Pacritinib

1 INDICATIONS AND USAGE VONJO is indicated for the treatment of adults with intermediate or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis (MF) with a platelet count below 50 × 10 9 /L. This indication is approved under accelerated approval based on spleen volume reduction [see Clinical Studies (14.2)] . Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). VONJO is a kinase inhibitor indicated for the treatment of adults with intermediate or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis with a platelet count below 50 × 10 9 /L ( 1 ). This indication is approved under accelerated approval based on spleen volume reduction. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

2 DOSAGE AND ADMINISTRATION Recommended dosage is 200 mg orally twice daily ( 2.1 ). May be taken with or without food ( 2.1 ). 2.1 Recommended Dosage The recommended dosage of VONJO is 200 mg orally twice daily. VONJO may be taken with or without food. Swallow capsules whole. Do not open, break, or chew capsules. Patients who are on treatment with other kinase inhibitors before the initiation of VONJO must taper or discontinue according to the prescribing information for that drug. 2.2 Monitoring for Safety Perform a complete blood count (CBC; including white blood cell count differential and platelet count), coagulation testing (prothrombin time, partial thromboplastin time, thrombin time, and international normalized ratio) and a baseline electrocardiogram (ECG), prior to starting VONJO, and monitor as clinically indicated while the patient is on treatment. 2.3 Missed Dose If a dose of VONJO is missed, the patient should take the next prescribed dose at its scheduled time. Extra capsules should not be taken to make up for the missed dose. 2.4 Dose Interruption for Planned Surgical Procedures or Other Interventions Discontinue VONJO 7 days prior to elective surgery or invasive procedures because of the risk of hemorrhage and restart only after hemostasis is assured. 2.5 Dose Modification for Adverse Reactions Dose modifications for diarrhea, thrombocytopenia, hemorrhage, and prolonged QT interval are described in Table 1 , Table 2 , Table 3 , and Table 4 respectively. See Warning and Precautions ( 5.1 , 5.2 , 5.3 , and 5.4 ) for additional risk minimization recommendations. Dose levels for VONJO are as follows: 200 mg twice daily (initial starting dose), 100 mg twice daily (first dose reduction), 100 mg once daily (second dose reduction). Discontinue VONJO in patients unable to tolerate a dose of 100 mg daily. Table 1 Dosage Modification for Diarrhea Toxicity Management/Action a Increase of at least 7 stools per day over baseline, or hospitalization indicated, or severe increase in ostomy output over baseline, or if limiting self-care. b Increase of <4 stools per day over baseline or mild increase in ostomy output compared to baseline. New onset of diarrhea Initiate anti-diarrheal medications. Encourage adequate oral hydration. Grade 3 or 4 a Hold VONJO until the diarrhea resolves to Grade 1 b or lower or baseline. Restart VONJO at the last given dose. Intensify anti-diarrheal regimen. Provide fluid replacement. If diarrhea recurs, hold VONJO until the diarrhea resolves to Grade 1 b or lower or baseline. Restart VONJO at 50% of the last given dose once the toxicity has resolved. Concomitant antidiarrheal treatment is required for patients restarting VONJO. Table 2 Dose Modification for Thrombocytopenia Worsening Thrombocytopenia Action For clinically significant worsening of thrombocytopenia that lasts more than 7 days Hold VONJO. Restart VONJO at 50% of the last given dose once the toxicity has resolved. If toxicity recurs hold VONJO. Restart VONJO at 50% of the last given dose once the toxicity has resolved. Table 3 Dose Modification for Hemorrhage Toxicity Action Moderate bleeding; intervention indicated Hold VONJO until hemorrhage resolves. Restart VONJO at the last given dose. If hemorrhage recurs, hold VONJO until resolution then restart at 50% of the last given dose. Severe bleeding; transfusion, invasive intervention, or hospitalization indicated Hold VONJO until hemorrhage resolves. Restart VONJO at 50% of the last given dose. If bleeding recurs, discontinue VONJO. Life-threatening bleeding; urgent intervention indicated. Discontinue VONJO. Table 4 Dose Modification for Prolonged QT Interval Toxicity Action QTc prolongation >500 msec or >60 msec from baseline Hold VONJO. If QTc prolongation resolves to ≤480 msec or baseline within 1 week, restart VONJO at the same dose. If time to resolution is greater than 1 week, restart VONJO at a reduced dose. 2.6 Dosage Modification for Patients with Severe Hepatic Impairment The recommended dosage of VONJO in patients with severe hepatic impairment [Child-Pugh C] is 100 mg twice daily. Dosage may be increased to 200 mg twice daily if the treatment is not effective after 12 weeks and there are no safety concerns; continue monitoring for safety [see Use in Specific Populations ( 8.6 ) and Clinical Pharmacology ( 12.3 )].

