RUXOLITINIB: 68,133 Adverse Event Reports & Safety Profile

Ruxolitinib phosphate is a Janus 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 g/mol. Ruxolitinib phosphate has the following structural formula: Ruxolitinib phosphate is a white to off-white to light yellow to light pink powder. OPZELURA (ruxolitinib) cream is a white to off-white oil-in-water, solubilized emulsion cream for topical use. Each gram of OPZELURA contains 15 mg of ruxolitinib (equivalent to 19.8 mg of ruxolitinib phosphate) in a cream containing cetyl alcohol, dimethicone 350, edetate disodium, glyceryl stearate SE, light mineral oil, medium chain triglycerides, methylparaben, phenoxyethanol, phosphoric acid, polyethylene glycol 200, polysorbate 20, propylene glycol, propylparaben, stearyl alcohol, purified water, white petrolatum, and xanthan gum. structural formula

AND USAGE OPZELURA is a Janus kinase (JAK) inhibitor indicated for: the topical short-term and non-continuous chronic treatment of mild to moderate atopic dermatitis in non-immunocompromised adult and pediatric patients 2 years of age and older whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable. ( 1.1 ) the topical treatment of nonsegmental vitiligo in adult and pediatric patients 12 years of age and older. ( 1.2 ) Limitations of Use Use of OPZELURA in combination with therapeutic biologics, other JAK inhibitors or potent immunosuppressants such as azathioprine or cyclosporine is not recommended. ( 1.3 )

1.1 Atopic Dermatitis OPZELURA is indicated for the topical short-term and non-continuous chronic treatment of mild to moderate atopic dermatitis in non-immunocompromised adult and pediatric patients 2 years of age and older whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable.

1.2 Nonsegmental Vitiligo OPZELURA is indicated for the topical treatment of nonsegmental vitiligo in adult and pediatric patients 12 years of age and older.

1.3 Limitations of Use Use of OPZELURA in combination with therapeutic biologics, other Janus kinase (JAK) inhibitors, or potent immunosuppressants such as azathioprine or cyclosporine is not recommended.

2.

Dosage And Administration

Doses should be individualized based on safety and efficacy. Starting doses per indication are noted below. Myelofibrosis ( 2.2 ) The starting dose of Jakafi is based on patient’s baseline platelet count:

• Greater than 200 x 10 9 /L: 20 mg given orally twice daily
• 100 x 10 9 /L to 200 x 10 9 /L: 15 mg given orally twice daily
• 50 x 10 9 /L to less than 100 x 10 9 /L: 5 mg given orally twice daily Monitor complete blood counts every 2 to 4 weeks until doses are stabilized, and then as clinically indicated. Modify or interrupt dosing for thrombocytopenia.

Polycythemia

Vera ( 2.3 ) The starting dose of Jakafi is 10 mg given orally twice daily.

Acute

Graft-Versus-Host Disease ( 2.4 ) The starting dose of Jakafi is 5 mg given orally twice daily.

Chronic

Graft-Versus-Host Disease ( 2.5 ) The starting dose of Jakafi is 10 mg given orally twice daily.

2.1 Monitoring to Assess Safety Prior to Jakafi treatment: Perform a complete blood count <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 )]</span> . Inquire about past infections, including tuberculosis, herpes simplex, herpes zoster, and hepatitis B <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.2 )]</span> . During treatment with Jakafi: Perform a complete blood count every 2 to 4 weeks until doses are stabilized, and then as clinically indicated <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 )]</span> . Assess lipid parameters approximately 8-12 weeks following initiation of Jakafi therapy <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.5 )]</span> .

2.2 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.

