INCY" on one side and "15" on the other. 20 mg tablets - capsule-shaped and white with "INCY" on one side and "20" on the other. 25 mg tablets - oval and white with "INCY" on one side and "25" on the other. JAKAFI XR : 11 mg extended-release tablets - round and light pink with “I” on one side and “11” on the other. 22 mg extended-release tablets - round and light yellow with “I” on one side and “22” on the other. 33 mg extended-release tablets - round and pink with “I” on one side and “33” on the other. 44 mg extended-release tablets - round and grey with “I” on one side and “44” on the other. 55 mg extended-release tablets - round and yellow with “I” on one side and “55” on the other. JAKAFI tablets: 5 mg, 10 mg, 15 mg, 20 mg and 25 mg. JAKAFI XR extended-release tablets: 11 mg, 22 mg, 33 mg, 44 mg and 55 mg.

Doses should be individualized based on safety and efficacy. Starting doses per indication are noted below. Myelofibrosis The starting dose of JAKAFI/JAKAFI XR is based on patient’s baseline platelet count: • Greater than 200 × 10 9 /L: JAKAFI 20 mg given orally twice daily or JAKAFI XR 44 mg given orally once daily. • 100 x 10 9 /L to 200 x 10 9 /L: JAKAFI 15 mg given orally twice daily or JAKAFI XR 33 mg given orally once daily. • 50 x 10 9 /L to less than 100 x 10 9 /L: JAKAFI 5 mg given orally twice daily or JAKAFI XR 11 mg given orally once daily. Polycythemia Vera The starting dose of JAKAFI is 10 mg given orally twice daily or JAKAFI XR 22 mg given orally once daily. Acute Graft-Versus-Host Disease The starting dose of JAKAFI is 5 mg given orally twice daily or JAKAFI XR 11 mg given orally once daily. Chronic Graft-Versus-Host Disease The starting dose of JAKAFI is 10 mg given orally twice daily or JAKAFI XR 22 mg given orally once daily

Monitoring to Assess Safety Prior to JAKAFI/JAKAFI XR treatment: Perform a complete blood count (CBC) . Inquire about past infections, including tuberculosis, herpes simplex, herpes zoster, and hepatitis B . During treatment with JAKAFI/JAKAFI XR : Perform a CBC every 2 to 4 weeks until doses are stabilized, and then as clinically indicated . Assess lipid parameters approximately 8 to 12 weeks following initiation of JAKAFI/JAKAFI XR therapy