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Hemorrhage [see Warnings and Precautions ( 5.1 )] Diarrhea [see Warnings and Precautions ( 5.2 )] Thrombocytopenia [see Warnings and Precautions ( 5.3 )] Prolonged QT Interval [see Warnings and Precautions ( 5.4 )] Major Adverse Cardiac Events [see Warnings and Precautions ( 5.5 )] Thrombosis [see Warnings and Precautions ( 5.6 )] Secondary Malignancies [see Warnings and Precautions ( 5.7 )] Risk of Infection [see Warnings and Precautions ( 5.8 )] The most common (≥20% of patients) adverse reactions are diarrhea, thrombocytopenia, nausea, anemia, and peripheral edema ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Sobi, Inc. at (866) 773-5274 and www.VONJO.com 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. PERSIST-2 Trial The safety of VONJO was evaluated in the randomized, controlled PERSIST-2 trial [see Clinical Studies ( 14 )] . In PERSIST-2, key eligibility criteria included adults with intermediate or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) MF with splenomegaly and a platelet count ≤100 × 10 9 /L. Prior Janus associated kinase (JAK) inhibitor therapy was permitted. Patients received VONJO at 200 mg twice daily (n=106), 400 mg once daily (n=104), or best available therapy (BAT) (n=98). Forty-seven (44%) of the 106 patients treated with VONJO 200 mg twice daily had a baseline platelet count of <50 × 10 9 /L. The 400 mg once daily dose could not be established to be safe, so further information on this arm is not provided. In PERSIST-2, among the 106 patients treated with VONJO 200 mg twice daily, the median baseline hemoglobin was 9.7 g/dL and the median drug exposure was 25 weeks. Fifty-four percent of patients were exposed for 6 months, and 18% were exposed for approximately 12 months. Accounting for dose reductions, the average daily dose (mean relative dose intensity) and median daily dose (median relative dose intensity) were 380 mg (95%) and 400 mg (100%), respectively, for patients receiving VONJO twice daily. The median age of patients who received VONJO 200 mg twice daily was 67 years (range: 39 to 85 years), 59% were male, 86% were White, 3% were Asian, 2% were Native Hawaiian or Other Pacific Islander, 0% were Black, 9% did not report race, and 87% had an Eastern Cooperative Oncology Group performance status of 0 to 1. Serious adverse reactions occurred in 47% of patients treated with VONJO 200 mg twice daily and in 31% of patients treated with BAT. The most frequent serious adverse reactions occurring in ≥3% patients receiving VONJO 200 mg twice daily were anemia (8%), thrombocytopenia (6%), pneumonia (6%), cardiac failure (4%), disease progression (3%), pyrexia (3%), and squamous cell carcinoma of skin (3%). Fatal adverse reactions occurred in 8% of patients receiving VONJO 200 mg twice daily and in 9% of patients treated with BAT. The fatal adverse reactions among patients treated with VONJO 200 mg twice daily included events of disease progression (3%), and multiorgan failure, cerebral hemorrhage, meningorrhagia, and acute myeloid leukemia in <1% of patients each, respectively. Permanent discontinuation due to an adverse reaction occurred in 15% of patients receiving VONJO 200 mg twice daily compared to 12% of patients treated with BAT. The most frequent reasons for permanent discontinuation in ≥2% of patients receiving VONJO 200 mg twice daily included anemia (3%) and thrombocytopenia (2%). Drug interruptions due to an adverse reaction occurred in 27% of patients who received VONJO 200 mg twice daily compared to 10% of patients treated with BAT. The most frequent reasons for drug interruption in ≥2% of patients receiving VONJO 200 mg twice daily were anemia (5%), thrombocytopenia (4%), diarrhea (3%), nausea (3%), cardiac failure (3%), neutropenia (2%), and pneumonia (2%). Dosage reductions due to an adverse reaction occurred in 12% of patients who received VONJO 200 mg twice daily compared to 7% of patients treated with BAT. Adverse reactions requiring dosage reduction in ≥2% of patients who received VONJO 200 mg twice daily included thrombocytopenia (2%), neutropenia (2%), conjunctival hemorrhage (2%), and epistaxis (2%). The most common adverse reactions in ≥20% of patients (N=106) were diarrhea, thrombocytopenia, nausea, anemia, and peripheral