Table

1: Jakafi Starting Doses for Myelofibrosis Platelet Count Starting Dose Greater than 200 x 10 9 /L 20 mg orally twice daily 100 x 10 9 /L to 200 x 10 9 /L 15 mg orally twice daily 50 x 10 9 /L to less than 100 x 10 9 /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 10 9 /L or Greater 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 x 10 9 /L and ANC above 0.75 x 10 9 /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 10 9 /L or Greater Current Platelet Count Maximum Dose When Restarting Jakafi Treatment Maximum doses are displayed. When restarting, begin with a dose at least 5 mg twice daily below the dose at interruption. Greater than or equal to 125 x 10 9 /L 20 mg twice daily 100 to less than 125 x 10 9 /L 15 mg twice 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 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 Less than 50 x 10 9 /L Continue hold Following treatment interruption for ANC below 0.5 x 10 9 /L, after ANC recovers to 0.75 x 10 9 /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 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 Dose Modification Based on Insufficient Response for Patients with Myelofibrosis Starting Treatment with a Platelet Count of 100 x 10 9 /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 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 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 10 9 /L to Less Than 100 x 10 9 /L This section applies only to patients with platelet counts of 50 x 10 9 /L to less than 100 x 10 9 /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 10 9 /L or Greater ) for hematological toxicity in patients whose platelet counts were 100 x 10 9 /L or more prior to starting treatment with Jakafi.

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 x 10 9 /L and ANC above 0.75 x 10 9 /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 10 9 /L or ANC below 0.5 x 10 9 /L that led to dose interruption.

Dose Reductions

Reduce the dose of Jakafi for platelet counts less than 35 x 10 9 /L as described in Table 4.

Table

4: Myelofibrosis: Dosing Modifications for Thrombocytopenia for Patients with Starting Platelet Count of 50 x 10 9 /L to Less Than 100 x 10 9 /L Platelet Count Dosing Recommendations Less than 25 x 10 9 /L Interrupt dosing. 25 x 10 9 /L to less than 35 x 10 9 /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 10 9 /L to less than 35 x 10 9 /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.

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 (see Dose Modification Based on Insufficient Response with Myelofibrosis Starting Treatment with a platelet count of 100 x 10 9 /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 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 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 10 9 /L No change required.

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, decrease the dose to 5 mg once daily. 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 1.0 x 10 9 /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 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 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 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 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 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 10 9 /L, and ANC is greater than or equal to 1.5 x 10 9 /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 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 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 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 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 bilirubin ≤ 1.5 x ULN; resume at current dose upon recovery. Total bilirubin > 10.0 x ULN: Hold Jakafi for up to 14 days until bilirubin ≤ 1.5 x ULN; resume at 1 dose level lower upon recovery.

Total

Bilirubin elevation, liver GVHD > 3.0 × ULN: Continue Jakafi at 1 dose level lower until 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 × 10 9 /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 × 10 9 /L considered related to Jakafi Reduce Jakafi by 1 dose level; resume at initial dose level upon recovery. ANC less than 0.5 × 10 9 /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 × 10 9 /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 <span class="opacity-50 text-xs">[see Drug Interactions ( 7 ) ]</span> , 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 10 9 /L 10 mg twice daily 50 x 10 9 /L to less than 100 x 10 9 /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 ) ].

2.7 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 <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.6 )]</span> .

Table

10: Dose Modifications for Renal Impairment 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 10 9 /L No dose adjustment 100 to 150 x 10 9 /L 10 mg twice daily 50 to less than 100 x 10 9 /L 5 mg daily Less than 50 x 10 9 /L Avoid use [see Use in Specific Populations ( 8.6 )] ESRD on dialysis 100 to 200 x 10 9 /L 15 mg once after dialysis session Greater than 200 x 10 9 /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.

Table

11: Dose Modifications for Hepatic Impairment Hepatic Impairment Status Platelet Count 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 50 to less than 100 x 10 9 /L 5 mg daily Less than 50 x 10 9 /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 )] .

2.8 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.

4.

Contraindications

None. None. ( 4 )

6.

