Jakafi
(ruxolitinib)Dosage & Administration
Doses should be individualized based on safety and efficacy. Starting doses per indication are noted below.
Myelofibrosis
Polycythemia Vera
Acute Graft-Versus-Host Disease
Chronic Graft-Versus-Host Disease
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Jakafi Prescribing Information
Myelofibrosis
Jakafi 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 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 is indicated for treatment of steroid-refractory acute graft-versus-host disease (aGVHD) in adult and pediatric patients 12 years and older.
ChronicGraft-Versus-Host Disease
Jakafi 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.
2.1 Monitoring to Assess Safety
Prior to Jakafi treatment:
- Perform a complete blood count [see Warnings and Precautions ].
- Inquire about past infections, including tuberculosis, herpes simplex, herpes zoster, and hepatitis B [see Warnings and Precautions ].
During treatment with Jakafi:
- Perform a complete blood count every 2 to 4 weeks until doses are stabilized, and then as clinically indicated [see Warnings and Precautions ].
- Assess lipid parameters approximately 8-12 weeks following initiation of Jakafi therapy [see Warnings and Precautions ].
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.
| Platelet Count | Starting Dose |
| Greater than 200 x 109/L | 20 mg orally twice daily |
| 100 x 109/L to 200 x 109/L | 15 mg orally twice daily |
| 50 x 109/L to less than 100 x 109/L | 5 mg orally twice daily |
Dose Modification Guidelines for Hematologic Toxicity for Patients with Myelofibrosis Starting Treatment with a Platelet Count of 100 x 109/L or Greater
Treatment Interruption and Restarting Dosing
Interrupt treatment for platelet counts less than 50 x 109/L or absolute neutrophil count (ANC) less than 0.5 x 109/L.
After recovery of platelet counts above 50 x 109/L and ANC above 0.75 x 109/L, dosing may be restarted. Table 2 illustrates the maximum allowable dose that may be used in restarting Jakafi after a previous interruption.
| |
| Current Platelet Count | Maximum Dose When Restarting Jakafi Treatment * |
| Greater than or equal to 125 x 109/L | 20 mg twice daily |
| 100 to less than 125 x 109/L | 15 mg twice daily |
| 75 to less than 100 x 109/L | 10 mg twice daily for at least 2 weeks; if stable, may increase to 15 mg twice daily |
| 50 to less than 75 x 109/L | 5 mg twice daily for at least 2 weeks; if stable, may increase to 10 mg twice daily |
| Less than 50 x 109/L | Continue hold |
Following treatment interruption for ANC below 0.5 x 109/L, after ANC recovers to 0.75 x 109/L or greater, restart dosing at the higher of 5 mg once daily or 5 mg twice daily below the largest dose in the week prior to the treatment interruption.
Dose Reductions
Dose reductions should be considered if the platelet counts decrease as outlined in Table 3 with the goal of avoiding dose interruptions for thrombocytopenia.
| 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 109/L | 20 mg twice daily | 15 mg twice daily | No Change | No Change | No Change |
| 75 to less than 100 x 109/L | 10 mg twice daily | 10 mg twice daily | 10 mg twice daily | No Change | No Change |
| 50 to less than 75 x 109/L | 5 mg twice daily | 5 mg twice daily | 5 mg twice daily | 5 mg twice daily | No Change |
| Less than 50 x 109/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 109/L or Greater
If the response is insufficient and platelet and neutrophil counts are adequate, doses may be increased in 5 mg twice daily increments to a maximum of 25 mg twice daily. Doses should not be increased during the first 4 weeks of therapy and not more frequently than every 2 weeks.
Consider dose increases in patients who meet all of the following conditions:
- 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 109/L at 4 weeks and platelet count never below 100 x 109/L;
- ANC Levels greater than 0.75 x 109/L.
