Pacritinib

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 )] . 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).

Capsule: 100 mg, oblong, size 0 hard gelatin capsule with an opaque scarlet cap printed with “Pacritinib 100 mg” and opaque gray body printed with “C78837”. Capsules: 100 mg ( 3 )

VONJO is contraindicated in patients concomitantly using strong CYP3A4 inhibitors or inducers as these medications can significantly alter exposure to pacritinib, which may increase the risk of adverse reactions or impair efficacy [see Warnings and Precautions ( 5.1 , 5.2 , 5.3 , 5.4 ), Drug Interactions ( 7.1 ), and Clinical Pharmacology ( 12.3 )] . Concomitant use of strong CYP3A4 inhibitors or inducers ( 4 )

Hemorrhage: Avoid use in patients with active bleeding and hold VONJO prior to any planned surgical procedures. May require dose interruption, dose reduction or permanent discontinuation depending on severity ( 5.1 ). Diarrhea: Manage significant diarrhea with anti-diarrheals, dose reduction, or dose interruption ( 5.2 ). Thrombocytopenia: Manage by dose reduction or interruption ( 5.3 ). Prolonged QT Interval: Avoid use in patients with baseline QTc >480 msec. Interrupt and reduce VONJO dosage in patients who have a QTcF >500 msec. Correct hypokalemia prior to and during VONJO administration ( 5.4 ). Major Adverse Cardiac Events (MACE): Risk may be increased in current/past smokers and patients with other cardiovascular risk factors. Monitor for signs, evaluate and treat promptly ( 5.5 ). Thrombosis: Including deep venous thrombosis, pulmonary embolism, and arterial thrombosis may occur. Monitor for signs, evaluate and treat promptly ( 5.6 ). Secondary Malignancies: Lymphoma and other malignancies may occur. Past/current smokers may be at increased risk ( 5.7 ). Risk of Infection: Delay starting VONJO until active serious infections have resolved. Observe for signs and symptoms of infection and manage promptly ( 5.8 ). Symptom Exacerbation Following Interruption or Discontinuation: Manage with supportive care and consider resuming treatment with VONJO ( 5.9 ).

5.1 Hemorrhage Serious (11%) and fatal (2%) hemorrhages have occurred in VONJO-treated patients with platelet counts <100 x 10 9 /L. Serious (13%) and fatal (2%) hemorrhages have occurred in VONJO-treated patients with platelet counts <50 x 10 9 /L. Grade ≥3 bleeding events (defined as requiring transfusion or invasive intervention) occurred in 15% of patients treated with VONJO compared to 7% of patients treated on the control arm. Due to hemorrhage, VONJO dose-reductions, dose interruptions, or permanent discontinuations occurred in 3%, 3%, and 5% of patients, respectively. Avoid use of VONJO in patients with active bleeding and hold VONJO 7 days prior to any planned surgical or invasive procedures. Assess platelet counts periodically, as clinically indicated [see Warnings and Precautions ( 5.3 )] . Manage hemorrhage using treatment interruption and medical intervention [see Dosage and Administration ( 2.5 )] .

5.2 Diarrhea VONJO caused diarrhea in approximately 48% of patients compared to 15% of patients treated on the control arm in a clinical trial. The median time to resolution in VONJO-treated patients was 2 weeks. The incidence of reported diarrhea decreased over time with 41% of patients reporting diarrhea in the first 8 weeks of treatment, 15% in Weeks 8 through 16, and 8% in Weeks 16 through 24. Diarrhea resulted in treatment interruption in 3% of VONJO-treated patients. Serious diarrhea adverse reactions occurred in 2% of patients treated with VONJO compared to no such adverse reactions in patients in the control arm. In postmarketing reports, severe diarrhea leading to acute kidney injury and treatment discontinuation has been reported with VONJO. Control pre-existing diarrhea before starting VONJO treatment. Manage diarrhea with antidiarrheal medications, fluid replacement, and dose-modification. Upon initiation of therapy, prescribe an anti-diarrheal medication (e.g., loperamide), and instruct patients to treat diarrhea promptly at the first onset of symptoms (change in frequency or consistency of bowel movements) after starting VONJO. Interrupt or reduce VONJO dose in patients with significant diarrhea despite optimal supportive care [see Dosage and Administration ( 2.5 )] .

