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
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. Myelofibrosis The safety of JAKAFI was assessed in 617 patients in 6 clinical studies with a median duration of follow-up of 10.9 months, including 301 patients with MF in 2 Phase 3 studies.
In these 2 Phase 3 studies, patients had a median duration of exposure to JAKAFI of 9.5 months (range: 0.5 to 17 months), with 89% of patients treated for more than 6 months and 25% treated for more than 12 months. One hundred and eleven patients started treatment at 15 mg twice daily and 190 patients started at 20 mg twice daily. In patients starting treatment with 15 mg twice daily (pretreatment platelet counts of 100 to 200 × 10 9 /L) and 20 mg twice daily (pretreatment platelet counts greater than 200 × 10 9 /L), 65% and 25% of patients, respectively, required a dose reduction below the starting dose within the first 8 weeks of therapy.
In a double-blind, randomized, placebo-controlled study of JAKAFI, among the 155 patients treated with JAKAFI, the most frequent adverse reactions were thrombocytopenia and anemia . 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 JAKAFI (N = 155) Placebo (N = 151) Adverse Reactions All Grades National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. (%) Grade 3 (%) Grade 4 (%) All Grades (%) Grade 3 (%) Grade 4 (%) Bruising includes contusion, ecchymosis, hematoma, injection site hematoma, periorbital hematoma, vessel puncture site hematoma, increased tendency to bruise, petechiae, purpura. 23 < 1 0 15 0 0 Dizziness includes dizziness, postural dizziness, vertigo, balance disorder, Meniere’s Disease, labyrinthitis. 18 < 1 0 7 0 0 Headache 15 0 0 5 0 0 Urinary Tract Infections includes urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, kidney infection, pyuria, bacteria urine, bacteria urine identified, nitrite urine present. 9 0 0 5 < 1 < 1 Weight Gain includes weight increased, abnormal weight gain. 7 < 1 0 1 < 1 0 Flatulence 5 0 0 < 1 0 0 Herpes Zoster includes herpes zoster and post-herpetic neuralgia. 2 0 0 < 1 0 0 Description of Selected Adverse Reactions Anemia In the 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 In the 2 Phase 3 clinical studies, in patients who developed Grade 3 or 4 thrombocytopenia, the median time to onset was approximately 8 weeks. Thrombocytopenia was generally reversible with dose reduction or dose interruption. The median time to recovery of platelet counts above 50 x 10 9 /L was 14 days.
Platelet transfusions were administered to 5% of patients receiving JAKAFI and to 4% of patients receiving control regimens. Discontinuation of treatment because of thrombocytopenia occurred in < 1% of patients receiving JAKAFI and < 1% of patients receiving control regimens. Patients with a platelet count of 100 x 10 9 /L to 200 x 10 9 /L before starting JAKAFI had a higher frequency of Grade 3 or 4 thrombocytopenia compared to patients with a platelet count greater than 200 x 10 9 /L (17% versus 7%). Neutropenia In the 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. JAKAFI (N = 155) Placebo (N = 151) Laboratory Parameter All Grades National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0. (%) Grade 3 (%) Grade 4 (%) All Grades (%) Grade 3 (%) Grade 4 (%) Thrombocytopenia 70 9 4 31 1 0 Anemia 96 34 11 87 16 3 Neutropenia 19 5 2 4 < 1 1 Additional Data From the Placebo-Controlled Study 25% of patients treated with JAKAFI and 7% of patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in alanine transaminase (ALT). The incidence of greater than or equal to Grade 2 elevations was 2% for JAKAFI with 1% Grade 3 and no Grade 4 ALT elevations. 17% of patients treated with JAKAFI and 6% of patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in aspartate transaminase (AST). The incidence of Grade 2 AST elevations was < 1% for JAKAFI with no Grade 3 or 4 AST elevations. 17% of patients treated with JAKAFI and < 1% of patients treated with placebo developed newly occurring or worsening Grade 1 elevations in cholesterol.
