Vonjo
(Pacritinib)
Dosage & Administration
Vonjo Prescribing Information
Warnings and Precautions (
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
- Recommended dosage is 200 mg orally twice daily ( ).
2.1 Recommended DosageThe 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.
- May be taken with or without food ( ).
2.1 Recommended DosageThe 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.
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”.
Lactation: Advise not to breastfeed (
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.
Hepatic Impairment: For patients with severe hepatic impairment (Child-Pugh C), the recommended dosage is 100 mg twice daily (
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
No dose modification is recommended for patients with mild [Child-Pugh A] or moderate [Child-Pugh B] hepatic impairment
Renal Impairment: Avoid use in patients with eGFR <30 mL/min (
Administration of a single dose of VONJO 400 mg to subjects with renal impairment resulted in approximately 30% increase in Cmaxand 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
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
Serious (11%) and fatal (2%) hemorrhages have occurred in VONJO-treated patients with platelet counts <100 x 109/L. Serious (13%) and fatal (2%) hemorrhages have occurred in VONJO-treated patients with platelet counts <50 x 109/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
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 109/L). VONJO dosing was reduced due to worsening thrombocytopenia in 2% of patients with pre-existing severe thrombocytopenia (platelet count <50 x 109/L).
Monitor platelet count prior to VONJO treatment and as clinically indicated during treatment
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
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
Co-administration of VONJO with strong CYP3A4 inhibitors is contraindicated
Monitor patients concomitantly receiving moderate CYP3A4 inhibitors (e.g., fluconazole) for increased adverse reactions and consider VONJO dose modifications based on safety
Pacritinib is predominantly metabolized by CYP3A4. Concomitant use of VONJO with strong CYP3A4 inducers decreases pacritinib exposure, which may reduce efficacy of VONJO
Co-administration of VONJO with strong CYP3A4 inducers is contraindicated
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.
Pacritinib achieves Cmaxwithin approximately 4 to 5 hours post-dose.
There was no significant effect of food on the pharmacokinetics of pacritinib following oral administration of VONJO 200 mg with a high-fat meal.
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%.
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.
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%).
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.
No clinically significant differences in the pharmacokinetics of pacritinib were observed based on age, sex, body weight, or race.
Pacritinib Cmaxand 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 Cmaxand AUC increased approximately 30% in subjects with eGFR 15 to 29 mL/min and eGFR <15 mL/min on hemodialysis.
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).
Hepatic impairment | Ratio (90% CI) of pacritinib exposure1 | |
Unbound Cmax | Unbound AUC0-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: AUC0-tau= Area under the curve from zero to tau post-dose after 14 days twice daily dosing with VONJO 200 mg; CI = Confidence Interval; Cmax= Maximum plasma concentration.
1Ratios for Cmaxand 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.
The effect of co-administered drugs on the exposure of pacritinib is shown in Table 7 and Table 8.
Co-administered Drug | Regimen of Co-administered Drug | Ratio (90% CI) of pacritinib exposure1 | |
Cmax | AUC0-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: AUC0-t= Area under the curve from zero to the last quantifiable concentration; CI = Confidence interval; CYP = Cytochrome P450
1Ratios for Cmaxand AUC compare co-administration of the medication with VONJO vs. administration of single dose 400 mg VONJO alone
Co-administered Drug | Regimen of Co-administered Drug | Ratio (90% CI) of pacritinib exposure1 | |
Cmax | AUC0-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: AUC0-tau= Area under the curve for a dosing interval; BID = Twice daily; CI = Confidence interval; Cmax= Maximum plasma concentration; CYP = Cytochrome P450.
1Ratios 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.
The effect of pacritinib on the exposure of other co-administered drugs is shown in Table 9.
Co-administered Drug | Regimen of Co-administered Drug (single dose) | Ratio (90% CI) of exposure of co-administered drug1 | |
Cmax | 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) |
1Ratios for Cmaxand 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.
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.
Co-administered Drug | Regimen of Co-administered Drug (single dose) | Ratio (90% CI) of exposure of co-administered drug1 | |
Cmax | 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; Cmax= Maximum plasma concentration; CYP = Cytochrome P450
1Ratios for Cmaxand 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.
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.