Jakafi Drug Information
Generic name: RUXOLITINIB
Kinase Inhibitor [EPC] Janus Kinase Inhibitor [EPC]
Uses of Jakafi
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.
Dosage & Administration of Jakafi
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/ 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 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. 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 Table 5: Myelofibrosis: Maximum Restarting Doses for JAKAFI/JAKAFI XR After Safety Interruption for Neutropenia (ANC < 0.5 x 10 9 /L) 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. 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.
For patients on JAKAFI 5 mg twice daily in the week prior to interruption, when restarting, reduce the dose to 5 mg once daily. 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.
If the response is insufficient as defined in Section 2.2 (see Dose Modification Based on Insufficient Response for Patients With Myelofibrosis Starting Treatment With a Platelet Count of 100 × 10 9 /L or Greater ), doses may be increased from, if the following conditions are met. Continuation of treatment for more than 6 months should be limited to patients in whom the benefits outweigh the potential risks. 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. 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.
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.
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.
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. 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 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
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 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 14: Dose Modifications for Hepatic Impairment 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. Swallow JAKAFI XR tablets whole. Do not split, chew, or crush.
| 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 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 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 |
| 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 | |
| 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 |
| 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. | |
| 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. | |
| 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 |
| 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 |
| 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. |
| 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. |
| 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 [see Dosage and Administration ( 2.4, 2.5 )]. | |
| 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 [see Dosage and Administration ( 2.4, 2.5 )]. | |
| 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 [see Use in Specific Populations ( 8.6 )] | ||
| 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 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 [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 | 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 [see Dosage and Administration ( 2.4, 2.5 )]. | |
Side Effects of Jakafi
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. The safety of JAKAFI XR has been established from adequate and well-controlled studies of JAKAFI in adult patients with myelofibrosis, polycythemia vera, and adult and pediatric patients with acute and chronic graft-versus-host-disease. Below is a display of the adverse reactions of JAKAFI in these adequate and well-controlled studies.
One hundred and eleven 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 /L) and 20 mg twice daily pretreatment platelet counts greater than 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.
Thrombocytopenia, anemia, and neutropenia are dose-related effects. The 3 most frequent nonhematologic adverse reactions were bruising, dizziness, and headache. Discontinuation for adverse events, regardless of causality, was observed in 11% of patients treated with JAKAFI and 11% of patients treated with placebo.
Table 15 presents the most common nonhematologic adverse reactions occurring in patients who received JAKAFI in the double-blind, placebo-controlled study during randomized treatment. Table 15: Myelofibrosis: Nonhematologic Adverse Reactions Occurring in Patients on JAKAFI in the Double-Blind, Placebo-Controlled Study During Randomized Treatment In the 2 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 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 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 was generally reversible with dose reduction or dose interruption. 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. Neutropenia In the 2 Phase 3 clinical studies, 1% of patients reduced or stopped JAKAFI because of neutropenia. Table 16 provides the frequency and severity of clinical hematology abnormalities reported for patients receiving treatment with JAKAFI or placebo in the placebo-controlled study.
Table 16: Myelofibrosis: Worst Hematology Laboratory Abnormalities in the Placebo-Controlled Study Presented values are worst Grade values regardless of baseline. 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). 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 (BAT). The most frequent adverse reaction was anemia.
Table 17 presents the most frequent nonhematologic adverse reactions occurring up to Week 32. Table 17: Polycythemia Vera: Nonhematologic Adverse Reactions Occurring in ≥ 5% of Patients on JAKAFI in the Open-Label, Active-Controlled Study up to Week Clinically relevant laboratory abnormalities are shown in Table 18. Table 18: 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. 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.
The median duration of treatment with JAKAFI was 46 days (range: 4 to 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 19 shows the adverse reactions other than laboratory abnormalities. Table 20: Acute Graft-Versus-Host Disease: Selected Laboratory Abnormalities Worsening from Baseline in the Open-Label, Single Cohort Study 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 BAT for cGVHD failing treatment with steroids with or without other immunosuppressive drugs; sixty-five patients crossed over from BAT 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 5 fatal adverse reactions to JAKAFI, including 1 from toxic epidermal necrolysis and 4 from neutropenia, anemia and/or thrombocytopenia.