Recommended Dosage for Myelofibrosis The recommended starting dose of JAKAFI/JAKAFI XR is based on platelet count (Table 1). Doses may be titrated based on safety and efficacy. Table 1: JAKAFI/JAKAFI XR Starting Doses for Myelofibrosis Platelet Count JAKAFI Starting Dose JAKAFI XR Starting Dose Greater than 200 x 10 9 /L 20 mg orally twice daily 44 mg orally once daily 100 x 10 9 /L to 200 x 10 9 /L 15 mg orally twice daily 33 mg orally once daily 50 x 10 9 /L to less than 100 x 10 9 /L 5 mg orally twice daily 11 mg orally once daily Dose Modification Guidelines for Hematologic Toxicity for Patients With Myelofibrosis Starting Treatment With a Platelet Count of 100 × 10 9 /L or Greater Dose Reductions JAKAFI dose reductions should be considered if the platelet counts decrease as outlined in Table 2 with the goal of avoiding dose interruptions for thrombocytopenia. Table 2: Myelofibrosis: JAKAFI Dosing Recommendations for Thrombocytopenia for Patients Starting Treatment With a Platelet Count of 100 × 10 9 /L or Greater 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 10 9 /L 20 mg twice daily 15 mg twice daily No Change No Change No Change 75 to less than 100 x 10 9 /L 10 mg twice daily 10 mg twice daily 10 mg twice daily No Change No Change 50 to less than 75 x 10 9 /L 5 mg twice daily 5 mg twice daily 5 mg twice daily 5 mg twice daily No Change Less than 50 x 10 9 /L Hold Hold Hold Hold Hold JAKAFI XR 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: JAKAFI XR Dosing Recommendations for Thrombocytopenia for Patients Starting Treatment With a Platelet Count of 100 × 10 9 /L or Greater Dose at Time of Platelet Decline Platelet Count 55 mg Once Daily 44 mg Once Daily 33 mg Once Daily 22 mg Once Daily 11 mg Once Daily New Dose New Dose New Dose New Dose New Dose 100 to less than 125 x 10 9 /L 44 mg once daily 33 mg once daily No change No change No change 75 to less than 100 x 10 9 /L 22 mg once daily 22 mg once daily 22 mg once daily No change No change 50 to less than 75 x 10 9 /L 11 mg once daily 11 mg once daily 11 mg once daily 11 mg once daily No change Less than 50 x 10 9 /L Hold Hold Hold Hold Hold Treatment Interruption and Restarting Dosing Interrupt treatment for platelet counts less than 50 x 10 9 /L or absolute neutrophil count (ANC) less than 0.5 x 10 9 /L. After recovery of platelet counts above 50 × 10 9 /L and ANC above 0.75 × 10 9 /L, dosing may be restarted. When restarting JAKAFI, begin with a dose that is at least 5 mg twice daily below the dose at interruption. When restarting JAKAFI XR, begin with a dose that is at least 11 mg once daily below the dose at interruption. The maximum allowable dose that may be used in restarting JAKAFI/JAKAFI XR after a previous interruption is outlined in Table 4 for thrombocytopenia and in Table 5 for neutropenia. Table 4: Myelofibrosis: Maximum Restarting Doses for JAKAFI/JAKAFI XR After Safety Interruption for Thrombocytopenia for Patients Starting Treatment With a Platelet Count of 100 × 10 9 /L or Greater Current Platelet Count Maximum Dose When Restarting JAKAFI Treatment Maximum Dose When Restarting JAKAFI XR Treatment Greater than or equal to 125 x 10 9 /L 20 mg twice daily 44 mg once daily 100 to less than 125 x 10 9 /L 15 mg twice daily 33 mg once daily 75 to less than 100 x 10 9 /L 10 mg twice daily for at least 2 weeks; if stable, may increase to 15 mg twice daily 22 mg once daily for at least 2 weeks; if stable, may increase to 33 mg once daily 50 to less than 75 x 10 9 /L 5 mg twice daily for at least 2 weeks; if stable, may increase to 10 mg twice daily 11 mg once daily for at least 2 weeks; if stable, may increase to 22 mg once daily Less than 50 x 10 9 /L Continue hold Table 5: Myelofibrosis: Maximum Restarting Doses for JAKAFI/JAKAFI XR After Safety Interruption for Neutropenia (ANC < 0.5 x 10 9 /L) Current Neutrophil Count Maximum Dose When Restarting JAKAFI Treatment Maximum Dose When Restarting JAKAFI XR Treatment ANC ≥ 0.75 x 10 9 /L For patients on 5 mg twice daily prior to interruption, restart at 5 mg once daily OR For patients with dose greater than 5 mg twice daily prior to interruption, restart at 5 mg twice daily below the largest dose in the week prior to interruption For patients on 11 mg once daily prior to the first interruption, restart at 11 mg once daily. Discontinue for a second interruption OR For patients with dose greater than 11 mg once daily prior to interruption, restart at 11 mg once daily below the largest dose in the week prior to interruption Dose Modification Based on Insufficient Response for Patients With Myelofibrosis Starting Treatment With a Platelet Count of 100 × 10 9 /L or Greater If the response is insufficient and platelet and neutrophil counts are adequate, JAKAFI doses may be increased in 5 mg twice daily increments to a maximum of 25 mg twice daily. JAKAFI XR doses may be increased in 11 mg once daily increments to a maximum of 55 mg once 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 10 9 /L at 4 weeks and platelet count never below 100 x 10 9 /L; ANC Levels greater than 0.75 x 10 9 /L. Based on limited clinical data, long-term maintenance at a JAKAFI 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/JAKAFI XR 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 × 10 9 /L to Less Than 100 × 10 9 /L This section applies only to patients with platelet counts of 50 × 10 9 /L to less than 100 × 10 9 /L prior to any treatment with JAKAFI/JAKAFI XR. See dose modifications in Section 2.2 ( Dose Modification Guidelines for Hematologic Toxicity for Patients With Myelofibrosis Starting Treatment With a Platelet Count of 100 × 10 9 /L or Greater ) for hematological toxicity in patients whose platelet counts were 100 × 10 9 /L or more prior to starting treatment with JAKAFI/JAKAFI XR. Dose Reductions Reduce the dose of JAKAFI/JAKAFI XR for platelet counts less than 35 x 10 9 /L as described in Table 6. Table 6: Myelofibrosis: Dosing Modifications for Thrombocytopenia for Patients With Starting Platelet Count of 50 × 10 9 /L to Less Than 100 × 10 9 /L Platelet Count JAKAFI Dosing Recommendations JAKAFI XR Dosing Recommendations 25 × 10 9 /L to less than 35 × 10 9 /L AND the platelet count decline is 20% or greater during the prior 4 weeks For patients with dose greater than 5 mg twice daily, reduce the dose by 5 mg twice daily. For patients on 5 mg twice daily, reduce the dose to 5 mg once daily. For patients on 5 mg once daily, maintain dose at 5 mg once daily. Reduce dose by 11 mg once daily. For patients on 11 mg once daily, interrupt dosing. 25 × 10 9 /L to less than 35 × 10 9 /L AND the platelet count decline is less than 20% during the prior 4 weeks Less than 25 × 10 9 /L Interrupt dosing. Treatment Interruption and Restarting Dosing Interrupt treatment for platelet counts less than 25 x 10 9 /L or ANC less than 0.5 x 10 9 /L. After recovery of platelet counts above 35 × 10 9 /L and ANC above 0.75 × 10 9 /L, dosing may be restarted. For patients on a dose higher than 5 mg twice daily, when restarting JAKAFI, begin with a dose that is at least 5 mg twice daily below the largest dose in the week prior to interruption. For patients on JAKAFI 5 mg twice daily in the week prior to interruption, when restarting, reduce the dose to 5 mg once daily. When restarting JAKAFI XR, begin with a dose that is at least 11 mg once daily below the largest dose in the week prior to the treatment interruption. For patients on JAKAFI XR 11 mg once daily prior to the first interruption, continue JAKAFI XR 11 mg once daily. Discontinue JAKAFI XR for a second interruption. Dose Modifications Based on Insufficient Response for Patients With Myelofibrosis and Starting Platelet Count of 50 x 10 9 /L to Less Than 100 x 10 9 /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 , doses may be increased from JAKAFI 5 mg once daily to JAKAFI 5 mg twice daily, or from JAKAFI 5 mg twice daily to a maximum of 10 mg twice daily, if the following conditions are met. For patients on JAKAFI XR 11 mg once daily, dose may be increased to a maximum of 22 mg once daily if: the platelet count has remained at least 40 x 10 9 /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 10 9 /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/JAKAFI XR 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/JAKAFI XR at a lower dose