5.3 Thrombocytopenia VONJO can cause worsening thrombocytopenia. VONJO dosing was reduced due to worsening thrombocytopenia in 2% of patients with pre-existing moderate to severe thrombocytopenia (platelet count <100 x 10 9 /L). VONJO dosing was reduced due to worsening thrombocytopenia in 2% of patients with pre-existing severe thrombocytopenia (platelet count <50 x 10 9 /L). Monitor platelet count prior to VONJO treatment and as clinically indicated during treatment [see Dosage and Administration ( 2.2 )] . Interrupt VONJO in patients with clinically significant worsening of thrombocytopenia that lasts for more than 7 days. 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 [see Dosage and Administration ( 2.5 )] .

5.4 Prolonged QT Interval VONJO can cause prolongation of the QTc interval. QTc prolongation of >500 msec was higher in VONJO-treated patients than in patients in the control arm (1.4% vs 1%). QTc increase from baseline by 60 msec or higher was greater in VONJO-treated patients than in control arm patients (1.9% vs 1%). Adverse reactions of QTc prolongation were reported for 3.8% of VONJO-treated patients and 2% of control arm patients. No cases of torsades de pointes were reported. Avoid use of VONJO in patients with a baseline QTc of >480 msec. Avoid use of drugs with significant potential for QTc prolongation in combination with VONJO. Correct hypokalemia prior to and during VONJO treatment. Manage QTc prolongation using VONJO interruption and electrolyte management [see Dosage and Administration ( 2.5 )] .

5.5 Major Adverse Cardiac Events (MACE) Another Janus associated kinase (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 VONJO is not indicated. Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with VONJO 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.

5.6 Thrombosis Another JAK-inhibitor has increased the risk of thrombosis, including deep venous thrombosis, pulmonary embolism, and arterial thrombosis (compared to those treated with TNF blockers) in patients with rheumatoid arthritis, a condition for which VONJO is not indicated. Patients with symptoms of thrombosis should be promptly evaluated and treated appropriately.

5.7 Secondary Malignancies Another JAK-inhibitor has increased the risk of lymphoma and other malignancies excluding non-melanoma skin cancer (NMSC) (compared to those treated with TNF blockers) in patients with rheumatoid arthritis, a condition for which VONJO 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 VONJO, particularly in patients with a known malignancy (other than a successfully treated NMSC), patients who develop a malignancy, and patients who are current or past smokers.

5.8 Risk of Infection Another JAK-inhibitor increased the risk of serious infections (compared to best available therapy) in patients with myeloproliferative neoplasms. Serious bacterial, mycobacterial, fungal and viral infections may occur in patients treated with VONJO. Delay starting therapy with VONJO until active serious infections have resolved. Observe patients receiving VONJO for signs and symptoms of infection and manage promptly. Use active surveillance and prophylactic antibiotics according to clinical guidelines.

5.9 Symptom Exacerbation Following Interruption or Discontinuation of Treatment Following discontinuation of JAK-inhibitors, including VONJO, 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. […]

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 )] Symptom Exacerbation Following Interruption or Discontinuation of Treatment [see Warnings and Precautions ( 5.9 )] 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 )]
• Skin and subcutaneous tissue disorders: Rash
• Metabolism and nutrition disorder: Hypoglycemia (class effect)

Co-administration of VONJO with moderate CYP3A4 inhibitors can increase the exposure to pacritinib. Monitor for increased adverse reactions of VONJO when administered with moderate CYP3A4 inhibitors ( 7.1 ). VONJO is an inhibitor of P-gp, BCRP, and CYP1A2 and an inducer of CYP3A4 and CYP2C19. Monitor patients concomitantly receiving substrates of these transporters and enzymes, and adjust dose of the substrates as needed ( 7.2 ). VONJO may reduce the effectiveness of hormonal contraceptives ( 7.2 )