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 21 presents the most frequent nonlaboratory adverse reactions occurring up to Cycle 7 Day 1 of randomized treatment. Table 22: 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. 4
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 Metabolism and Nutrition disorders: hypoglycemia (class effect)
| 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 |
| 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 |
| JAKAFI (N = 110) | Best Available Therapy (N = 111) | |||
|---|---|---|---|---|
| Adverse Reactions | All Grades National Cancer Institute Common Terminology Criteria for Adverse Events, 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 |
| 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 |
| JAKAFI (N = 71) | ||
| Adverse Reactions Selected laboratory abnormalities are listed in Table 20 below. | All Grades National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), 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 |
| 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 |
| Adverse Reaction Grouped terms that are composites of applicable adverse reaction terms. | JAKAFI (N = 165) | Best Available Therapy (N = 158) | ||
|---|---|---|---|---|
| All Grades (%) | 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 |
| 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 |
Warnings & Cautions for Jakafi
Thrombocytopenia, Anemia, and Neutropenia Treatment with JAKAFI/JAKAFI XR can cause thrombocytopenia, anemia, and neutropenia. Manage thrombocytopenia by reducing the dose or temporarily interrupting JAKAFI/JAKAFI XR. Platelet transfusions may be necessary.
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.
Risk of Infection
Serious bacterial, mycobacterial, fungal, and viral infections have occurred. 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. 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.
Drug Interactions with Jakafi
Effect of Other Drugs on JAKAFI/JAKAFI XR Fluconazole
Concomitant use of JAKAFI/JAKAFI XR with fluconazole increases ruxolitinib exposure, 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.
Reduce the JAKAFI/JAKAFI XR dosage when used concomitantly with strong CYP3A4 inhibitors except in patients with aGVHD or cGVHD. Strong CYP3A4 Inducers Concomitant use of JAKAFI/JAKAFI XR with strong CYP3A4 inducers may decrease ruxolitinib exposure, which may reduce efficacy of JAKAFI/JAKAFI XR. Monitor patients frequently and adjust the JAKAFI/JAKAFI XR dose based on safety and efficacy.
Pregnancy Safety for Jakafi
Pregnancy Risk Summary When pregnant rats and rabbits were administered ruxolitinib during the period of organogenesis adverse developmental outcomes occurred at doses associated with maternal toxicity (see Data). There are no studies with the use of JAKAFI/JAKAFI XR in pregnant women to inform drug-associated risks. The background risk of major birth defects and miscarriage for the indicated populations is unknown.
Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. There were no treatment-related malformations. Adverse developmental outcomes, such as decreases of approximately 9% in fetal weights were noted in rats at the highest and maternally toxic dose of 60 mg/kg/day.
This dose results in an exposure (AUC) that is approximately 2 times the clinical exposure at the maximum recommended dose of 25 mg twice daily. In rabbits, lower fetal weights of approximately 8% and increased late resorptions were noted at the highest and maternally toxic dose of 60 mg/kg/day. In a pre- and post-natal development study in rats, pregnant animals were dosed with ruxolitinib from implantation through lactation at doses up to 30 mg/kg/day.
There were no drug-related adverse findings in pups for fertility indices or for maternal or embryofetal survival, growth, and development parameters at the highest dose evaluated (34% the clinical exposure at the maximum recommended dose of 25 mg twice daily).
Pediatric Use of Jakafi
Pediatric Use Myelofibrosis The safety and effectiveness of JAKAFI/JAKAFI XR for treatment of MF in pediatric patients have not been established. Polycythemia Vera The safety and effectiveness of JAKAFI/JAKAFI XR for treatment of PV in pediatric patients have not been established. Acute Graft-Versus-Host Disease The safety and effectiveness of JAKAFI for treatment of steroid-refractory aGVHD has been established for treatment of pediatric patients 12 years and older.
Use of JAKAFI in pediatric patients with steroid-refractory aGVHD is supported by evidence from adequate and well-controlled trials of JAKAFI in adults and additional pharmacokinetic and safety data in pediatric patients. The safety and effectiveness of JAKAFI/JAKAFI XR for treatment of steroid-refractory aGVHD has not been established in pediatric patients younger than 12 years old. Chronic Graft-Versus-Host Disease The safety and effectiveness of JAKAFI for treatment of cGVHD after failure of one or two lines of systemic therapy has been established for treatment of pediatric patients 12 years and older.