The incidence of Grade 2 cholesterol elevations was < 1% for JAKAFI with no Grade 3 or 4 cholesterol elevations. Polycythemia Vera In a randomized, open-label, active-controlled study, 110 patients with PV resistant to or intolerant of hydroxyurea received JAKAFI and 111 patients received best available therapy (BAT) . The most frequent adverse reaction was anemia. Discontinuation for adverse events, regardless of causality, was observed in 4% of patients treated with JAKAFI. 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 32 of Randomized Treatment JAKAFI (N = 110) Best Available Therapy (N = 111) Adverse Reactions All Grades National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0. (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%) Diarrhea 15 0 7 < 1 Dizziness includes dizziness and vertigo. 15 0 13 0 Dyspnea includes dyspnea and dyspnea exertional. 13 3 4 0 Muscle Spasms 12 < 1 5 0 Constipation 8 0 3 0 Herpes Zoster includes herpes zoster and post-herpetic neuralgia. 6 < 1 0 0 Nausea 6 0 4 0 Weight Gain includes weight increased and abnormal weight gain. 6 0 < 1 0 Urinary Tract Infections includes urinary tract infection and cystitis. 6 0 3 0 Hypertension 5 < 1 3 < 1 Clinically relevant laboratory abnormalities are shown in Table 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.
JAKAFI (N = 110) Best Available Therapy (N = 111) Laboratory Parameter All Grades National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0. (%) Grade 3 (%) Grade 4 (%) All Grades (%) Grade 3 (%) Grade 4 (%) Hematology Anemia 72 < 1 < 1 58 0 0 Thrombocytopenia 27 5 < 1 24 3 < 1 Neutropenia 3 0 < 1 10 < 1 0 Chemistry Hypercholesterolemia 35 0 0 8 0 0 Elevated ALT 25 < 1 0 16 0 0 Elevated AST 23 0 0 23 < 1 0 Hypertriglyceridemia 15 0 0 13 0 0 Acute Graft-Versus-Host Disease In a single-arm, open-label study, 71 adults (ages 18-73 years) were treated with JAKAFI for aGVHD failing treatment with steroids with or without other immunosuppressive drugs . 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 19: Acute Graft-Versus-Host Disease: Nonhematologic Adverse Reactions Occurring in ≥ 15% of Patients in the Open-Label, Single Cohort Study JAKAFI (N = 71) Adverse Reactions Selected laboratory abnormalities are listed in Table 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 Selected laboratory abnormalities during treatment with JAKAFI are shown in Table 20. Table 20: Acute Graft-Versus-Host Disease: Selected Laboratory Abnormalities Worsening from Baseline in the Open-Label, Single Cohort Study JAKAFI (N = 71) Worst grade during treatment Laboratory Parameter All Grades National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03. (%) Grade 3-4 (%) Hematology Anemia 75 45 Thrombocytopenia 75 61 Neutropenia 58 40 Chemistry Elevated ALT 48 8 Elevated AST 48 6 Hypertriglyceridemia 11 1 Chronic Graft-Versus-Host Disease In a Phase 3, randomized, open-label, multi-center study, 165 patients were treated with JAKAFI and 158 patients were treated with 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 treatment discontinuation occurred in 18% of patients treated with JAKAFI. An adverse reaction resulting in dose modification occurred in 27%, and an adverse reaction resulting in treatment interruption occurred in 23%. The most common hematologic adverse reactions (incidence > 35%) are anemia and thrombocytopenia. The most common nonhematologic adverse reactions (incidence ≥ 20%) are infections (pathogen not specified) and viral infection. Table 21 presents the most frequent nonlaboratory adverse reactions occurring up to Cycle 7 Day 1 of randomized treatment.