Recommended Dosage for Polycythemia Vera The recommended starting dose of JAKAFI is 10 mg orally twice daily. The recommended starting dose of JAKAFI XR is 22 mg orally once 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 7. Table 7: Polycythemia Vera: Dose Reductions Hemoglobin and/or Platelet Count JAKAFI Dosing Recommendations JAKAFI XR Dosing Recommendations Hemoglobin 10 to less than 12 g/dL AND platelet count 75 to less than 100 x 10 9 /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 10 9 /L Reduce dose by 5 mg twice daily. For patients on 5 mg twice daily, reduce the dose to 5 mg once daily. Reduce dose by 11 mg once daily. For patients on 11 mg once daily, interrupt dosing. Hemoglobin less than 8 g/dL OR platelet count less than 50 x 10 9 /L Interrupt dosing. Treatment Interruption and Restarting Dosing Interrupt treatment for hemoglobin less than 8 g/dL, platelet counts less than 50 x 10 9 /L or ANC less than 1 x 10 9 /L. After recovery of the hematologic parameter(s) to acceptable levels, dosing may be restarted. Table 8 illustrates the dose that may be used in restarting JAKAFI/JAKAFI XR after a previous interruption. Table 8: Polycythemia Vera: Restarting Doses for JAKAFI/JAKAFI XR 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 JAKAFI Maximum Restarting Dose JAKAFI XR Maximum Restarting Dose Hemoglobin less than 8 g/dL OR platelet count less than 50 x 10 9 /L OR ANC less than 1 x 10 9 /L Continue hold Hemoglobin 8 to less than 10 g/dL OR platelet count 50 to less than 75 x 10 9 /L OR ANC 1 to less than 1.5 x 10 9 /L 5 mg twice daily Continue JAKAFI treatment for at least 2 weeks; if stable, may increase dose by 5 mg twice daily. or no more than 5 mg twice daily less than the dose which resulted in dose interruption 11 mg once daily Continue JAKAFI XR treatment for at least 2 weeks; if stable, may increase dose by 11 mg once daily. or no more than 11 mg once 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 10 9 /L OR ANC 1.5 to less than 2 x 10 9 /L 10 mg twice daily or no more than 5 mg twice daily less than the dose which resulted in dose interruption 22 mg once daily or no more than 11 mg once 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 10 9 /L OR ANC greater than or equal to 2 x 10 9 /L 15 mg twice daily or no more than 5 mg twice daily less than the dose which resulted in dose interruption 33 mg once daily or no more than 11 mg once daily less than the dose which resulted in dose interruption JAKAFI Patients who had required dose interruption while receiving a dose of 5 mg twice daily, may restart JAKAFI 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 × 10 9 /L, and ANC is greater than or equal to 1.5 × 10 9 /L. JAKAFI XR Patients who had required dose interruption while receiving a dose of 11 mg once daily, may restart JAKAFI XR at a dose of 11 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 × 10 9 /L, and ANC is greater than or equal to 1.5 × 10 9 /L. Dose Management After Restarting Treatment After restarting JAKAFI/JAKAFI XR following treatment interruption, doses may be titrated, but the maximum total daily dose should not exceed 5 mg twice daily (JAKAFI) or 11 mg once daily (JAKAFI XR) 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/JAKAFI XR 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: JAKAFI: in 5 mg twice daily increments to a maximum of 25 mg twice daily. JAKAFI XR: in 11 mg once daily increments to a maximum of 55 mg once 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: Inadequate efficacy as demonstrated by 1 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 10 9 /L Hemoglobin greater than or equal to 12 g/dL ANC greater than or equal to 1.5 x 10 9 /L 2.4 Recommended Dosage for Acute Graft-Versus-Host Disease JAKAFI 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. JAKAFI XR The recommended starting dose of JAKAFI XR is 11 mg given orally once daily. Consider increasing the dose to 22 mg once 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 XR. Treatment Completion Consider tapering JAKAFI/JAKAFI XR after 6 months of treatment in patients with response who have discontinued therapeutic doses of corticosteroids. Taper JAKAFI/JAKAFI XR by one dose level approximately every 8 weeks using the dose levels shown in Table 9. If aGVHD signs or symptoms recur during or after the taper of JAKAFI/JAKAFI XR, consider retreatment. Table 9: Reduced Dose Levels for Patients With aGVHD or cGVHD Dose Level Recommended JAKAFI Dose Recommended JAKAFI XR Dose Maximum dose 10 mg twice daily 22 mg once daily Reduced dose level -1 5 mg twice daily 11 mg once daily Reduced dose level -2 5 mg once daily Do not use JAKAFI XR Dose Modification Guidelines for Patients With Acute Graft-Versus-Host Disease Monitor 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/JAKAFI XR for adverse reactions as described in Table 10. See Table 9 for the recommended dose when a dose reduction is needed. 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 10: Dose Modifications for Adverse Reactions in Patients With Acute GVHD Laboratory Parameter Dosing Recommendations Clinically significant thrombocytopenia after supportive measures Reduce dose by 1 dose level. When platelets recover to previous values, dosing may return to prior dose level. ANC less than 1 x 10 9 /L considered related to JAKAFI/JAKAFI XR Hold JAKAFI/JAKAFI XR up to 14 days; resume at 1 dose level lower upon recovery See Table 9 for reduced dose levels. . Total bilirubin elevation, no liver GVHD 3−5 x ULN: Continue JAKAFI/JAKAFI XR at 1 dose level lower until recovery . > 5−10 x ULN: Hold JAKAFI/JAKAFI XR for up to 14 days until bilirubin ≤ 1.5 x ULN; resume at current dose upon recovery. Total bilirubin > 10 x ULN: Hold JAKAFI/JAKAFI XR for up to 14 days until bilirubin ≤ 1.5 x ULN; resume at 1 dose level lower upon recovery . Total bilirubin elevation, liver GVHD > 3 × ULN: Continue JAKAFI/JAKAFI XR at 1 dose level lower until recovery

