Ruxolitinib

JAKAFI/JAKAFI XR is a kinase inhibitor indicated for treatment of: intermediate or high-risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis in adults. ( 1.1 ) polycythemia vera in adults who have had an inadequate response to or are intolerant of hydroxyurea. ( 1.2 ) steroid-refractory acute graft-versus-host disease in adult and pediatric patients 12 years and older. ( 1.3 ) chronic graft-versus-host disease after failure of one or two lines of systemic therapy in adult and pediatric patients 12 years and older. ( 1.4 )

1.1 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.

1.2 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.

1.3 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.

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

JAKAFI : 5 mg tablets – round and white with "INCY" on one side and "5" on the other. 10 mg tablets – round and white with "INCY" on one side and "10" on the other. 15 mg tablets – oval and white with "INCY" on one side and "15" on the other. 20 mg tablets – capsule-shaped and white with "INCY" on one side and "20" on the other. 25 mg tablets – oval and white with "INCY" on one side and "25" on the other. JAKAFI XR : 11 mg extended-release tablets – round and light pink with “I” on one side and “11” on the other. 22 mg extended-release tablets – round and light yellow with “I” on one side and “22” on the other. 33 mg extended-release tablets – round and pink with “I” on one side and “33” on the other. 44 mg extended-release tablets – round and grey with “I” on one side and “44” on the other. 55 mg extended-release tablets – round and yellow with “I” on one side and “55” on the other. JAKAFI tablets: 5 mg, 10 mg, 15 mg, 20 mg and 25 mg. ( 3 ) JAKAFI XR extended-release tablets: 11 mg, 22 mg, 33 mg, 44 mg and 55 mg. ( 3 )

None. None. ( 4 )

Thrombocytopenia, Anemia, and Neutropenia: Manage by dose reduction or interruption, or transfusion. ( 5.1 ) Risk of Infection: Assess patients for signs and symptoms of infection and initiate appropriate treatment promptly. Serious infections should have resolved before starting therapy with JAKAFI/JAKAFI XR. ( 5.2 ) Symptom Exacerbation Following Interruption or Discontinuation: Manage with supportive care and consider resuming treatment with JAKAFI/JAKAFI XR. ( 5.3 ) Risk of Non-Melanoma Skin Cancer: Perform periodic skin examinations. ( 5.4 ) Lipid Elevations: Assess lipid levels 8 to 12 weeks from start of therapy and treat as needed. ( 5.5 ) Major Adverse Cardiovascular Events (MACE): Monitor for development of MACE. ( 5.6 ) Thrombosis: Evaluate and treat symptoms of thrombosis promptly. ( 5.7 ) Secondary Malignancies: Monitor for development of secondary malignancies, particularly in patients who are current or past smokers. ( 5.8 )

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

5.2 Risk of Infection Serious bacterial, mycobacterial, fungal, and viral infections have occurred [ see Adverse Reactions ( 6.1 )] . Delay starting therapy with JAKAFI/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 [see Adverse Reactions ( 6.1 )] . Advise patients about early signs and symptoms of herpes zoster and to seek treatment as early as possible if suspected. Herpes simplex virus reactivation and/or dissemination has been reported in patients receiving JAKAFI [see Adverse Reactions ( 6.2 )] . Monitor patients for the development of herpes simplex infections. If a patient develops evidence of dissemination of herpes simplex, consider interrupting treatment with JAKAFI/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.

5.3 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 [see Dosage and Administration ( 2.8 )] .

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

5.5 Lipid Elevations Treatment with JAKAFI has been associated with increases in lipid parameters including total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides [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/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.

5.6 Major Adverse Cardiovascular Events (MACE) Another JAK inhibitor has increased the risk of MACE, including cardiovascular death, myocardial infarction, and stroke (compared to those treated with TNF blockers) in patients with rheumatoid arthritis, a condition for which JAKAFI/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.

5.7 Thrombosis Another JAK-inhibitor has increased the risk of thrombosis, including deep venous thrombosis (DVT), pulmonary embolism (PE), and arterial thrombosis (compared to those treated with TNF blockers) in patients with rheumatoid arthritis, a condition for which JAKAFI/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.