Table 21: Chronic Graft-Versus-Host Disease: All-Grade (≥ 10%) and Grades 3-5 (≥ 3%) Nonlaboratory Adverse Reactions Occurring in Patients in the Open-Label, Active-Controlled Study up to Cycle 7 Day 1 of Randomized Treatment Adverse Reaction Grouped terms that are composites of applicable adverse reaction terms. JAKAFI (N = 165) Best Available Therapy (N = 158) All Grades (%) Grade ≥ 3 (%) All Grades (%) Grade ≥ 3 (%) Infections and infestations Infections (pathogen not specified) 45 15 44 16 Viral infections 28 5 23 5 Musculoskeletal and connective tissue disorders Musculoskeletal pain 18 1 13 0 General disorders and administration site conditions Pyrexia 16 2 9 1 Fatigue 13 1 10 2 Edema 10 1 12 1 Vascular disorders Hypertension 16 5 13 7 Hemorrhage 12 2 15 2 Respiratory, thoracic and mediastinal disorders Cough 13 0 8 0 Dyspnea 11 1 8 1 Gastrointestinal disorders Nausea 12 0 13 2 Diarrhea 10 1 13 1 Clinically relevant laboratory abnormalities are shown in Table 22. 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. 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
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
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. Observe patients receiving JAKAFI/JAKAFI XR for signs and symptoms of active tuberculosis and manage promptly. Prior to initiating JAKAFI/JAKAFI XR, patients should be evaluated for tuberculosis risk factors, and those at higher risk should be tested for latent infection. Risk factors include, but are not limited to, prior residence in or travel to countries with a high prevalence of tuberculosis, close contact with a person with active tuberculosis, and a history of active or latent tuberculosis where an adequate course of treatment cannot be confirmed.
For patients with evidence of active or latent tuberculosis, consult a physician with expertise in the treatment of tuberculosis before starting JAKAFI/JAKAFI XR. The decision to continue JAKAFI/JAKAFI XR during treatment of active tuberculosis should be based on the overall risk-benefit determination. Progressive Multifocal Leukoencephalopathy Progressive multifocal leukoencephalopathy (PML) has occurred with JAKAFI treatment. If PML is suspected, stop JAKAFI/JAKAFI XR and evaluate.
Herpes Zoster and Herpes Simplex Herpes zoster infection has been reported in patients receiving JAKAFI . Advise patients about early signs and symptoms of herpes zoster and to seek treatment as early as possible if suspected. Herpes simplex virus reactivation and/or dissemination has been reported in patients receiving JAKAFI . Monitor patients for the development of herpes simplex infections. If a patient develops evidence of dissemination of herpes simplex, consider interrupting treatment with JAKAFI/JAKAFI XR; patients should be promptly treated and monitored according to clinical guidelines.
Hepatitis B Hepatitis B viral load (HBV-DNA titer) increases, with or without associated elevations in alanine aminotransferase and aspartate aminotransferase, have been reported in patients with chronic HBV infections taking JAKAFI. The effect of JAKAFI/JAKAFI XR on viral replication in patients with chronic HBV infection is unknown. Patients with chronic HBV infection should be treated and monitored according to clinical guidelines.
Symptom
Exacerbation Following Interruption or Discontinuation of Treatment Following discontinuation of JAK-inhibitors, including JAKAFI/JAKAFI XR, signs and symptoms from myeloproliferative neoplasms may flare. Some patients with MF have experienced one or more of the following after discontinuing JAK-inhibitors: fever, respiratory distress, hypotension, disseminated intravascular coagulation, or multi-organ failure. If one or more of these signs and symptoms occur after discontinuation of JAKAFI/JAKAFI XR, or while tapering the dose, evaluate for and treat any intercurrent illness and consider restarting or increasing the dose of JAKAFI/JAKAFI XR. Instruct patients not to interrupt or discontinue therapy without consulting their healthcare provider.
When discontinuing or interrupting therapy with JAKAFI/JAKAFI XR for reasons other than life‑threatening toxicities, consider tapering the dose of JAKAFI/JAKAFI XR gradually rather than discontinuing abruptly .
Non-Melanoma Skin Cancer (NMSC) Non-melanoma skin cancers including basal cell, squamous cell
and Merkel cell carcinoma have occurred in patients treated with JAKAFI/JAKAFI XR. Perform periodic skin examinations.
