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warnings and cautions
5 WARNINGS AND PRECAUTIONS 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. If one or more of these signs and symptoms occur after discontinuation of VONJO, evaluate for and treat any intercurrent illness and consider restarting VONJO. Instruct patients not to interrupt or discontinue therapy without consulting their healthcare provider. When discontinuing or interrupting therapy with VONJO for reasons other than potentially life-threatening toxicities, consider tapering the dose of VONJO gradually rather than discontinuing abruptly [see Dosage and Administration ( 2.5 )] . 5.10 Interactions With CYP3A4 Inhibitors or Inducers Co-administration of VONJO with strong CYP3A4 inhibitors or inducers is contraindicated. Monitor for increased adverse reactions of VONJO when administered with moderate CYP3A4 inhibitors [see Contraindications ( 4 ), Drug Interactions ( 7.1 ), 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 )] 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)