7.1 Effect of Other Drugs on VONJO Strong and Moderate CYP3A4 Inhibitors Pacritinib is predominantly metabolized by CYP3A4. Concomitant use of VONJO with strong and moderate CYP3A4 inhibitors increases pacritinib exposure, which may increase the risk of exposure-related adverse reactions [see Clinical Pharmacology ( 12.3 )] Co-administration of VONJO with strong CYP3A4 inhibitors is contraindicated [see Contraindications ( 4 )]. Monitor patients concomitantly receiving moderate CYP3A4 inhibitors (e.g., fluconazole) for increased adverse reactions and consider VONJO dose modifications based on safety [see Dosage and Administration ( 2.5 )] . Concomitant use of VONJO with doses of fluconazole greater than 200 mg once daily has not been studied. Strong CYP3A4 Inducers Pacritinib is predominantly metabolized by CYP3A4. Concomitant use of VONJO with strong CYP3A4 inducers decreases pacritinib exposure, which may reduce efficacy of VONJO [see Clinical Pharmacology ( 12.3 )] . Co-administration of VONJO with strong CYP3A4 inducers is contraindicated [see Contraindications ( 4 )].

7.2 Effect of VONJO on Other Drugs CYP1A2 Substrates Pacritinib is an inhibitor of CYP1A2. VONJO increases the plasma concentrations of CYP1A2 substrates [see Clinical Pharmacology ( 12.3 )] ,which may increase the risk of adverse reactions from the CYP1A2 substrate. Monitor for CYP1A2 substrate related adverse reactions more frequently, unless otherwise recommended in the substrate Prescribing Information, when VONJO is used concomitantly with CYP1A2 substrates where minimal substrate concentration changes may lead to serious adverse reactions. CYP2C19 Substrates Pacritinib is an inducer of CYP2C19. VONJO decreases the plasma concentrations of CYP2C19 substrates [see Clinical Pharmacology ( 12.3 )] , which may decrease the efficacy from the CYP2C19 substrate. Monitor the efficacy of CYP2C19 substrate more frequently, unless otherwise recommended in the substrate Prescribing Information, when VONJO is used concomitantly with CYP2C19 substrates where minimal substrate concentration changes may lead to diminished efficacy. Dose adjustment of CYP2C19 substrates may be needed. CYP3A4 Substrates Pacritinib is an inducer of CYP3A4. VONJO decreases the plasma concentrations of CYP3A4 substrates [see Clinical Pharmacology ( 12.3 )] , which may decrease the efficacy from the CYP3A4 substrate. Monitor the efficacy of CYP3A4 substrate more frequently, unless otherwise recommended in the substrate Prescribing Information, when VONJO is used concomitantly with CYP3A4 substrates where minimal substrate concentration changes may lead to diminished efficacy. Dose adjustment of CYP3A4 substrates may be needed. Hormonal Contraceptives Avoid concomitant use of VONJO with hormonal contraceptives except for intrauterine systems containing levonorgestrel. The effectiveness of hormonal contraceptives, except for intrauterine systems containing levonorgestrel, may be reduced when used with VONJO. If contraception is needed or desired, an alternate contraceptive that is not affected by CYP3A4 inducers (e.g., an intrauterine system) or additional nonhormonal contraceptive (e.g., condoms) should be used when treated concomitantly with VONJO, and for 30 days after last dose of VONJO. P-gp Substrates Pacritinib is an inhibitor of P-gp. VONJO increases the plasma concentrations of P-gp substrates [see Clinical Pharmacology ( 12.3 )] , which may increase the risk of adverse reactions from the P-gp substrate. Monitor for P-gp substrate related adverse reactions more frequently, unless otherwise recommended in the substrate Prescribing Information, when VONJO is used concomitantly with P-gp substrates where minimal substrate concentration changes may lead to serious adverse reactions. Digoxin: Measure serum digoxin concentrations before initiating concomitant use with VONJO and continue monitoring serum digoxin concentrations as recommended in the Prescribing Information for digoxin [see Clinical Pharmacology ( 12.3 )] . BCRP substrates Pacritinib is an inhibitor of BCRP. VONJO increases the plasma concentrations of BCRP substrates [see Clinical Pharmacology ( 12.3 )] , which may increase the risk of adverse reactions from the BCRP substrate. When used concomitantly with VONJO, monitor for BCRP substrate related adverse reactions more frequently and consider dose reduction of the BCRP substrate according to its Prescribing Information. Rosuvastatin: The dose of rosuvastatin should not exceed 20 mg once daily when concomitantly used with VONJO [see Clinical Pharmacology ( 12.3 )] .

