PACRITINIB Drug Interactions: What You Need to Know

INTERACTIONS 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> Co-administration of VONJO with strong CYP3A4 inhibitors is contraindicated <span class="opacity-50 text-xs">[see Contraindications ( 4 )]</span>. Monitor patients concomitantly receiving moderate CYP3A4 inhibitors (e.g., fluconazole) for increased adverse reactions and consider VONJO dose modifications based on safety <span class="opacity-50 text-xs">[see Dose Modifications for Adverse Reactions ( 2.5 )]</span> . 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> . Co-administration of VONJO with strong CYP3A4 inducers is contraindicated <span class="opacity-50 text-xs">[see Contraindications ( 4 )]</span>.

7.2 Effect of VONJO on Other Drugs CYP1A2 Substrates Pacritinib is an inhibitor of CYP1A2. VONJO increases the plasma concentrations of CYP1A2 substrates <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> ,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 <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> , 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> , 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 )] .

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 )

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 ).

5.1 Hemorrhage Serious (11%) and fatal (2%) hemorrhages have occurred in VONJO-treated patients with platelet counts &lt;100 x 10 9 /L. Serious (13%) and fatal (2%) hemorrhages have occurred in VONJO-treated patients with platelet counts &lt;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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.3 )]</span> . Manage hemorrhage using treatment interruption and medical intervention <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.5 )]</span> .

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 <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.5 )]</span> .

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 &lt;100 x 10 9 /L). VONJO dosing was reduced due to worsening thrombocytopenia in 2% of patients with pre-existing severe thrombocytopenia (platelet count &lt;50 x 10 9 /L). Monitor platelet count prior to VONJO treatment and as clinically indicated during treatment <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.2 )]</span> . 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 <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.5 )]</span> .

5.4 Prolonged QT Interval VONJO can cause prolongation of the QTc interval. QTc prolongation of &gt;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 &gt;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 <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.5 )]</span> .

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 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 <span class="opacity-50 text-xs">[see Contraindications ( 4 ), Drug Interactions ( 7.1 ), and Clinical Pharmacology ( 12.3 )]</span>.