Lipid Elevations Treatment with
JAKAFI has been associated with increases in lipid parameters including total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides . The effect of these lipid parameter elevations on cardiovascular morbidity and mortality has not been determined in patients treated with JAKAFI/JAKAFI XR. Assess lipid parameters approximately 8 to 12 weeks following initiation of JAKAFI/JAKAFI XR therapy. Monitor and treat according to clinical guidelines for the management of hyperlipidemia.
Major Adverse Cardiovascular Events (MACE) Another
JAK inhibitor has increased the risk of MACE, including cardiovascular death, myocardial infarction, and stroke (compared to those treated with TNF blockers) in patients with rheumatoid arthritis, a condition for which JAKAFI/JAKAFI XR is not indicated. Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with JAKAFI/JAKAFI XR particularly in patients who are current or past smokers and patients with other cardiovascular risk factors. Patients should be informed about the symptoms of serious cardiovascular events and the steps to take if they occur.
Thrombosis Another
JAK-inhibitor has increased the risk of thrombosis, including deep venous thrombosis (DVT), pulmonary embolism (PE), and arterial thrombosis (compared to those treated with TNF blockers) in patients with rheumatoid arthritis, a condition for which JAKAFI/JAKAFI XR is not indicated. In patients with MF and PV treated with JAKAFI in clinical trials, the rates of thromboembolic events were similar in JAKAFI and control treated patients. Patients with symptoms of thrombosis should be promptly evaluated and treated appropriately.
Secondary Malignancies Another
JAK-inhibitor has increased the risk of lymphoma and other malignancies excluding NMSC (compared to those treated with TNF blockers) in patients with rheumatoid arthritis, a condition for which JAKAFI/JAKAFI XR is not indicated. Patients who are current or past smokers are at additional increased risk. Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with JAKAFI/JAKAFI XR, particularly in patients with a known secondary malignancy (other than a successfully treated NMSC), patients who develop a malignancy, and patients who are current or past smokers.
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 . Strong CYP3A4 Inhibitors Concomitant use of JAKAFI/JAKAFI XR with strong CYP3A4 inhibitors increases ruxolitinib exposure , which may increase the risk of exposure-related adverse reactions.
Reduce the JAKAFI/JAKAFI XR dosage when used concomitantly with strong CYP3A4 inhibitors except in patients with aGVHD or cGVHD . 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.
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% of 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).
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. The safety and effectiveness of JAKAFI/JAKAFI XR 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 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). 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 (eg, 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.
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.
Patients with a platelet count between 100 and 200 x 10 9 /L were started on JAKAFI 15 mg twice daily and patients with a platelet count greater than 200 x 10 9 /L were started on JAKAFI 20 mg twice daily. Doses were then individualized based upon tolerability and efficacy with maximum doses of 20 mg twice daily for patients with platelet counts between 100 to less than or equal to 125 x 10 9 /L, of 10 mg twice daily for patients with platelet counts between 75 to less than or equal to 100 x 10 9 /L, and of 5 mg twice daily for patients with platelet counts between 50 to less than or equal to 75 x 10 9 /L. 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. The median age was 68 years (range: 40 to 91 years) with 61% of patients older than 65 years, and 54% were male.
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. The median hemoglobin count was 10.5 g/dL and the median platelet count was 251 × 10 9 /L. 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: 478 cm 3 to 8881 cm 3 ; 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%). The median age was 66 years (range: 35 to 85 years) with 52% of patients older than 65 years and 57% were male. Fifty-three percent (53%) of patients had primary MF, 31% had post-polycythemia vera MF and 16% had post-essential thrombocythemia MF. Twenty-one percent (21%) of patients had red blood cell transfusions within 8 weeks of enrollment in the study. The median hemoglobin count was 10.4 g/dL and the median platelet count was 236 x 10 9 /L. Patients had a median palpable spleen length of 15 cm below the costal margin, with 70% having a spleen length 10 cm or greater below the costal margin.