Recommended Dosage for Chronic Graft-Versus-Host Disease JAKAFI The recommended starting dose of JAKAFI is 10 mg given orally twice daily. JAKAFI XR The recommended starting dose of JAKAFI XR is 22 mg given orally once daily. Treatment Completion Consider tapering JAKAFI/JAKAFI XR after 6 months of treatment in patients with response who have discontinued therapeutic doses of corticosteroids. Taper JAKAFI/JAKAFI XR by 1 dose level approximately every 8 weeks using the dose levels shown in Table 9. If GVHD signs or symptoms recur during or after the taper of JAKAFI/JAKAFI XR, consider retreatment. Dose Modification Guidelines for Patients With Chronic Graft-Versus-Host Disease Monitor 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/JAKAFI XR for adverse reactions as described in Table 11. See Table 9 for the recommended dose when a dose reduction is needed. 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 11: Dose Modifications for Adverse Reactions in Patients With Chronic GVHD Parameter Dosing Recommendations Platelet count less than 20 × 10 9 /L Reduce JAKAFI/JAKAFI XR by 1 dose level See Table 9 for reduced dose levels. . 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 × 10 9 /L considered related to JAKAFI/JAKAFI XR Reduce JAKAFI/JAKAFI XR by 1 dose level ; resume at initial dose level upon recovery. ANC less than 0.5 × 10 9 /L considered related to JAKAFI/JAKAFI XR Hold JAKAFI/JAKAFI XR for up to 14 days; resume at 1 dose level lower upon recovery. May resume initial dose level when ANC greater than 1 × 10 9 /L. Total bilirubin: 3-5 × ULN Continue JAKAFI/JAKAFI XR at 1 dose level lower until recovery. If resolved within 14 days, then increase by 1 dose level. If not resolved within 14 days, then maintain the reduced dose level. Total bilirubin: > 5-10 × ULN Hold JAKAFI/JAKAFI XR 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 × ULN Hold JAKAFI/JAKAFI XR 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/JAKAFI XR at 1 dose level lower until recovery. Other Adverse Reactions: Grade 4 Discontinue JAKAFI/JAKAFI XR