Adverse Reactions

The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling: Thrombocytopenia, Anemia and Neutropenia [see Warnings and Precautions ( 5.1 )] Risk of Infection [see Warnings and Precautions ( 5.2 )]

Symptom Exacerbation Following

Interruption or Discontinuation of Treatment with Jakafi [see Warnings and Precautions ( 5.3 )] Non-Melanoma Skin Cancer [see Warnings and Precautions ( 5.4 )]

Lipid

Elevations [ see Warnings and Precautions ( 5.5 )]

Major Adverse Cardiovascular

Events (MACE) [ see Warnings and Precautions ( 5.6 )] Thrombosis [ see Warnings and Precautions ( 5.7 )]

Secondary

Malignancies [ see Warnings and Precautions ( 5.8 )] In myelofibrosis and polycythemia vera, the most common hematologic adverse reactions (incidence > 20%) are thrombocytopenia and anemia. The most common nonhematologic adverse reactions (incidence ≥ 15%) are bruising, dizziness, headache, and diarrhea. ( 6.1 ) In acute graft-versus-host disease, the most common hematologic adverse reactions (incidence > 50%) are anemia, thrombocytopenia, and neutropenia. The most common nonhematologic adverse reactions (incidence > 50%) are infections (pathogen not specified) and edema. ( 6.1 ) In chronic graft-versus-host disease, the most common hematologic adverse reactions (incidence > 35%) are anemia and thrombocytopenia. The most common nonhematologic adverse reactions (incidence ≥ 20%) are infections (pathogen not specified) and viral infections. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Incyte Corporation at 1-855-463-3463 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Myelofibrosis

The safety of Jakafi was assessed in 617 patients in six clinical studies with a median duration of follow-up of 10.9 months, including 301 patients with MF in two Phase 3 studies. In these two Phase 3 studies, patients had a median duration of exposure to Jakafi of 9.5 months (range 0.5 to 17 months), with 89% of patients treated for more than 6 months and 25% treated for more than 12 months. One hundred and eleven (111) patients started treatment at 15 mg twice daily and 190 patients started at 20 mg twice daily. In patients starting treatment with 15 mg twice daily (pretreatment platelet counts of 100 to 200 x 10 9 /L) and 20 mg twice daily (pretreatment platelet counts greater than 200 x 10 9 /L), 65% and 25% of patients, respectively, required a dose reduction below the starting dose within the first 8 weeks of therapy. In a double-blind, randomized, placebo-controlled study of Jakafi, among the 155 patients treated with Jakafi, the most frequent adverse reactions were thrombocytopenia and anemia [see Table 13] . Thrombocytopenia, anemia and neutropenia are dose-related effects. The three most frequent nonhematologic adverse reactions were bruising, dizziness and headache [see Table 12] . Discontinuation for adverse events, regardless of causality, was observed in 11% of patients treated with Jakafi and 11% of patients treated with placebo.

Table

12 presents the most common nonhematologic adverse reactions occurring in patients who received Jakafi in the double-blind, placebo-controlled study during randomized treatment.

Table

12: Myelofibrosis: Nonhematologic Adverse Reactions Occurring in Patients on Jakafi in the Double-blind, Placebo-controlled Study During Randomized Treatment Jakafi (N=155) Placebo (N=151)

Adverse Reactions All Grades National

Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 (%)

Grade

3 (%)

Grade

4 (%)

All

Grades (%)

Grade

3 (%)