Lactation: Advise not to breastfeed ( 8.2 ). Hepatic Impairment: For patients with severe hepatic impairment (Child-Pugh C), the recommended dosage is 100 mg twice daily ( 8.6 ). Renal Impairment: Avoid use in patients with eGFR <30 mL/min ( 8.7 ).

8.1 Pregnancy Risk Summary There are no available data on VONJO use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, administration of pacritinib to pregnant mice or rabbits at exposures that were considerably lower than those observed at the recommended human dose were associated with maternal toxicity and embryonic and fetal loss (see Data ) . Advise pregnant women of the potential risk to a fetus. Consider the benefits and risks of VONJO for the mother and possible risks to the fetus when prescribing VONJO to a pregnant woman. The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data Pacritinib was administered orally to pregnant mice at doses of 30, 100, or 250 mg/kg/day from gestation day 6 to gestation day 15. Pacritinib was also administered orally to pregnant rabbits at doses of 15, 30, or 60 mg/kg/day from gestation day 7 until gestation day 20. In both species, pacritinib was associated with maternal toxicity, which resulted in post-implantation loss in mice, abortions in rabbits, and reduced fetal body weights in mice and rabbits at exposures 0.1 times (mice) and 0.3 times (rabbits) the exposure at the recommended human dose (AUC-based). In mice, the high dose was associated with an increased incidence of an external malformation (cleft palate) in the presence of maternal toxicity. In a pre- and post-natal development study in mice, pregnant animals were dosed with pacritinib from implantation through lactation at 30, 100, or 250 mg/kg/day. Maternal toxicity was noted at 250 mg/kg and associated with increased gestation length and dystocia, lowered mean birth weights and neonatal survival, and transiently delayed startle response, learning, and memory development at weaning.

8.2 Lactation Risk Summary There are no data on the presence of pacritinib in either human or animal milk, the effects on the breastfed child, or the effects on milk production. It is not known whether VONJO is excreted in human milk. Because of the potential for serious adverse reactions in the breastfed child, advise patients that breastfeeding is not recommended during treatment with VONJO, and for 2 weeks after the last dose.

8.3 Females and Males of Reproductive Potential Infertility Males Pacritinib reduced male mating and fertility indices in BALB/c mice [see Nonclinical Toxicology ( 13.1 )]. Pacritinib may impair male fertility in humans.

8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use Clinical studies of VONJO did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects.

8.6 Hepatic Impairment In patients with severe hepatic impairment [Child-Pugh C], the recommended dosage of VONJO 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. Monitor hepatically-impaired patients for adverse reactions and consider VONJO dose modifications based on safety and efficacy [see Dosage and Administration (2.5), Clinical Pharmacology ( 12.3 )]. No dose modification is recommended for patients with mild [Child-Pugh A] or moderate [Child-Pugh B] hepatic impairment [see Clinical Pharmacology ( 12.3 )].

8.7 Renal Impairment Administration of a single dose of VONJO 400 mg to subjects with renal impairment resulted in approximately 30% increase in C max and AUC of pacritinib in subjects with eGFR 15 to 29 mL/min and eGFR <15 mL/min on hemodialysis compared to subjects with normal renal function (eGFR ≥90 mL/min). Avoid use of VONJO in patients with eGFR <30 mL/min [see Clinical Pharmacology ( 12.3 )] .

Pacritinib is an oral kinase inhibitor with activity against wild type Janus associated kinase 2 (JAK2), mutant JAK2V617F, FMS-like tyrosine kinase 3 (FLT3), and interleukin 1 receptor associated kinase-1 (IRAK1) which contribute to signaling of a number of cytokines and growth factors that are important for hematopoiesis and immune function. Pacritinib is also an inhibitor of activin A receptor, type 1/activin receptor like-kinase 2 (ACVR1/ALK2). MF is often associated with dysregulated JAK2 signaling. At clinically relevant concentrations, pacritinib does not inhibit JAK1. Pacritinib has higher inhibitory activity for JAK2 compared to JAK3 and tyrosine kinase 2 (TYK2). Pacritinib exhibits inhibitory activity against additional cellular kinases, such as colony stimulating factor 1 receptor (CSF1R), of which the clinical relevance in myelofibrosis is unknown.