ASH Clinical News January 2017 Annual Meeting Edition | Page 22

BRIEF SUMMARY : For Full Prescribing Information , see package insert . CONTRAINDICATIONS None . WARNINGS AND PRECAUTIONS Thrombocytopenia , Anemia and Neutropenia Treatment with Jakafi can cause thrombocytopenia , anemia and neutropenia . [ see Dosage and Administration ( 2.1 ) in Full Prescribing Information ]. Manage thrombocytopenia by reducing the dose or temporarily interrupting Jakafi . Platelet transfusions may be necessary [ see Dosage and Administration ( 2.1.1 ) and Adverse Reactions ( 6.1 ) in Full Prescribing Information ]. Patients developing anemia may require blood transfusions and / or dose modifications of Jakafi . Severe neutropenia ( ANC less than 0.5 X 10 9 / L ) was generally reversible by withholding Jakafi until recovery [ see Adverse Reactions ( 6.1 ) in Full Prescribing Information ]. 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 ( 2.1.1 ) and Adverse Reactions ( 6.1 ) in Full Prescribing Information ]. Risk of Infection Serious bacterial , mycobacterial , fungal and viral infections have occurred . Delay starting therapy with Jakafi until active serious infections have resolved . Observe patients receiving Jakafi for signs and symptoms of infection and manage promptly . 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 . PML Progressive multifocal leukoencephalopathy ( PML ) has occurred with ruxolitinib treatment for myelofibrosis . If PML is suspected , stop Jakafi and evaluate . Herpes Zoster Advise patients about early signs and symptoms of herpes zoster and to seek treatment as early as possible if suspected [ see Adverse Reactions ( 6.1 ) in Full Prescribing Information ]. 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 myelofibrosis 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 ( 2.5 ) in Full Prescribing Information ], consider tapering the dose of Jakafi gradually rather than discontinuing abruptly . Non-Melanoma Skin Cancer 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 . 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 . ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the labeling : • Thrombocytopenia , Anemia and Neutropenia [ see Warnings and Precautions ( 5.1 ) in Full Prescribing Information ] • Risk of Infection [ see Warnings and Precautions ( 5.2 ) in Full Prescribing Information ]

• Symptom Exacerbation Following Interruption or Discontinuation of Treatment with Jakafi [ see Warnings and Precautions ( 5.3 ) in Full Prescribing Information ] • Non-Melanoma Skin Cancer [ see Warnings and Precautions ( 5.4 ) in Full Prescribing Information ]. 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 . Clinical Trials Experience in Myelofibrosis The safety of Jakafi was assessed in 617 patients in six clinical studies with a median duration of follow-up of 10.9 months , including 301 patients with myelofibrosis in two Phase 3 studies . In these two Phase 3 studies , patients had a median duration of exposure to Jakafi of 9.5 months ( range 0.5 to 17 months ), with 89 % of patients treated for more than 6 months and 25 % treated for more than 12 months . One hundred and eleven ( 111 ) patients started treatment at 15 mg twice daily and 190 patients started at 20 mg twice daily . In patients starting treatment with 15 mg twice daily ( pretreatment platelet counts of 100 to 200 X 10 9 / L ) and 20 mg twice daily ( pretreatment platelet counts greater than 200 X 10 9 / L ), 65 % and 25 % of patients , respectively , required a dose reduction below the starting dose within the first 8 weeks of therapy . In a double-blind , randomized , placebocontrolled study of Jakafi , among the 155 patients treated with Jakafi , the most frequent adverse drug reactions were thrombocytopenia and anemia [ see Table 2 ]. Thrombocytopenia , anemia and neutropenia are dose related effects . The three most frequent non-hematologic adverse reactions were bruising , dizziness and headache [ see Table 1 ]. Discontinuation for adverse events , regardless of causality , was observed in 11 % of patients treated with Jakafi and 11 % of patients treated with placebo . Table 1 presents the most common adverse reactions occurring in patients who received Jakafi in the double-blind , placebo-controlled study during randomized treatment .