Patients had a median spleen volume as measured by MRI or CT of 2381 cm 3 (range: 451 cm 3 to 7765 cm 3 ). The primary efficacy endpoint was the proportion of patients achieving 35% or greater reduction from baseline in spleen volume at Week 48 as measured by MRI or CT. 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. Study 1 and 2 Efficacy Results Efficacy analyses of the primary endpoint in Studies 1 and 2 are presented in Table 23 below. 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. Table 23: Percent of Patients With Myelofibrosis Achieving 35% or Greater Reduction From Baseline in Spleen Volume at Week 24 in Study 1 and at Week 48 in Study 2 (Intent to Treat) 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 1 (< 1) 41 0 P-value < 0.0001 < 0.0001 Figure 1 shows the percent change from baseline in spleen volume for each patient at Week 24 (JAKAFI N = 139, placebo N = 106) or the last evaluation prior to Week 24 for patients who did not complete 24 weeks of randomized treatment (JAKAFI N = 16, placebo N = 47). 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). Symptom scores ranged from 0 to 10 with 0 representing symptoms “absent” and 10 representing “worst imaginable” symptoms. These scores were added to create the daily total score, which has a maximum of 60. Table 24 presents assessments of Total Symptom Score from baseline to Week 24 in Study 1 including the proportion of patients with at least a 50% reduction (ie, improvement in symptoms). 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. Table 24: Improvement in Total Symptom Score in Patients with Myelofibrosis JAKAFI (N = 148) Placebo (N = 152) Number (%) of Patients with 50% or Greater Reduction in Total Symptom Score by Week 24 68 8 P-value < 0.0001 Figure 2 shows the percent change from baseline in Total Symptom Score for each patient at Week 24 (JAKAFI N = 129, placebo N = 103) or the last evaluation on randomized therapy prior to Week 24 for patients who did not complete 24 weeks of randomized treatment (JAKAFI N = 16, placebo N = 42). 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. Patients in the control groups were eligible for crossover in both studies, and the median times to crossover were 9 months in Study 1 and 17 months in 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
The effectiveness of JAKAFI XR has been established for polycythemia vera based on adequate and well-controlled studies of JAKAFI in adult patients with polycythemia vera. Below is a display of the efficacy results of the adequate and well-controlled studies of JAKAFI in adult patients with 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. The age ranged from 33 to 90 years with 30% of patients over 65 years of age, and 66% were male. Patients had a median spleen volume as measured by MRI or CT of 1272 cm 3 (range: 254 cm 3 to 5147 cm 3 ) 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. At Week 32, 98 patients were still on JAKAFI with 8% receiving greater than 20 mg twice daily, 15% receiving 20 mg twice daily, 33% receiving 15 mg twice daily, 34% receiving 10 mg twice daily, and 10% receiving less than 10 mg twice daily.
Best available therapy was selected by the investigator on a patient‑by-patient basis and included hydroxyurea (60%), interferon/pegylated interferon (12%), anagrelide (7%), pipobroman (2%), lenalidomide/thalidomide (5%), and observation (15%). 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) 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 1 (< 1) 95% CI of the response rate (%) P-value < 0.0001 Number (%) of Patients Achieving a Durable Primary Response at Week 48 22 1 (< 1) 95% CI of the response rate (%) P-value < 0.0001 Number (%) of Patients Achieving Complete Hematological Remission at Week 32 26 9 95% CI of the response rate (%) P-value 0.0016 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. Of the 25 patients who achieved a primary response at Week 32, 19 (76% of the responders) maintained their response through Week 80, and of the 26 patients who achieved complete hematological remission at Week 32, 15 (58% of the responders) maintained their response through Week 80. In an assessment of the individual components that make up the primary endpoint, there were 66 (60%) patients with hematocrit control on the JAKAFI arm versus 21 (19%) patients on BAT at Week 32; 51 (77% of hematocrit responders) patients on the JAKAFI arm maintained hematocrit control through Week 80. There were 44 (40%) patients with spleen volume reduction from baseline greater than or equal to 35% on the JAKAFI arm versus 1 (< 1%) patient on BAT at Week 32; 43 (98% of spleen volume reduction responders) patients on the JAKAFI arm maintained spleen volume reduction through Week 80.