Dose Modifications for Concomitant Use With Strong CYP3A4 Inhibitors or Fluconazole Modify the JAKAFI/JAKAFI XR dosage when coadministered with strong CYP3A4 inhibitors or doses of less than or equal to 200 mg of fluconazole , according to Table 12. Avoid concomitant use of JAKAFI/JAKAFI XR with fluconazole doses of greater than 200 mg daily. Table 12: 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 Recommended JAKAFI XR Dose Modification Starting dose for patients with MF with a platelet count: Greater than or equal to 100 x 10 9 /L 10 mg twice daily 22 mg once daily 50 x 10 9 /L to less than 100 x 10 9 /L JAKAFI 5 mg once daily Do not use JAKAFI XR Starting dose for patients with PV: 5 mg twice daily 11 mg once daily If on stable dose for patients with MF or PV: JAKAFI: Greater than or equal to 10 mg twice daily JAKAFI XR: Greater than or equal to 22 mg once daily Reduce dose by 50% (round up to the closest available tablet strength) JAKAFI: 5 mg twice daily JAKAFI 5 mg once daily Do not use JAKAFI XR JAKAFI: 5 mg once daily JAKAFI XR: 11 mg once daily Avoid strong CYP3A4 inhibitor or fluconazole treatment or interrupt JAKAFI/JAKAFI XR treatment for the duration of strong CYP3A4 inhibitor or fluconazole use Starting dose for patients with aGVHD: Fluconazole doses of less than or equal to 200 mg JAKAFI 5 mg once daily Do not use JAKAFI XR Other CYP3A4 inhibitors Monitor blood counts more frequently for toxicity and modify the JAKAFI/JAKAFI XR dosage for adverse reactions if they occur . Starting dose for patients with cGVHD: Fluconazole doses of less than or equal to 200 mg JAKAFI 5 mg twice daily JAKAFI XR 11 mg once daily Other CYP3A4 inhibitors Monitor blood counts more frequently for toxicity and modify the JAKAFI/JAKAFI XR dosage for adverse reactions if they occur