edema. Table 5 summarizes the common adverse reactions in PERSIST-2 during randomized treatment. Table 5 Adverse Reactions Reported in ≥10% Patients Receiving VONJO 200 mg Twice Daily or Best Available Therapy During Randomized Treatment in PERSIST-2 a Grade by CTCAE Version 4.03 Adverse Reactions VONJO (200 mg Twice Daily) (N=106) Best Available Therapy (N=98) All Grades a % Grade ≥3 % All Grades a % Grade ≥3 % Diarrhea 48 4 15 0 Thrombocytopenia 34 32 23 18 Nausea 32 1 11 1 Anemia 24 22 15 14 Peripheral edema 20 1 15 0 Vomiting 19 0 5 1 Dizziness 15 1 5 0 Pyrexia 15 1 3 0 Epistaxis 12 5 13 1 Dyspnea 10 0 9 3 Pruritus 10 2 6 0 Upper respiratory tract infection 10 0 6 0 Cough 8 2 10 0 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of VONJO. 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: Renal: Acute or subacute kidney injury (secondary to diarrhea) [see Warnings and Precautions (5.2)]

12.3 Pharmacokinetics Pacritinib steady-state mean (CV%) Cmax is 8.4 mg/L (32.4%) and AUC0-12 is 95.6 mg×h/L (33.1%) following administration of VONJO 200 mg twice daily in patients with MF. Pharmacokinetics of pacritinib increases in a less than dose-proportional manner. VONJO 200 mg twice daily accumulates 386% and reaches steady-state within a week. Absorption Pacritinib achieves C max within approximately 4 to 5 hours post-dose. Effect of Food There was no significant effect of food on the pharmacokinetics of pacritinib following oral administration of VONJO 200 mg with a high-fat meal. Distribution The median (range) apparent volume of distribution of pacritinib at steady state is 229 L (156 to 591 L) in patients with MF taking 200 mg twice daily. Plasma protein binding of pacritinib is approximately 98.8%. Metabolism Pacritinib is predominantly metabolized by the CYP3A4 isozyme. Pacritinib is the major circulating component and the pharmacologic activity is mainly attributed to the parent molecule. Two major metabolites, M1 and M2, in human whole plasma represent 9.6% and 10.5% of parent drug exposure, respectively. Elimination The mean apparent clearance at steady-state (CV%) of pacritinib is 2.09 L/h (33.1%), and mean effective half-life (CV%) is 27.7 hours (17.0%). Excretion Following a single oral administration of radiolabeled pacritinib 400 mg in healthy adult subjects, 87% of the radioactivity was recovered in feces, and 6% was recovered in urine. No unchanged drug was excreted in feces and 0.12% of unchanged drug was excreted in urine. Specific Populations No clinically significant differences in the pharmacokinetics of pacritinib were observed based on age, sex, body weight, or race. Patients With Renal Impairment Pacritinib C max and AUC were similar in subjects with eGFR 30 to 89 mL/min, as estimated by the MDRD study equation, compared to subjects with eGFR ≥90 mL/min. The C max and AUC increased approximately 30% in subjects with eGFR 15 to 29 mL/min and eGFR <15 mL/min on hemodialysis. Patients With Hepatic Impairment The effect of hepatic impairment on the pharmacokinetics of pacritinib was studied in subjects with normal or impaired hepatic function at 200 mg VONJO twice daily for 14 days. The geometric mean AUC of total pacritinib decreased in subjects with moderate [Child-Pugh B, n=8] or severe hepatic impairment [Child-Pugh C, n=6] compared to subjects with normal hepatic function (n=11) due to reduced plasma protein binding. The geometric mean AUC of unbound pacritinib, the pharmacologically relevant parameter, was similar in healthy subjects compared to subjects with moderate hepatic impairment and increased by 23% in subjects with severe hepatic impairment (see Table 6). Table 6 Steady-State Pharmacokinetic Changes in Pacritinib at 200 mg VONJO BID: Subjects with Moderate / Severe Hepatic Impairment vs. Normal Hepatic Function Hepatic impairment Ratio (90% CI) of pacritinib exposure 1 Unbound C max Unbound AUC 0-tau Moderate impairment (Child-Pugh B) 1.06 (0.72, 1.58) 1.05 (0.69, 1.60) Severe impairment (Child-Pugh C) 1.24 (0.93, 1.65) 1.23 (0.91, 1.66) Notes: AUC 0-tau = Area under the curve from zero to tau post-dose after 14 days twice daily dosing with VONJO 200 mg; CI = Confidence Interval; C max = Maximum plasma concentration. 