Grade

4 (%) Bruising includes contusion, ecchymosis, hematoma, injection site hematoma, periorbital hematoma, vessel puncture site hematoma, increased tendency to bruise, petechiae, purpura 23 < 1 0 15 0 0 Dizziness includes dizziness, postural dizziness, vertigo, balance disorder, Meniere’s Disease, labyrinthitis 18 < 1 0 7 0 0 Headache 15 0 0 5 0 0 Urinary Tract Infections includes urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, kidney infection, pyuria, bacteria urine, bacteria urine identified, nitrite urine present 9 0 0 5 < 1 < 1 Weight Gain includes weight increased, abnormal weight gain 7 < 1 0 1 < 1 0 Flatulence 5 0 0 < 1 0 0 Herpes Zoster includes herpes zoster and post-herpetic neuralgia 2 0 0 < 1 0 0 Description of Selected Adverse Reactions Anemia In the two Phase 3 clinical studies, median time to onset of first CTCAE Grade 2 or higher anemia was approximately 6 weeks. One patient (< 1%) discontinued treatment because of anemia. In patients receiving Jakafi, mean decreases in hemoglobin reached a nadir of approximately 1.5 to 2.0 g/dL below baseline after 8 to 12 weeks of therapy and then gradually recovered to reach a new steady state that was approximately 1.0 g/dL below baseline. This pattern was observed in patients regardless of whether they had received transfusions during therapy. In the randomized, placebo-controlled study, 60% of patients treated with Jakafi and 38% of patients receiving placebo received red blood cell transfusions during randomized treatment. Among transfused patients, the median number of units transfused per month was 1.2 in patients treated with Jakafi and 1.7 in placebo treated patients. Thrombocytopenia In the two Phase 3 clinical studies, in patients who developed Grade 3 or 4 thrombocytopenia, the median time to onset was approximately 8 weeks. Thrombocytopenia was generally reversible with dose reduction or dose interruption. The median time to recovery of platelet counts above 50 x 10 9 /L was 14 days. Platelet transfusions were administered to 5% of patients receiving Jakafi and to 4% of patients receiving control regimens. Discontinuation of treatment because of thrombocytopenia occurred in < 1% of patients receiving Jakafi and < 1% of patients receiving control regimens. Patients with a platelet count of 100 x 10 9 /L to 200 x 10 9 /L before starting Jakafi had a higher frequency of Grade 3 or 4 thrombocytopenia compared to patients with a platelet count greater than 200 x 10 9 /L (17% versus 7%). Neutropenia In the two Phase 3 clinical studies, 1% of patients reduced or stopped Jakafi because of neutropenia.

Table

13 provides the frequency and severity of clinical hematology abnormalities reported for patients receiving treatment with Jakafi or placebo in the placebo-controlled study.

Table

13: Myelofibrosis: Worst Hematology Laboratory Abnormalities in the Placebo-Controlled Study Presented values are worst Grade values regardless of baseline Jakafi (N=155) Placebo (N=151)

Laboratory Parameter All Grades National

Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0 (%)

Grade

3 (%)

Grade

4 (%)

All

Grades (%)

Grade

3 (%)

Grade

4 (%)

Thrombocytopenia

70 9 4 31 1 0 Anemia 96 34 11 87 16 3 Neutropenia 19 5 2 4 < 1 1 Additional Data from the Placebo-Controlled Study 25% of patients treated with Jakafi and 7% of patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in alanine transaminase (ALT). The incidence of greater than or equal to Grade 2 elevations was 2% for Jakafi with 1% Grade 3 and no Grade 4 ALT elevations. 17% of patients treated with Jakafi and 6% of patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in aspartate transaminase (AST). The incidence of Grade 2 AST elevations was < 1% for Jakafi with no Grade 3 or 4 AST elevations. 17% of patients treated with Jakafi and < 1% of patients treated with placebo developed newly occurring or worsening Grade 1 elevations in cholesterol. The incidence of Grade 2 cholesterol elevations was < 1% for Jakafi with no Grade 3 or 4 cholesterol elevations.

Polycythemia

Vera In a randomized, open-label, active-controlled study, 110 patients with PV resistant to or intolerant of hydroxyurea received Jakafi and 111 patients received best available therapy [see Clinical Studies ( 14.2 )] . The most frequent adverse reaction was anemia. Discontinuation for adverse events, regardless of causality, was observed in 4% of patients treated with Jakafi.

Table

14 presents the most frequent nonhematologic adverse reactions occurring up to Week 32.

Table

14: Polycythemia Vera: Nonhematologic Adverse Reactions Occurring in ≥ 5% of Patients on Jakafi in the Open-Label, Active-controlled Study up to Week 32 of Randomized Treatment Jakafi (N=110)

Best Available

Therapy (N=111)

Adverse Reactions All Grades National

Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 (%)

Grade

3-4 (%)

All

Grades (%)

Grade

3-4 (%)

Diarrhea

15 0 7 < 1 Dizziness includes dizziness and vertigo 15 0 13 0 Dyspnea includes dyspnea and dyspnea exertional 13 3 4 0 Muscle Spasms 12 < 1 5 0 Constipation 8 0 3 0 Herpes Zoster includes herpes zoster and post-herpetic neuralgia 6 < 1 0 0 Nausea 6 0 4 0 Weight Gain includes weight increased and abnormal weight gain 6 0 < 1 0 Urinary Tract Infections includes urinary tract infection and cystitis 6 0 3 0 Hypertension 5 < 1 3 < 1 Clinically relevant laboratory abnormalities are shown in Table 15.