Dose Modifications for Renal or Hepatic Impairment Moderate to Severe Renal Impairment or End Stage Renal Disease on Dialysis Modify the JAKAFI/JAKAFI XR 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 13. Avoid use of JAKAFI/JAKAFI XR in patients with ESRD (CLcr less than 15 mL/min) not requiring dialysis . Table 13: Dose Modifications for Renal Impairment CLcr = creatinine clearance; ESRD = end stage renal disease Renal Impairment Status Platelet Count JAKAFI Recommended Starting Dosage JAKAFI XR Recommended Starting Dosage Patients with MF Moderate or Severe Greater than 150 x 10 9 /L No dose adjustment 100 to 150 x 10 9 /L JAKAFI 10 mg twice daily JAKAFI XR 22 mg once daily 50 to less than 100 x 10 9 /L JAKAFI 5 mg once daily Do not use JAKAFI XR Less than 50 x 10 9 /L Avoid use ESRD on dialysis 100 to 200 x 10 9 /L JAKAFI 15 mg once after dialysis session Do not use JAKAFI XR Greater than 200 x 10 9 /L JAKAFI 20 mg once after dialysis session Do not use JAKAFI XR Patients with PV Moderate or Severe Any JAKAFI 5 mg twice daily JAKAFI XR 11 mg once daily ESRD on dialysis Any JAKAFI 10 mg once after dialysis session Do not use JAKAFI XR Patients with aGVHD Moderate or Severe Any JAKAFI 5 mg once daily Do not use JAKAFI XR ESRD on dialysis Any JAKAFI 5 mg once after dialysis session Do not use JAKAFI XR P atients with cGVHD Moderate or Severe Any JAKAFI 5 mg twice daily JAKAFI XR 11 mg once daily ESRD on dialysis Any JAKAFI 10 mg once after dialysis session Do not use JAKAFI XR Hepatic Impairment Modify the JAKAFI/JAKAFI XR dosage for patients with hepatic impairment according to Table 14. Table 14: Dose Modifications for Hepatic Impairment Hepatic Impairment Status Platelet Count JAKAFI Recommended Starting Dosage JAKAFI XR Recommended Starting Dosage Patients with MF Mild, Moderate, or Severe (Child-Pugh Class A, B, C) Greater than 150 x 10 9 /L No dose adjustment 100 x 10 9 /L to 150 x 10 9 /L 10 mg twice daily 22 mg once daily 50 to less than 100 x 10 9 /L JAKAFI 5 mg once daily Do not use JAKAFI XR Less than 50 x 10 9 /L Avoid use Patients with PV Mild, Moderate, or Severe (Child-Pugh Class A, B, C) Any 5 mg twice daily 11 mg once 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 JAKAFI 5 mg once daily Do not use JAKAFI XR 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/JAKAFI XR dosage for adverse reactions if they occur

Method of Administration JAKAFI 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 potentially life-threatening toxicities, gradually taper the dose of JAKAFI, 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 1 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. JAKAFI XR JAKAFI XR is dosed orally and can be administered with or without food. Swallow JAKAFI XR tablets whole. Do not split, chew, or crush. If a dose is missed, the patient should not take an additional dose, but should take the next usual prescribed dose. When discontinuing JAKAFI XR therapy for reasons other than potentially life-threatening toxicities, gradually taper the dose of JAKAFI XR, for example by 11 mg once daily each week for JAKAFI XR.