Use of JAKAFI in pediatric patients with cGVHD after failure of one or two lines of systemic therapy is supported by evidence from adequate and well-controlled trials of JAKAFI in adults and adolescents and additional pharmacokinetic and safety data in pediatric patients. Other Myeloproliferative Neoplasms, Leukemias, and Solid Tumors The safety and effectiveness of ruxolitinib were assessed but not established in a single-arm trial (NCT01164163) in patients with relapsed or refractory solid tumors, leukemias, or myeloproliferative neoplasms. Overall, 19% of patients received more than 1 cycle.
No new safety signals were observed in pediatric patients in this trial. The safety and effectiveness of ruxolitinib in combination with chemotherapy for treatment of high-risk, de novo CRLF2 rearranged or JAK pathway–mutant Ph-like acute lymphoblastic leukemia (ALL) were assessed but not established in a single-arm trial (NCT02723994). Juvenile Animal Toxicity Data Administration of ruxolitinib to juvenile rats resulted in effects on growth and bone measures.
When administered starting at postnatal Day 7 (the equivalent of a human newborn) at doses of 1.5 to 75 mg/kg/day, evidence of fractures occurred at doses ≥ 30 mg/kg/day, and effects on body weight and other bone measures (eg, bone mineral content, peripheral quantitative computed tomography, and x-ray analysis) occurred at doses ≥ 5 mg/kg/day. Males were more severely affected than females in all age groups, and effects were generally more severe when administration was initiated earlier in the postnatal period. These findings were observed at exposures that are at least 27% the clinical exposure at the maximum recommended dose of 25 mg twice daily.
Overdosage Information for Jakafi
There is no known antidote for overdoses with JAKAFI/JAKAFI XR. Single doses up to 200 mg have been given with acceptable acute tolerability. Higher than recommended repeat doses are associated with increased myelosuppression including leukopenia, anemia, and thrombocytopenia.
Appropriate supportive treatment should be given. Hemodialysis is not expected to enhance the elimination of JAKAFI/JAKAFI XR.
Clinical Studies of Jakafi
Myelofibrosis
The effectiveness of JAKAFI XR has been established for myelofibrosis based on adequate and well-controlled studies of JAKAFI in adult patients with myelofibrosis. Below is a display of the efficacy results of the adequate and well-controlled studies of JAKAFI in adult patients with myelofibrosis. Two randomized Phase 3 studies (Studies 1 and 2) were conducted in patients with MF (either primary MF, post-polycythemia vera MF or post-essential thrombocythemia MF).
In both studies, patients had palpable splenomegaly at least 5 cm below the costal margin and risk category of intermediate 2 (2 prognostic factors) or high risk (3 or more prognostic factors) based on the International Working Group Consensus Criteria (IWG). The starting dose of JAKAFI was based on platelet count. Study 1 Study 1 (NCT00952289) was a double-blind, randomized, placebo-controlled study in 309 patients who were refractory to or were not candidates for available therapy.
Fifty percent (50%) of patients had primary MF, 31% had post-polycythemia vera MF, and 18% had post-essential thrombocythemia MF. Twenty-one percent (21%) of patients had red blood cell transfusions within 8 weeks of enrollment in the study. Patients had a median palpable spleen length of 16 cm below the costal margin, with 81% having a spleen length 10 cm or greater below the costal margin.
Patients had a median spleen volume as measured by magnetic resonance imaging (MRI) or computed tomography (CT) of 2595 cm 3 (range:; the upper limit of normal is approximately 300 cm 3 ). Patients were dosed with JAKAFI or matching placebo. The primary efficacy endpoint was the proportion of patients achieving greater than or equal to a 35% reduction from baseline in spleen volume at Week 24 as measured by MRI or CT.
Secondary endpoints included duration of a 35% or greater reduction in spleen volume and proportion of patients with a 50% or greater reduction in Total Symptom Score from baseline to Week 24 as measured by the modified Myelofibrosis Symptom Assessment Form (MFSAF) v2.0 diary. Study 2 Study 2 (NCT00934544) was an open-label, randomized study in 219 patients. Patients were randomized 2:1 to JAKAFI versus BAT.