Based on limited clinical data, long-term maintenance at a 5 mg twice daily dose has not shown responses and continued use at this dose should be limited to patients in whom the benefits outweigh the potential risks. Discontinue Jakafi if there is no spleen size reduction or symptom improvement after 6 months of therapy.
Dose Modifications for Hematologic Toxicity for Patients with Myelofibrosis Starting Treatment with Platelet Counts of 50 x 109/L to Less Than 100 x 109/L
This section applies only to patients with platelet counts of 50 x 109/L to less than 100 x 109/L prior to any treatment with Jakafi. See dose modifications in Section 2.2 (Dose Modification Guidelines for Hematological Toxicity for Patients with Myelofibrosis Starting Treatment with a Platelet Count of 100 x 109/L or Greater) for hematological toxicity in patients whose platelet counts were 100 x 109/L or more prior to starting treatment with Jakafi.
Treatment Interruption and Restarting Dosing
Interrupt treatment for platelet counts less than 25 x 109/L or ANC less than 0.5 x 109/L.
After recovery of platelet counts above 35 x 109/L and ANC above 0.75 x 109/L, dosing may be restarted. Restart dosing at the higher of 5 mg once daily or 5 mg twice daily below the largest dose in the week prior to the decrease in platelet count below 25 x 109/L or ANC below 0.5 x 109/L that led to dose interruption.
Dose Reductions
Reduce the dose of Jakafi for platelet counts less than 35 x 109/L as described in Table 4.
| Platelet Count | Dosing Recommendations |
| Less than 25 x 109/L |
|
25 x 109/L to less than 35 x 109/L |
|
25 x 109/L to less than 35 x 109/L |
|
Dose Modifications Based on Insufficient Response for Patients with Myelofibrosis and Starting Platelet Count of 50 x 109/L to Less Than 100 x 109/L
Do not increase doses during the first 4 weeks of therapy, and do not increase the dose more frequently than every 2 weeks.
If the response is insufficient as defined in Section 2.2 (see Dose Modification Based on Insufficient Response with Myelofibrosis Starting Treatment with a platelet count of 100 x 109/L or Greater), doses may be increased by increments of 5 mg daily to a maximum of 10 mg twice daily if:
- the platelet count has remained at least 40 x 109/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 109/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.
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.
| Hemoglobin and/or Platelet Count | Dosing Recommendations |
| Hemoglobin greater than or equal to 12 g/dL AND platelet count greater than or equal to 100 x 109/L |
|
| Hemoglobin 10 to less than 12 g/dL AND platelet count 75 to less than 100 x 109/L |
|
| Hemoglobin 8 to less than 10 g/dL OR platelet count 50 to less than 75 x 109/L |
|
| Hemoglobin less than 8 g/dL OR platelet count less than 50 x 109/L |
|
Treatment Interruption and Restarting Dosing
Interrupt treatment for hemoglobin less than 8 g/dL, platelet counts less than 50 x 109/L or ANC less than 1.0 x 109/L.
After recovery of the hematologic parameter(s) to acceptable levels, dosing may be restarted.
Table 6 illustrates the dose that may be used in restarting Jakafi after a previous interruption.
Table 6: Polycythemia Vera: Restarting Doses for Jakafi after Safety Interruption for Hematologic Parameter(s)
Use the most severe category of a patient’s hemoglobin, platelet count, or ANC abnormality to determine the corresponding maximum restarting dose.
| |
| Hemoglobin, Platelet Count, or ANC | Maximum Restarting Dose |
| Hemoglobin less than 8 g/dL OR platelet count less than 50 x 109/L OR ANC less than 1 x 109/L | Continue hold |
| Hemoglobin 8 to less than 10 g/dL OR platelet count 50 to less than 75 x 109/L OR ANC 1 to less than 1.5 x 109/L | 5 mg twice daily *or no more than 5 mg twice daily less than the dose which resulted in dose interruption |
| Hemoglobin 10 to less than 12 g/dL OR platelet count 75 to less than 100 x 109/L OR ANC 1.5 to less than 2 x 109/L | 10 mg twice 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 109/L OR ANC greater than or equal to 2 x 109/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 109/L, and ANC is greater than or equal to 1.5 x 109/L.