Thrombocytopenia, Anemia, and Neutropenia: Manage by dose reduction or interruption, or transfusion. Risk of Infection: Assess patients for signs and symptoms of infection and initiate appropriate treatment promptly. Serious infections should have resolved before starting therapy with JAKAFI/JAKAFI XR. Symptom Exacerbation Following Interruption or Discontinuation: Manage with supportive care and consider resuming treatment with JAKAFI/JAKAFI XR. Risk of Non-Melanoma Skin Cancer: Perform periodic skin examinations. Lipid Elevations: Assess lipid levels 8 to 12 weeks from start of therapy and treat as needed. Major Adverse Cardiovascular Events (MACE): Monitor for development of MACE. Thrombosis: Evaluate and treat symptoms of thrombosis promptly. Secondary Malignancies: Monitor for development of secondary malignancies, particularly in patients who are current or past smokers. 5.1 Thrombocytopenia, Anemia and Neutropenia Treatment with JAKAFI/JAKAFI XR can cause thrombocytopenia, anemia, and neutropenia [ see Adverse Reactions] . Manage thrombocytopenia by reducing the dose or temporarily interrupting JAKAFI/JAKAFI XR. Platelet transfusions may be necessary [ see Dosage and Administration ] . Patients developing anemia may require blood transfusions and/or dose modifications of JAKAFI/JAKAFI XR. Severe neutropenia (ANC less than 0.5 × 10 9 /L) was generally reversible by withholding JAKAFI/JAKAFI XR until recovery. Perform a pre-treatment CBC and monitor CBCs every 2 to 4 weeks until doses are stabilized, and then as clinically indicated [ see Dosage and Administration]

Risk of Infection Serious bacterial, mycobacterial, fungal, and viral infections have occurred [ see Adverse Reactions] . Delay starting therapy with JAKAFI/JAKAFI XR until active serious infections have resolved. Observe patients receiving JAKAFI/JAKAFI XR for signs and symptoms of infection and manage promptly. Use active surveillance and prophylactic antibiotics according to clinical guidelines. Tuberculosis Tuberculosis infection has been reported in patients receiving JAKAFI. Observe patients receiving JAKAFI/JAKAFI XR for signs and symptoms of active tuberculosis and manage promptly. Prior to initiating JAKAFI/JAKAFI XR, patients should be evaluated for tuberculosis risk factors, and those at higher risk should be tested for latent infection. Risk factors include, but are not limited to, prior residence in or travel to countries with a high prevalence of tuberculosis, close contact with a person with active tuberculosis, and a history of active or latent tuberculosis where an adequate course of treatment cannot be confirmed. For patients with evidence of active or latent tuberculosis, consult a physician with expertise in the treatment of tuberculosis before starting JAKAFI/JAKAFI XR. The decision to continue JAKAFI/JAKAFI XR during treatment of active tuberculosis should be based on the overall risk-benefit determination. Progressive Multifocal Leukoencephalopathy Progressive multifocal leukoencephalopathy (PML) has occurred with JAKAFI treatment. If PML is suspected, stop JAKAFI/JAKAFI XR and evaluate. Herpes Zoster and Herpes Simplex Herpes zoster infection has been reported in patients receiving JAKAFI . Advise patients about early signs and symptoms of herpes zoster and to seek treatment as early as possible if suspected. Herpes simplex virus reactivation and/or dissemination has been reported in patients receiving JAKAFI . Monitor patients for the development of herpes simplex infections. If a patient develops evidence of dissemination of herpes simplex, consider interrupting treatment with JAKAFI/JAKAFI XR; patients should be promptly treated and monitored according to clinical guidelines. Hepatitis B Hepatitis B viral load (HBV-DNA titer) increases, with or without associated elevations in alanine aminotransferase and aspartate aminotransferase, have been reported in patients with chronic HBV infections taking JAKAFI. The effect of JAKAFI/JAKAFI XR on viral replication in patients with chronic HBV infection is unknown. Patients with chronic HBV infection should be treated and monitored according to clinical guidelines

Symptom Exacerbation Following Interruption or Discontinuation of Treatment Following discontinuation of JAK-inhibitors, including JAKAFI/JAKAFI XR, signs and symptoms from myeloproliferative neoplasms may flare. Some patients with MF have experienced one or more of the following after discontinuing JAK-inhibitors: fever, respiratory distress, hypotension, disseminated intravascular coagulation, or multi-organ failure. If one or more of these signs and symptoms occur after discontinuation of JAKAFI/JAKAFI XR, or while tapering the dose, evaluate for and treat any intercurrent illness and consider restarting or increasing the dose of JAKAFI/JAKAFI XR. Instruct patients not to interrupt or discontinue therapy without consulting their healthcare provider. When discontinuing or interrupting therapy with JAKAFI/JAKAFI XR for reasons other than life‑threatening toxicities, consider tapering the dose of JAKAFI/JAKAFI XR gradually rather than discontinuing abruptly