Best available therapy was selected by the investigator on a patient-by-patient basis. In the BAT arm, the medications received by more than 10% of patients were hydroxyurea (47%) and glucocorticoids (16%). Fifty-three percent (53%) of patients had primary MF, 31% had post-polycythemia vera MF and 16% had post-essential thrombocythemia MF.
A secondary endpoint in Study 2 was the proportion of patients achieving a 35% or greater reduction of spleen volume as measured by MRI or CT from baseline to Week 24. A significantly larger proportion of patients in the JAKAFI group achieved a 35% or greater reduction in spleen volume from baseline in both studies compared to placebo in Study 1 and BAT in Study 2. A similar proportion of patients in the JAKAFI group achieved a 50% or greater reduction in palpable spleen length.
One patient (placebo) with a missing baseline spleen volume is not included. In Study 1, MF symptoms were a secondary endpoint and were measured using the modified MFSAF v2.0 diary. The modified MFSAF is a daily diary capturing the core symptoms of MF (abdominal discomfort, pain under left ribs, night sweats, itching, bone/muscle pain, and early satiety).
These scores were added to create the daily total score, which has a maximum of 60. At baseline, the mean Total Symptom Score was 18.0 in the JAKAFI group and 16.5 in the placebo group. A higher proportion of patients in the JAKAFI group had a 50% or greater reduction in Total Symptom Score than in the placebo group, with a median time to response of less than 4 weeks.
Results are excluded for 5 patients with a baseline Total Symptom Score of zero, 8 patients with missing baseline, and 6 patients with insufficient post baseline data. Worsening of Total Symptom Score is truncated at 150%. Figure 3 displays the proportion of patients with at least a 50% improvement in each of the individual symptoms that comprise the Total Symptom Score, indicating that all 6 of the symptoms contributed to the higher Total Symptom Score response rate in the group treated with JAKAFI.
Individual score range = 0 to 10 An exploratory analysis of patients receiving JAKAFI also showed improvement in fatigue‑related symptoms (i.e., tiredness, exhaustion, mental tiredness, and lack of energy) and associated impacts on daily activities (i.e., activity limitations related to work, self-care, and exercise) as measured by the PROMIS ® Fatigue 7-item short form total score at Week 24. Patients who achieved a reduction of 4.5 points or more from baseline to Week 24 in the PROMIS ® Fatigue total score were considered to have achieved a fatigue response. Fatigue response was reported in 35% of patients in the JAKAFI group versus 14% of the patients in the placebo group.
Overall survival was a secondary endpoint in both Study 1 and Study 2. Figure 4 and Figure 5 show Kaplan-Meier curves of overall survival at prospectively planned analyses after all patients remaining on study had completed 144 weeks on study. Figure 1: Percent Change From Baseline in Spleen Volume at Week 24 or Last Observation for Each Patient (Study 1) Figure 2: Percent Change From Baseline in Total Symptom Score at Week 24 or Last Observation for Each Patient (Study 1) Figure 3: Proportion of Patients With Myelofibrosis Achieving 50% or Greater Reduction in Individual Symptom Scores at Week 24 Overall Survival - Kaplan-Meier Curves by Treatment Group in Study 1 Overall Survival - Kaplan Meier Curves by Treatment Group in Study 2
Polycythemia Vera
Study 3 (NCT01243944) was a randomized, open-label, active-controlled Phase 3 study conducted in 222 patients with PV. Patients had been diagnosed with PV for at least 24 weeks, had an inadequate response to or were intolerant of hydroxyurea, required phlebotomy, and exhibited splenomegaly. All patients were required to demonstrate hematocrit control between 40-45% prior to randomization.
Patients had a median spleen volume as measured by MRI or CT of 1272 cm 3 (range: ) and median palpable spleen length below the costal margin was 7 cm. Patients were randomized to JAKAFI or BAT. The starting dose of JAKAFI was 10 mg twice daily.
Doses were then individualized based upon tolerability and efficacy with a maximum dose of 25 mg twice daily. The primary endpoint was the proportion of subjects achieving a response at Week 32, with response defined as having achieved both hematocrit control (the absence of phlebotomy eligibility beginning at the Week 8 visit and continuing through Week 32) and spleen volume reduction (a greater than or equal to 35% reduction from baseline in spleen volume at Week 32). Phlebotomy eligibility was defined as a confirmed hematocrit greater than 45% that is at least 3% higher than the hematocrit obtained at baseline or a confirmed hematocrit greater than 48%, whichever was lower.