Acute Graft-Versus-Host Disease
The effectiveness of JAKAFI XR has been established for acute graft-versus-host-disease (aGVHD) based on adequate and well-controlled studies of JAKAFI in adult patients with aGVHD. Below is a display of the efficacy results of the adequate and well-controlled studies of JAKAFI in adult patients with aGVHD. 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. JAKAFI was administered at 5 mg twice daily, and the dose could be increased to 10 mg twice daily after 3 days in the absence of toxicity. There were 49 patients with aGVHD refractory to steroids alone.
These patients had a median age of 57 years (range: 18 to 72 years), 47% were male, 92% were Caucasian, and 14% were Hispanic. At baseline, aGVHD was Grade 2 in 27%, Grade 3 in 55%, and Grade 4 in 18%; 84% had visceral GVHD; the median MAGIC biomarker score was 0.47 (range: 0.10 to 0.92); and the median ST2 level was 334 mcg/L (range: 55 to 1286 mcg/L). 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 ORR results are presented in Table 26; Day-28 ORR was 100% for Grade 2 GVHD, 40.7% for Grade 3 GVHD, and 44.4% for Grade 4 GVHD. 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 16 days (95% CI 9, 83). 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 Refractory to Steroids Alone (n = 49) Overall Response, n (%) (95% CI) 28 Complete Response, n (%) 15 Very Good Partial Response, n (%) 2 Partial Response, n (%) 11
Chronic Graft-Versus-Host Disease
The effectiveness of JAKAFI XR has been established for chronic graft-versus-host-disease (cGVHD) based on adequate and well-controlled studies of JAKAFI in adult and pediatric patients with cGVHD. Below is a display of the efficacy results of the adequate and well‑controlled studies of JAKAFI in adult and pediatric patients with cGVHD. 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. Patients were excluded if they had ANC < 1 Gi/L and platelet count < 25 Gi/L, estimated creatinine clearance < 30 ml/min, progressive onset cGVHD, oxygen saturation < 90%, total bilirubin > 2 mg/dL, or diarrhea due to GVHD. A total of 329 patients were randomized 1:1 to receive either JAKAFI 10 mg twice daily (n = 165) or BAT (n = 164). 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 JAKAFI (N = 165) Best Available Therapy (N = 164) Median Age, Years (range) 49 50 Age 12 to < 18 Years, n (%) 4 8 Age > 65 Years, n (%) 18 22 Male, n (%) 109 92 Race, n (%) White 116 132 Black 2 0 Asian 33 21 American Indian or Alaska native 2 0 Other 9 4 Unknown 3 7 Median (range) time (days) from cGVHD diagnosis to randomization 174 (7-2017) 150 (10-1947) Prior Therapy No prior treatment for cGVHD 2 1 Failed first-line steroids alone 115 125 Failed first-line combination including steroids 42 30 Failed two lines of therapy 6 8 ≥ 4 Organs involved, n (%) 67 63 Severe cGVHD, n (%) 86 79 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) 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 13% (95% CI 3, 23). The median time to first response in the responders was 3 weeks (range: 2 to 24) for the JAKAFI arm and 4 weeks (range: 2 to 25) for the BAT arm. The median duration of response, calculated from first response to progression, death, or new systemic therapies for cGVHD was 4.2 months (95% CI 3.2, 6.7) for the JAKAFI arm and 2.1 months (95% CI 1.6, 3.2) for the BAT arm; and the median time from first response to death or new systemic therapies for cGVHD was 25 months (95% CI 16.8, NE) for the JAKAFI arm and 5.6 months (95% CI 4.1, 7.8) for the BAT arm.
Table 28: Overall Response Rate Through Cycle 7 Day 1 for Patients with Chronic GVHD in Study 5 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 94 Complete Response, n (%) 14 8 Partial Response, n (%) 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 7 Day 1 in 66 (40%; 95% CI 32, 48) patients in the JAKAFI arm and 47 (29%; 95% CI 22, 36) patients in the BAT arm.
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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