1 Ratios for C max and AUC compare exposure of unbound pacritinib in subjects with hepatic impairment vs normal hepatic function following administration of VONJO 200 mg BID for 14 days. Drug Interactions Effects of Other Drugs on the Pharmacokinetics of VONJO The effect of co-administered drugs on the exposure of pacritinib is shown in Table 7 and Table 8. Table 7 Change in Pharmacokinetics of Pacritinib Following Administration of a Single 400 mg Dose VONJO in the Presence of Co-administered Drugs Co-administered Drug Regimen of Co-administered Drug Ratio (90% CI) of pacritinib exposure 1 C max AUC 0-t Clarithromycin (strong CYP3A4 inhibitor) 500 mg every 12 hours for 5 days 1.30 (1.22, 1.39) 1.80 (1.67, 1.94) Rifampin (strong CYP3A4 inducer) 600 mg once daily for 10 days 0.49 (0.43, 0.55) 0.13 (0.11, 0.15) Notes: AUC 0-t = Area under the curve from zero to the last quantifiable concentration; CI = Confidence interval; CYP = Cytochrome P450 1 Ratios for C max and AUC compare co-administration of the medication with VONJO vs. administration of single dose 400 mg VONJO alone Table 8 Change in Pharmacokinetics of 200 mg VONJO BID at Steady State in the Presence of Co-administered Drugs Co-administered Drug Regimen of Co-administered Drug Ratio (90% CI) of pacritinib exposure 1 C max AUC 0-tau Fluconazole (moderate CYP3A4 inhibitor) 200 mg once daily for 7 days 1.41 (1.35, 1.48) 1.45 (1.39, 1.52) Bosentan (moderate CYP3A4 inducer) 125 mg twice daily for 7 days 0.84 (0.76, 0.92) 0.79 (0.72, 0.87) Notes: AUC 0-tau = Area under the curve for a dosing interval; BID = Twice daily; CI = Confidence interval; C max = Maximum plasma concentration; CYP = Cytochrome P450. 1 Ratios for Cmax and AUC0-tau compare co-administration of the medication with 200 mg VONJO BID vs. administration of 200 mg VONJO alone at steady state. Effects of VONJO on the Pharmacokinetics of Other Drugs The effect of pacritinib on the exposure of other co-administered drugs is shown in Table 9. Table 9 Change in Pharmacokinetics of Co-administered Drugs with 200 mg VONJO BID at Steady State Co-administered Drug Regimen of Co-administered Drug (single dose) Ratio (90% CI) of exposure of co-administered drug 1 C max AUC Caffeine (CYP1A2 substrate) 100 mg 0.99 (0.92, 1.07) 1.22 (1.12, 1.32) Midazolam (CYP3A4 substrate) 2 mg 0.40 (0.34, 0.46) 0.40 (0.35, 0.46) Omeprazole (CYP2C19 substrate) 20 mg 0.73 (0.46, 1.15) 0.49 (0.27, 0.89) Notes: AUC = Area under the curve from zero to the last quantifiable concentration displayed for caffeine and AUC from zero extrapolated to infinity displayed for midazolam and omeprazole; BID = Twice daily; CI = Confidence interval; C max = Maximum plasma concentration; CYP = Cytochrome P450. 1 Ratios for C max and AUC compare a single dose of co-administered drug with 200 mg VONJO BID at steady state vs. administration of a single dose of the co-administered drug alone. In Vitro Studies Cytochrome P450 (CYP) Enzymes: Pacritinib is a time-dependent inhibitor of CYP1A2 and CYP3A4, and a reversible inhibitor of CYP3A4 and CYP2C19 (Ki ≤10 µM). Pacritinib shows less direct inhibition towards CYP1A2, CYP2B6, CYP2C8, CYP2C9, and CYP2D6 (Ki >10 µM). Pacritinib is an inducer of CYP1A2 and CYP3A4. Transporter Systems Table 10 Change in Pharmacokinetics of Co-administered Drugs with 200 mg VONJO BID at Steady State Co-administered Drug Regimen of Co-administered Drug (single dose) Ratio (90% CI) of exposure of co-administered drug 1 C max AUC Metformin (OCT1 substrate) 500 mg 0.96 (0.87, 1.07) 1.05 (0.96, 1.15) Digoxin (P-gp substrate) 0.25 mg 1.29 (1.13, 1.47) 1.15 (1.05, 1.27) Rosuvastatin (BCRP substrate) 5 mg 2.04 (1.79, 2.31) 1.80 (1.63, 1.99) Notes: AUC = Area under the curve from zero to the last quantifiable concentration displayed for digoxin and rosuvastatin and AUC from zero extrapolated to infinity displayed for metformin; BID = Twice daily; CI = Confidence interval; C max = Maximum plasma concentration; CYP = Cytochrome P450 1 Ratios for C max and AUC compare a single dose of co-administered drug with 200 mg VONJO BID at steady state vs. administration of a single dose of the co-administered drug alone. In Vitro Studies Transporter Systems: Pacritinib is not a substrate of BCRP, MRP2, OAT1, OAT3, OATP1B1, OATP1B3, OCT1, OCT2, or P-gp. Pacritinib is an inhibitor of BCRP, OCT1, OCT2, and P-gp. Pacritinib is not an inhibitor of BSEP, MRP2, OAT1, or OAT3.