Secondary endpoints included the proportion of all randomized subjects who achieved the primary endpoint and who maintained their response 48 weeks after randomization, and the proportion of subjects achieving complete hematological remission at Week 32 with complete hematological remission defined as achieving hematocrit control, platelet count less than or equal to 400 × 10 9 /L, and white blood cell count less than or equal to 10 × 10 9 /L. Results of the primary and secondary endpoints are presented in Table 25. A significantly larger proportion of patients on the JAKAFI arm achieved a response for the primary endpoint compared to BAT at Week 32 and maintained their response 48 weeks after randomization.
A significantly larger proportion of patients on the JAKAFI arm compared to BAT also achieved complete hematological remission at Week 32. Table 25: Percent of Patients With Polycythemia Vera Achieving the Primary and Key Secondary Endpoints in Study 3 (Intent to Treat) Additional analyses for Study 3 to assess durability of response were conducted at Week 80 only in the JAKAFI arm. On this arm, 91 (83%) patients were still on treatment at the time of the Week 80 data cut-off.
Study 4 (NCT02953678) was an open-label, single-arm, multicenter study of JAKAFI for treatment of patients with steroid-refractory aGVHD Grades 2 to 4 (Mount Sinai Acute GVHD International Consortium criteria) occurring after allogeneic hematopoietic stem cell transplantation. There were 49 patients with aGVHD refractory to steroids alone. The median duration of prior corticosteroid exposure at baseline was 15 days (range: 3 to 106 days).
The efficacy of JAKAFI was based on Day-28 overall response rate (ORR) (complete response, very good partial response, or partial response by Center for International Blood and Marrow Transplant Research criteria) and the duration of response. The median duration of response, calculated from Day-28 response to progression, new salvage therapy for aGVHD or death from any cause (with progression being defined as worsening by 1 stage in any organ without improvement in other organs in comparison to prior response assessment) was Also, for the Day-28 responders, the median time from Day-28 response to either death or need for new therapy for aGVHD (additional salvage therapy or increase in steroids) was 173 days (95% CI 66, NE). Table 26: Day-28 Overall Response Rate for Patients With Steroid-Refractory Acute GVHD in Study 4 11
Chronic Graft-Versus-Host Disease
Study 5 (REACH-3; NCT03112603) was a randomized, open-label, multicenter study of JAKAFI in comparison to BAT for treatment of corticosteroid-refractory cGVHD after allogeneic stem cell transplantation. Eligible patients were ≥ 12 years old with moderate or severe cGVHD as defined by NIH Consensus Criteria requiring additional therapy after failure of corticosteroid therapy and no more than 1 additional salvage treatment. Best available therapy was selected by the investigator prior to randomization and included the following treatments: extracorporeal photopheresis (ECP), low‑dose methotrexate (MTX), mycophenolate mofetil (MMF), mTOR inhibitors (everolimus or sirolimus), infliximab, rituximab, pentostatin, imatinib, or ibrutinib.
Randomization was stratified by cGVHD severity (moderate versus severe). On Cycle 7 Day 1 and thereafter, patients randomized to BAT could cross over to JAKAFI if they had disease progression, mixed response, unchanged response, cGVHD flare, or toxicity to BAT. All patients also received standard supportive care, including anti-infective medications.
GVHD prophylaxis and cGVHD treatment medications initiated before randomization, including systemic corticosteroids, calcineurin inhibitors, and topical or inhaled corticosteroid therapy, were allowed to be continued per institutional guidelines. Table 27 shows the demographics and baseline disease characteristics of the randomized population. Table 27: REACH-3: Demographics and Baseline Chronic GVHD Characteristics The efficacy of JAKAFI was based on ORR through Cycle 7 Day 1, where overall response included complete response or partial response according to the 2014 NIH Response Criteria and durability of the response.