Non-Melanoma Skin Cancer (NMSC) Non-melanoma skin cancers including basal cell, squamous cell, and Merkel cell carcinoma have occurred in patients treated with JAKAFI/JAKAFI XR. Perform periodic skin examinations

Lipid Elevations Treatment with JAKAFI has been associated with increases in lipid parameters including total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides . The effect of these lipid parameter elevations on cardiovascular morbidity and mortality has not been determined in patients treated with JAKAFI/JAKAFI XR. Assess lipid parameters approximately 8 to 12 weeks following initiation of JAKAFI/JAKAFI XR therapy. Monitor and treat according to clinical guidelines for the management of hyperlipidemia

Major Adverse Cardiovascular Events (MACE) Another JAK inhibitor has increased the risk of MACE, including cardiovascular death, myocardial infarction, and stroke (compared to those treated with TNF blockers) in patients with rheumatoid arthritis, a condition for which JAKAFI/JAKAFI XR is not indicated. Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with JAKAFI/JAKAFI XR particularly in patients who are current or past smokers and patients with other cardiovascular risk factors. Patients should be informed about the symptoms of serious cardiovascular events and the steps to take if they occur

Thrombosis Another JAK-inhibitor has increased the risk of thrombosis, including deep venous thrombosis (DVT), pulmonary embolism (PE), and arterial thrombosis (compared to those treated with TNF blockers) in patients with rheumatoid arthritis, a condition for which JAKAFI/JAKAFI XR is not indicated. In patients with MF and PV treated with JAKAFI in clinical trials, the rates of thromboembolic events were similar in JAKAFI and control treated patients. Patients with symptoms of thrombosis should be promptly evaluated and treated appropriately

Secondary Malignancies Another JAK-inhibitor has increased the risk of lymphoma and other malignancies excluding NMSC (compared to those treated with TNF blockers) in patients with rheumatoid arthritis, a condition for which JAKAFI/JAKAFI XR is not indicated. Patients who are current or past smokers are at additional increased risk. Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with JAKAFI/JAKAFI XR, particularly in patients with a known secondary malignancy (other than a successfully treated NMSC), patients who develop a malignancy, and patients who are current or past smokers.

Fluconazole: Avoid concomitant use with fluconazole doses greater than 200 mg. Reduce JAKAFI/JAKAFI XR dosage with fluconazole doses less than or equal to 200 mg. ( 2.6 , 7 ) Strong CYP3A4 Inhibitors: Reduce, interrupt, or discontinue JAKAFI/JAKAFI XR doses as recommended except in patients with acute or chronic graft-versus-host-disease. ( 2.6 , 7 ) 7.1 Effect of Other Drugs on JAKAFI/JAKAFI XR Fluconazole Concomitant use of JAKAFI/JAKAFI XR with fluconazole increases ruxolitinib exposure [ see Clinical Pharmacology] , which may increase the risk of exposure-related adverse reactions. Avoid concomitant use of JAKAFI/JAKAFI XR with fluconazole doses of greater than 200 mg daily. Reduce the JAKAFI/JAKAFI XR dosage when used concomitantly with fluconazole doses of less than or equal to 200 mg [ see Dosage and Administration] . Strong CYP3A4 Inhibitors Concomitant use of JAKAFI/JAKAFI XR with strong CYP3A4 inhibitors increases ruxolitinib exposure [ see Clinical Pharmacology] , which may increase the risk of exposure-related adverse reactions. Reduce the JAKAFI/JAKAFI XR dosage when used concomitantly with strong CYP3A4 inhibitors except in patients with aGVHD or cGVHD [ see Dosage and Administration] . Strong CYP3A4 Inducers Concomitant use of JAKAFI/JAKAFI XR with strong CYP3A4 inducers may decrease ruxolitinib exposure [ see Clinical Pharmacology] , which may reduce efficacy of JAKAFI/JAKAFI XR. Monitor patients frequently and adjust the JAKAFI/JAKAFI XR dose based on safety and efficacy [ see Clinical Pharmacology] .