Dose Management after Restarting Treatment
After restarting Jakafi following treatment interruption, doses may be titrated, but the maximum total daily dose should not exceed 5 mg less than the dose that resulted in the dose interruption. An exception to this is dose interruption following phlebotomy-associated anemia, in which case the maximal total daily dose allowed after restarting Jakafi would not be limited.
Dose Modifications Based on Insufficient Response for Patients with Polycythemia Vera
If the response is insufficient and platelet, hemoglobin, and neutrophil counts are adequate, doses may be increased in 5 mg twice daily increments to a maximum of 25 mg twice daily. Doses should not be increased during the first 4 weeks of therapy and not more frequently than every two weeks.
Consider dose increases in patients who meet all of the following conditions:
- Inadequate efficacy as demonstrated by one or more of the following:
- Continued need for phlebotomy
- WBC greater than the upper limit of normal range
- Platelet count greater than the upper limit of normal range
- Palpable spleen that is reduced by less than 25% from Baseline
- Platelet count greater than or equal to 140 x 109/L
- Hemoglobin greater than or equal to 12 g/dL
- ANC greater than or equal to 1.5 x 109/L
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.
| Laboratory Parameter | Dosing Recommendations |
| Clinically significant thrombocytopenia after supportive measures | Reduce dose by 1 dose level. |
| ANC less than 1 x 109/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 Total bilirubin > 10.0 x ULN: Hold Jakafi for up to |
| Total Bilirubin elevation, liver GVHD | > 3.0 × ULN: Continue Jakafi at 1 dose level lower until recovery. |
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.
| Parameter | Dosing Recommendations |
| Platelet count less than 20 × 109/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 × 109/L considered related to Jakafi | Reduce Jakafi by 1 dose level; resume at initial dose level upon recovery. |
ANC less than 0.5 × 109/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 × 109/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. |
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 [see Drug Interactions ( 7)], according to Table 9. Avoid concomitant use of Jakafi with fluconazole doses of greater than 200 mg daily.
| 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: | ||
| 10 mg twice daily | |
| 5 mg once daily | |
| Starting dose for patients with PV: | 5 mg twice daily | |
| If on stable dose for patients with MF or PV: | ||
| Decrease dose by 50% (round up to the closest available tablet strength) | |
| 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 dosefor patients with aGVHD or cGVHD: | ||
| Fluconazole doses of less than or equal to 200 mg | 5 mg once daily for patients with aGVHD; | |
| 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 ] | |
ESRD on dialysis | 100 to 200 x 109/L | 15 mg once after dialysis session |
Greater than 200 x 109/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.
| Hepatic Impairment Status | Platelet Count | Recommended Starting Dosage |
Patients with MF | Greater than 150 x 109/L | No dose adjustment |
| 100 x 109/L to 150 x 109/L | 10 mg twice daily | |
| 50 to less than 100 x 109/L | 5 mg daily | |
| Less than 50 x 109/L | Avoid use [see Use in Specific Populations ] | |
| 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 ]. |
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.
5 mg tablets - round and white with "INCY" on one side and "5" on the other.
10 mg tablets - round and white with "INCY" on one side and "10" on the other.
15 mg tablets - oval and white with "INCY" on one side and "15" on the other.
20 mg tablets - capsule-shaped and white with "INCY" on one side and "20" on the other.
25 mg tablets - oval and white with "INCY" on one side and "25" on the other.
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 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. The background risk in the U.S. general population of major birth defects is 2% to 4% and miscarriage is 15% to 20% of clinically recognized pregnancies.
Data
Animal Data
Ruxolitinib was administered orally to pregnant rats or rabbits during the period of organogenesis, at doses of 15, 30 or 60 mg/kg/day in rats and 10, 30 or 60 mg/kg/day in rabbits. 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. This dose is approximately 7% the clinical exposure at the maximum recommended dose.