5.8 Secondary Malignancies Another JAK-inhibitor has increased the risk of lymphoma and other malignancies excluding NMSC (compared to those treated with TNF blockers) in patients with rheumatoid arthritis, a condition for which JAKAFI/JAKAFI XR is not indicated. Patients who are current or past smokers are at additional increased risk. […]

The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling: Thrombocytopenia, Anemia and Neutropenia [see Warnings and Precautions ( 5.1 )] Risk of Infection [see Warnings and Precautions ( 5.2 )] Symptom Exacerbation Following Interruption or Discontinuation of Treatment [see Warnings and Precautions ( 5.3 )] Non-Melanoma Skin Cancer [see Warnings and Precautions ( 5.4 )] Lipid Elevations [ see Warnings and Precautions ( 5.5 )] Major Adverse Cardiovascular Events (MACE) [ see Warnings and Precautions ( 5.6 )] Thrombosis [ see Warnings and Precautions ( 5.7 )] Secondary Malignancies [ see Warnings and Precautions ( 5.8 )] In myelofibrosis and polycythemia vera, the most common hematologic adverse reactions (incidence > 20%) are thrombocytopenia and anemia. The most common nonhematologic adverse reactions (incidence ≥ 15%) are bruising, dizziness, headache, and diarrhea. ( 6.1 ) In acute graft-versus-host disease, the most common hematologic adverse reactions (incidence > 50%) are anemia, thrombocytopenia, and neutropenia. The most common nonhematologic adverse reactions (incidence > 50%) are infections (pathogen not specified) and edema. ( 6.1 ) In chronic graft-versus-host disease, the most common hematologic adverse reactions (incidence > 35%) are anemia and thrombocytopenia. The most common nonhematologic adverse reactions (incidence ≥ 20%) are infections (pathogen not specified) and viral infections. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Incyte Corporation at 1-855-463-3463 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. 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 [see Clinical Studies ( 14 )] . 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 (111) patients started treatment at 15 mg twice daily and 190 patients started at 20 mg twice daily. In patients starting treatment with 15 mg twice daily (pretreatment platelet counts of 100 to 200 × 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 [see Table 14] . Thrombocytopenia, anemia, and neutropenia are dose-related effects. The 3 most frequent nonhematologic adverse reactions were bruising, dizziness, and headache [see Table 13 ] . 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. […]

Fluconazole: Avoid concomitant use with fluconazole doses greater than 200 mg. Reduce JAKAFI/JAKAFI XR dosage with fluconazole doses less than or equal to 200 mg. ( 2.6 , 7 ) Strong CYP3A4 Inhibitors: Reduce, interrupt, or discontinue JAKAFI/JAKAFI XR doses as recommended except in patients with acute or chronic graft-versus-host-disease. ( 2.6 , 7 )

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

Renal Impairment: Reduce JAKAFI/JAKAFI XR starting dose or avoid treatment as recommended. ( 2.7 , 8.6 ) Hepatic Impairment: Reduce JAKAFI/JAKAFI XR starting dose or avoid treatment as recommended. ( 2.7 , 8.7 ) Lactation: Advise not to breastfeed. ( 8.2 )

8.1 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).

8.2 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/JAKAFI XR and for 2 weeks after the final dose. Data Animal Data Lactating rats were administered a single dose of [ 14 C]-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.

8.4 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 [ see Clinical Studies ( 14.3 )] 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 [ see Clinical Studies ( 14.4 )] 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.

8.5 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.

8.6 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/JAKAFI XR dosage as recommended [see Dosage and Administration ( 2.7 )].

8.7 Hepatic Impairment Exposure of ruxolitinib increased with mild (Child-Pugh A), moderate (Child-Pugh B), and severe (Child-Pugh C) hepatic impairment [see Clinical Pharmacology ( 12.3 )]. […]

Ruxolitinib, a kinase inhibitor, inhibits Janus Associated Kinases (JAKs), JAK1 and JAK2, which mediate the signaling of a number of cytokines and growth factors that are important for hematopoiesis and immune function. JAK signaling involves recruitment of STATs (signal transducers and activators of transcription) to cytokine receptors, activation, and subsequent localization of STATs to the nucleus leading to modulation of gene expression. MF and PV are myeloproliferative neoplasms (MPNs) known to be associated with dysregulated JAK1 and JAK2 signaling. In a mouse model of JAK2V617F-positive MPN, oral administration of ruxolitinib prevented splenomegaly, preferentially decreased JAK2V617F mutant cells in the spleen and decreased circulating inflammatory cytokines (eg, TNF-α, IL-6). JAK-STAT signaling pathways play a role in regulating the development, proliferation, and activation of several immune cell types important for GVHD pathogenesis. In a mouse model of aGVHD, oral administration of ruxolitinib was associated with decreased expression of inflammatory cytokines in colon homogenates and reduced immune-cell infiltration in the colon.