Table

15: Polycythemia Vera: Selected Laboratory Abnormalities in the Open-Label, Active-controlled Study up to Week 32 of Randomized Treatment Presented values are worst Grade values regardless of baseline Jakafi (N=110)

Best Available

Therapy (N=111)

Laboratory Parameter All Grades National

Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0 (%)

Grade

3 (%)

Grade

4 (%)

All

Grades (%)

Grade

3 (%)

Grade

4 (%)

Hematology Anemia

72 < 1 < 1 58 0 0 Thrombocytopenia 27 5 < 1 24 3 < 1 Neutropenia 3 0 < 1 10 < 1 0 Chemistry Hypercholesterolemia 35 0 0 8 0 0 Elevated ALT 25 < 1 0 16 0 0 Elevated AST 23 0 0 23 < 1 0 Hypertriglyceridemia 15 0 0 13 0 0 Acute Graft-Versus-Host Disease In a single-arm, open-label study, 71 adults (ages 18-73 years) were treated with Jakafi for aGVHD failing treatment with steroids with or without other immunosuppressive drugs [ see Clinical Studies ( 14.3 )] . The median duration of treatment with Jakafi was 46 days (range, 4‑382 days). There were no fatal adverse reactions to Jakafi. An adverse reaction resulting in treatment discontinuation occurred in 31% of patients. The most common adverse reaction leading to treatment discontinuation was infection (10%).

Table

16 shows the adverse reactions other than laboratory abnormalities.

Table

16: Acute Graft-Versus-Host Disease: Nonhematologic Adverse Reactions Occurring in ≥ 15% of Patients in the Open-Label, Single-Cohort Study Jakafi (N=71)

Adverse Reactions

Selected laboratory abnormalities are listed in Table 17 below All Grades National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03 (%)

Grade

3-4 (%) Infections (pathogen not specified) 55 41 Edema 51 13 Hemorrhage 49 20 Fatigue 37 14 Bacterial infections 32 28 Dyspnea 32 7 Viral infections 31 14 Thrombosis 25 11 Diarrhea 24 7 Rash 23 3 Headache 21 4 Hypertension 20 13 Dizziness 16 0 Selected laboratory abnormalities during treatment with Jakafi are shown in Table 17.

Table

17: Acute Graft-Versus-Host Disease: Selected Laboratory Abnormalities Worsening from Baseline in the Open-Label, Single Cohort Study Jakafi (N=71) Worst grade during treatment Laboratory Parameter All Grades National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03 (%)

Grade

3-4 (%)

Hematology Anemia

75 45 Thrombocytopenia 75 61 Neutropenia 58 40 Chemistry Elevated ALT 48 8 Elevated AST 48 6 Hypertriglyceridemia 11 1 Chronic Graft-Versus-Host Disease In a Phase 3, randomized, open-label, multi-center study, 165 patients were treated with Jakafi and 158 patients were treated with best available therapy for cGVHD failing treatment with steroids with or without other immunosuppressive drugs [ see Clinical Studies ( 14.4 )] ; sixty-five patients crossed over from best available therapy to treatment with Jakafi, for a total of 230 patients treated with Jakafi. The median duration of exposure to Jakafi for the study was 49.7 weeks (range, 0.7 to 144.9 weeks) in the Jakafi arm. One hundred and nine (47%) patients were on Jakafi for at least 1 year. There were five fatal adverse reactions to Jakafi, including 1 from toxic epidermal necrolysis and 4 from neutropenia, anemia and/or thrombocytopenia. An adverse reaction resulting in treatment discontinuation occurred in 18% of patients treated with Jakafi. An adverse reaction resulting in dose modification occurred in 27%, and an adverse reaction resulting in treatment interruption occurred in 23%. The most common hematologic adverse reactions (incidence > 35%) are anemia and thrombocytopenia. The most common nonhematologic adverse reactions (incidence ≥ 20%) are infections (pathogen not specified) and viral infection.