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).
Lactation
Risk Summary
No data are available regarding the presence of ruxolitinib in human milk, the effects on the breast fed child, or the effects on milk production. Ruxolitinib and/or its metabolites were present in the milk of lactating rats (see Data). Because many drugs are present in human milk and because of the potential for thrombocytopenia and anemia shown for Jakafi in human studies, discontinue breastfeeding during treatment with Jakafi and for two weeks after the final dose.
Data
Animal Data
Lactating rats were administered a single dose of [14C]-labeled ruxolitinib (30 mg/kg) on postnatal Day 10, after which plasma and milk samples were collected for up to 24 hours. The AUC for total radioactivity in milk was approximately 13-fold the maternal plasma AUC. Additional analysis showed the presence of ruxolitinib and several of its metabolites in milk, all at levels higher than those in maternal plasma.
Pediatric Use
Myelofibrosis
The safety and effectiveness of Jakafi for treatment of myelofibrosis in pediatric patients have not been established.
Polycythemia Vera
The safety and effectiveness of Jakafi for treatment of polycythemia vera 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 [see Clinical Studies ( 14.3)] and additional pharmacokinetic and safety data in pediatric patients. The safety and effectiveness of Jakafi 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 [see Clinical Studies ( 14.4)] and additional pharmacokinetic and safety data in pediatric patients. The safety and effectiveness of Jakafi for treatment of cGVHD has not been established in pediatric patients younger than 12 years old.
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. The patients included 18 children (age 2 to < 12 years) and 14 adolescents (age 12 to < 17 years). Overall, 19% of patients received more than one 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). The patients included 2 infants (age < 2 years), 42 children (age 2 to < 12 years) and 62 adolescents (age 12 to < 17 years). No new safety signals were observed in pediatric patients in this trial.
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 [e.g., bone mineral content, peripheral quantitative computed tomography, and x-ray analysis] occurred at doses ≥ 5 mg/kg/day. When administered starting at postnatal day 21 (the equivalent of a human 2-3 years of age) at doses of 5 to 60 mg/kg/day, effects on body weight and bone occurred at doses ≥ 15 mg/kg/day, which were considered adverse at 60 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.
Geriatric Use
Of the total number of patients with MF in clinical studies with Jakafi, 52% were 65 years and older, while 15% were 75 years and older. No overall differences in safety or effectiveness of Jakafi were observed between these patients and younger patients.
Clinical studies of Jakafi in patients with aGVHD did not include sufficient numbers of subjects age 65 and over to determine whether they respond differently from younger subjects.
Of the total number of patients with cGVHD treated with Jakafi in clinical trials, 11% were 65 years and older. No overall differences in safety or effectiveness of Jakafi were observed between these patients and younger patients.
Renal Impairment
Total exposure of ruxolitinib and its active metabolites increased with moderate (CLcr 30 to 59 mL/min) and severe (CLcr 15 to 29 mL/min) renal impairment, and ESRD (CLcr less than 15 mL/min) on dialysis [see Clinical Pharmacology ( 12.3)]. Modify Jakafi dosage as recommended [see Dosage and Administration ].
Reduce Jakafi dosage as recommended in patients with MF or PV with hepatic impairment [see Dosage and Administration ( 2.7)]. Reduce Jakafi dosage as recommended for patients with Stage 4 liver aGVHD.
Monitor blood counts more frequently for toxicity and modify the Jakafi dosage for adverse reactions if they occur for patients with Score 3 liver cGVHD [see Dosage and Administration ( 2.7) and Clinical Pharmacology ( 12.3)].
None.
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 × 109/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)].
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 ]. 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 ]. 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.
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 [see Dosage and Administration ], consider tapering the dose of Jakafi 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. 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 [see Adverse Reactions ( 6.1)]. 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.
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.
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.
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.