The ORR results are presented in Table 28; the difference in ORR between JAKAFI and BAT arms was Table 28: Overall Response Rate Through Cycle 7 Day 1 for Patients with Chronic GVHD in Study 5 102 86 ORR results were supported by exploratory analyses of patient-reported symptom severity which showed at least a 7-point decrease in the cGVHD Total Symptom Score at any time through Cycle patients in the JAKAFI arm and patients in the BAT arm.
| Study 1 | Study 2 | |||
|---|---|---|---|---|
| JAKAFI (N = 155) | Placebo (N = 154) | JAKAFI (N = 146) | Best Available Therapy (N = 73) | |
| Time points | Week 24 | Week 48 | ||
| Number (%) of Patients with Spleen Volume Reduction by 35% or More | 65 (42) | 1 (< 1) | 41 (29) | 0 |
| P-value | < 0.0001 | < 0.0001 | ||
| JAKAFI (N = 148) | Placebo (N = 152) | |
|---|---|---|
| Number (%) of Patients with 50% or Greater Reduction in Total Symptom Score by Week 24 | 68 (46) | 8 (5) |
| P-value | < 0.0001 | |
| JAKAFI (N = 110) | Best Available Therapy (N = 112) | |
|---|---|---|
| Number (%) of Patients Achieving a Primary Response Primary Response defined as having achieved both the absence of phlebotomy eligibility beginning at the Week 8 visit and continuing through Week 32 and a greater than or equal to 35% reduction from baseline in spleen volume at Week 32. at Week 32 | 25 (23) | 1 (< 1) |
| 95% CI of the response rate (%) | (15, 32) | (0, 5) |
| P-value | < 0.0001 | |
| Number (%) of Patients Achieving a Durable Primary Response at Week 48 | 22 (20) | 1 (< 1) |
| 95% CI of the response rate (%) | (13, 29) | (0, 5) |
| P-value | < 0.0001 | |
| Number (%) of Patients Achieving Complete Hematological Remission at Week 32 | 26 (24) | 9 (8) |
| 95% CI of the response rate (%) | (16, 33) | (4, 15) |
| P-value | 0.0016 | |
| Refractory to Steroids Alone (n = 49) | |
| Overall Response, n (%) (95% CI) | 28 (57.1) (42.2, 71.2) |
| Complete Response, n (%) | 15 (30.6) |
| Very Good Partial Response, n (%) | 2 (4.1) |
| Partial Response, n (%) | 11 (22.4) |
| JAKAFI (N = 165) | Best Available Therapy (N = 164) | |
|---|---|---|
| Median Age, Years (range) | 49 (13, 73) | 50 (12, 76) |
| Age 12 to < 18 Years, n (%) | 4 (2) | 8 (5) |
| Age > 65 Years, n (%) | 18 (11) | 22 (13) |
| Male, n (%) | 109 (66) | 92 (56) |
| Race, n (%) | ||
| White | 116 (70) | 132 (81) |
| Black | 2 (1) | 0 |
| Asian | 33 (20) | 21 (13) |
| American Indian or Alaska native | 2 (1) | 0 |
| Other | 9 (6) | 4 (2) |
| Unknown | 3 (2) | 7 (4) |
| Median (range) time (days) from cGVHD diagnosis to randomization | 174 (7-2017) | 150 (10-1947) |
| Prior Therapy | ||
| No prior treatment for cGVHD | 2 (1) | 1 (1) |
| Failed first-line steroids alone | 115 (70) | 125 (76) |
| Failed first-line combination including steroids | 42 (25) | 30 (18) |
| Failed two lines of therapy | 6 (4) | 8 (5) |
| ≥ 4 Organs involved, n (%) | 67 (41) | 63 (38) |
| Severe cGVHD, n (%) | 86 (52) | 79 (48) |
| Median (range) cGVHD Total Symptom Score | 19 (0-80) | 18 (1-54) |
| Median (range) corticosteroid dose at baseline (PE mg/kg) Prednisone equivalent milligrams/kilogram. | 0.29 (0.01-1.81) | 0.26 (0.06-1.21) |
| JAKAFI (N = 165) | Best Available Therapy (N = 164) | |
|---|---|---|
| Overall Response, n (%) (95% CI) 95% CI of Overall Response Rate is estimated using Clopper-Pearson method. | 116 (70) (63, 77) | 94 (57) (49, 65) |
| Complete Response, n (%) | 14 (8) | 8 (5) |
| Partial Response, n (%) | 102 (62) | 86 (52) |
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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