Table 1 : Myelofibrosis : Adverse Reactions Occurring in Patients on Jakafi in the Double-blind , Placebo-controlled Study During Randomized Treatment a

National Cancer Institute Common Terminology Criteria for Adverse Events ( CTCAE ), version 3.0 b includes contusion , ecchymosis , hematoma , injection site hematoma , periorbital hematoma , vessel puncture site hematoma , increased tendency to bruise , petechiae , purpura c includes dizziness , postural dizziness , vertigo , balance disorder , Meniere ’ s Disease , labyrinthitis d includes urinary tract infection , cystitis , urosepsis , urinary tract infection bacterial , kidney infection , pyuria , bacteria urine , bacteria urine identified , nitrite urine present e includes weight increased , abnormal weight gain f includes herpes zoster and post-herpetic neuralgia

Description of Selected Adverse Drug Reactions Anemia In the two Phase 3 clinical studies , median time to onset of first CTCAE Grade 2 or higher anemia was approximately 6 weeks . One patient (< 1 %) discontinued treatment because of anemia . In patients receiving Jakafi , mean decreases in hemoglobin reached a nadir of approximately 1.5 to 2.0 g / dL below baseline after 8 to 12 weeks of therapy and then gradually recovered to reach a new steady state that was approximately 1.0 g / dL below baseline . This pattern was observed in patients regardless of whether they had received transfusions during therapy . In the randomized , placebo-controlled study , 60 % of patients treated with Jakafi and 38 % of patients receiving placebo received red blood cell transfusions during randomized treatment . Among transfused patients , the median number of units transfused per month was 1.2 in patients treated with Jakafi and 1.7 in placebo treated patients . Thrombocytopenia In the two Phase 3 clinical studies , in patients who developed Grade 3 or 4 thrombocytopenia , the median time to onset was approximately 8 weeks . Thrombocytopenia was generally reversible with dose reduction or dose interruption . The median time to recovery of platelet counts above 50 X 10 9 / L was 14 days . Platelet transfusions were administered to 5 % of patients receiving Jakafi and to 4 % of patients receiving control regimens . Discontinuation of treatment because of thrombocytopenia occurred in < 1 % of patients receiving Jakafi and < 1 % of patients receiving control regimens . Patients with a platelet count of 100 X 10 9 / L to 200 X 10 9 / L before starting Jakafi had a higher frequency of Grade 3 or 4 thrombocytopenia compared to patients with a platelet count greater than 200 X 10 9 / L ( 17 % versus 7 %). Neutropenia In the two Phase 3 clinical studies , 1 % of patients reduced or stopped Jakafi because of neutropenia . Table 2 provides the frequency and severity of clinical hematology abnormalities reported for patients receiving treatment with Jakafi or placebo in the placebo-controlled study .

Table 2 : Myelofibrosis : Worst Hematology Laboratory Abnormalities in the Placebo-Controlled Study a

Laboratory Parameter

All Grades b (%)

Jakafi ( N = 155 )

Jakafi ( N = 155 )

Grade 3 (%)

Grade 4 (%)

All Grades (%)

Placebo ( N = 151 )

Placebo ( N = 151 )

Grade 3 (%)

Grade 4 (%)

a

Presented values are worst Grade values regardless of baseline b

National Cancer Institute Common Terminology Criteria for Adverse Events , version 3.0

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 . Clinical Trial Experience in Polycythemia Vera In a randomized , open-label , active-controlled study , 110 patients with polycythemia vera resistant to or intolerant of hydroxyurea received Jakafi and 111 patients received best available therapy [ see Clinical Studies ( 14.2 ) in Full Prescribing Information ]. The most frequent adverse drug reaction was anemia . Table 3 presents the most frequent non-hematologic treatment emergent adverse events occurring up to Week 32 . Discontinuation for adverse events , regardless of causality , was observed in 4 % of patients treated with Jakafi .