Table

18 presents the most frequent nonlaboratory adverse reactions occurring up to Cycle 7 Day 1 of randomized treatment.

Table

18: Chronic Graft-Versus-Host Disease: All-Grade (≥ 10%) and Grades 3-5 (≥ 3%)

Nonlaboratory Adverse Reactions

Occurring in Patients in the Open-Label, Active-controlled Study up to Cycle 7 Day 1 of Randomized Treatment Adverse Reaction Grouped terms that are composites of applicable adverse reaction terms. Jakafi (N = 165)

Best Available

Therapy (N = 158)

All Grades National Cancer Institute

Common Terminology Criteria for Adverse Events (CTCAE), version 4.03 (%) Grade ≥ 3 (%)

All

Grades (%) Grade ≥ 3 (%) Infections and infestations Infections (pathogen not specified) 45 15 44 16 Viral infections 28 5 23 5 Musculoskeletal and connective tissue disorders Musculoskeletal pain 18 1 13 0 General disorders and administration site conditions Pyrexia 16 2 9 1 Fatigue 13 1 10 2 Edema 10 1 12 1 Vascular disorders Hypertension 16 5 13 7 Hemorrhage 12 2 15 2 Respiratory, thoracic and mediastinal disorders Cough 13 0 8 0 Dyspnea 11 1 8 1 Gastrointestinal disorders Nausea 12 0 13 2 Diarrhea 10 1 13 1 Clinically relevant laboratory abnormalities are shown in Table 19.

Table

19: Chronic Graft-Versus-Host Disease: Selected Laboratory Abnormalities in the Open-Label, Active-controlled Study up to Cycle 7 Day 1 of Randomized Treatment Presented values are worst Grade values regardless of baseline Laboratory Test Jakafi (N = 165)

Best Available

Therapy (N = 158)

All Grades National Cancer Institute

Common Terminology Criteria for Adverse Events, version 4.03 (%) Grade ≥ 3 (%)

All

Grades (%) Grade ≥ 3 (%)

Hematology Anemia

82 13 75 8 Neutropenia 27 12 23 9 Thrombocytopenia 58 20 54 17 Chemistry Hypercholesterolemia 88 10 85 8 Elevated AST 65 5 54 6 Elevated ALT 73 11 71 16 Gamma glutamyltransferase increased 81 42 75 38 Creatinine increased 47 1 40 2 Elevated lipase 38 12 30 9 Elevated amylase 35 8 25 4

6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of Jakafi. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: Infections and Infestations: Herpes simplex virus reactivation and/or dissemination

5.

Warnings And Precautions

Thrombocytopenia, Anemia and Neutropenia: Manage by dose reduction, or interruption, or transfusion. ( 5.1 ) 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. ( 5.2 )

Symptom Exacerbation Following

Interruption or Discontinuation: Manage with supportive care and consider resuming treatment with Jakafi. ( 5.3 ) Risk of Non-Melanoma Skin Cancer: Perform periodic skin examinations. ( 5.4 )

Lipid

Elevations: Assess lipid levels 8-12 weeks from start of therapy and treat as needed. ( 5.5 )

Major Adverse Cardiovascular

Events (MACE): Monitor for development of MACE. ( 5.6 ) Thrombosis: Evaluate and treat symptoms of thrombosis promptly. ( 5.7 )

Secondary

Malignancies: Monitor for development of secondary malignancies, particularly in patients who are current or past smokers. ( 5.8 )

5.1 Thrombocytopenia, Anemia and Neutropenia Treatment with Jakafi can cause thrombocytopenia, anemia and neutropenia [ see Adverse Reactions ( 6.1 )] . Manage thrombocytopenia by reducing the dose or temporarily interrupting Jakafi. Platelet transfusions may be necessary [ see Dosage and Administration ( 2 ) ] . Patients developing anemia may require blood transfusions and/or dose modifications of Jakafi. Severe neutropenia (ANC less than 0.5 × 10 9 /L) was generally reversible by withholding Jakafi until recovery. Perform a pre-treatment complete blood count (CBC) and monitor CBCs every 2 to 4 weeks until doses are stabilized, and then as clinically indicated [ see Dosage and Administration ( 2 )] .

5.2 Risk of Infection Serious bacterial, mycobacterial, fungal and viral infections have occurred [ see Adverse Reactions ( 6.1 )] . Delay starting therapy with Jakafi until active serious infections have resolved. Observe patients receiving Jakafi 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 for signs and symptoms of active tuberculosis and manage promptly. Prior to initiating Jakafi, 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. The decision to continue Jakafi 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 and evaluate.

Herpes

Zoster and Herpes Simplex Herpes zoster infection has been reported in patients receiving Jakafi [see Adverse Reactions ( 6.1 )] . 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 [see Adverse Reactions ( 6.2 )] . Monitor patients for the development of herpes simplex infections. If a patient develops evidence of dissemination of herpes simplex, consider interrupting treatment with Jakafi; 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 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.

5.3 Symptom Exacerbation Following Interruption or Discontinuation of Treatment with Jakafi Following discontinuation of Jakafi, symptoms from myeloproliferative neoplasms may return to pretreatment levels over a period of approximately one week. Some patients with MF have experienced one or more of the following adverse events after discontinuing Jakafi: fever, respiratory distress, hypotension, DIC, or multi-organ failure. If one or more of these occur after discontinuation of, or while tapering the dose of Jakafi, evaluate for and treat any intercurrent illness and consider restarting or increasing the dose of Jakafi. Instruct patients not to interrupt or discontinue Jakafi therapy without consulting their physician. When discontinuing or interrupting therapy with Jakafi for reasons other than thrombocytopenia or neutropenia <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.8 )]</span> , consider tapering the dose of Jakafi gradually rather than discontinuing abruptly.

5.4 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. Perform periodic skin examinations.

5.5 Lipid Elevations Treatment with Jakafi has been associated with increases in lipid parameters including total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> . The effect of these lipid parameter elevations on cardiovascular morbidity and mortality has not been determined in patients treated with Jakafi. Assess lipid parameters approximately 8-12 weeks following initiation of Jakafi therapy. Monitor and treat according to clinical guidelines for the management of hyperlipidemia.

5.6 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 is not indicated. Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with Jakafi 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.

5.7 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 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.

5.8 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 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, 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.

7.

Drug Interactions

Fluconazole: Avoid concomitant use with fluconazole doses greater than 200 mg.

Reduce

Jakafi dosage with fluconazole doses less than or equal to 200 mg. ( 2.6 , 7 ) Strong CYP3A4 Inhibitors: Reduce, interrupt, or discontinue Jakafi 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 Fluconazole Concomitant use of Jakafi with fluconazole increases ruxolitinib exposure [ see Clinical Pharmacology ( 12.3 )] , which may increase the risk of exposure-related adverse reactions. Avoid concomitant use of Jakafi with fluconazole doses of greater than 200 mg daily. Reduce the Jakafi dosage when used concomitantly with fluconazole doses of less than or equal to 200 mg [ see Dosage and Administration ( 2.6 )] . Strong CYP3A4 Inhibitors Concomitant use of Jakafi with strong CYP3A4 inhibitors increases ruxolitinib exposure [ see Clinical Pharmacology ( 12.3 )] , which may increase the risk of exposure-related adverse reactions. Reduce the Jakafi dosage when used concomitantly with strong CYP3A4 inhibitors except in patients with aGVHD or cGVHD [ see Dosage and Administration ( 2.6 )] . Strong CYP3A4 Inducers Concomitant use of Jakafi with strong CYP3A4 inducers may decrease ruxolitinib exposure [ see Clinical Pharmacology ( 12.3 )] , which may reduce efficacy of Jakafi. Monitor patients frequently and adjust the Jakafi dose based on safety and efficacy [ see Clinical Pharmacology ( 12.3 )] .