Brand Name
Vonjo
Generic Name
Pacritinib
View Brand Information FDA approval date: February 28, 2022
Classification: Kinase Inhibitor
Form: Capsule
What is Vonjo (Pacritinib)?
VONJO is indicated for the treatment of adults with intermediate or high-risk primary or secondary myelofibrosis with a platelet count below 50 × 10 9 /L. This indication is approved under accelerated approval based on spleen volume reduction [see Clinical Studies (1.
Approved To Treat
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Brand Information
Vonjo (Pacritinib)
1INDICATIONS 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).
2DOSAGE AND ADMINISTRATION
2.1Recommended 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.
2.2Monitoring 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.
2.3Missed 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.
2.4Dose 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.
2.5Dose 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.
3DOSAGE FORMS AND STRENGTHS
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”.
4CONTRAINDICATIONS
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)] .
5WARNINGS AND PRECAUTIONS
5.1Hemorrhage
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.
5.2Diarrhea
VONJO causes diarrhea in approximately 48% of patients compared to 15% of patients treated on the control arm. 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. None of the VONJO-treated patients reported diarrhea that resulted in treatment discontinuation. Serious diarrhea adverse reactions occurred in 2% of patients treated with VONJO compared to no such adverse reactions in patients in the control arm.
Control pre-existing diarrhea before starting VONJO treatment. Manage diarrhea with antidiarrheal medications, fluid replacement, and dose-modification. Treat diarrhea with anti-diarrheal medications promptly at the first onset of symptoms. Interrupt or reduce VONJO dose in patients with significant diarrhea despite optimal supportive care [see Dosage and Administration ( 2.5)] .
5.3Thrombocytopenia
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)] .
5.4Prolonged 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)] .
5.5Major 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.
5.6Thrombosis
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.
5.7Secondary 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.
5.8Risk 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.
5.9Interactions With CYP3A4 Inhibitors or Inducers
6ADVERSE 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)]
6.1Clinical 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.
7DRUG INTERACTIONS
7.1Effect of Other Drugs on VONJO
7.2Effect of VONJO on Other Drugs
8USE IN SPECIFIC POPULATIONS
8.1Pregnancy
8.2Lactation
8.3Females and Males of Reproductive Potential
8.4Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
8.5Geriatric 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.
8.6Hepatic Impairment
Administration of a single dose of VONJO 400 mg to subjects with hepatic impairment resulted in a decrease in the geometric mean AUC of pacritinib by 8.5%, 36%, and 45% in subjects with mild [Child-Pugh A], moderate [Child-Pugh B], or severe hepatic impairment [Child-Pugh C], respectively, compared to subjects with normal hepatic function.
Avoid use of VONJO in patients with moderate [Child-Pugh B] or severe hepatic impairment [Child-Pugh C] [see Clinical Pharmacology ( 12.3)] .
8.7Renal Impairment
Administration of a single dose of VONJO 400 mg to subjects with renal impairment resulted in approximately 30% increase in C maxand 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)] .
9OVERDOSAGE
Overdosage may lead to gastrointestinal toxicities, myelosuppression, blurred vision, dizziness, worsening performance status, and sepsis. There is no known antidote for overdose with VONJO. Hemodialysis is not expected to enhance the elimination of VONJO.
10DESCRIPTION
VONJO contains pacritinib citrate, a kinase inhibitor with the chemical name (2E,16E)-11-[2-(pyrrolidin-1-yl)ethoxy]-14,19-dioxa-5,7,27-triazatetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2,4,6,8,10,12(26),16,21,23-decaene citrate and a molecular weight of 664.7 as citrate salt and 472.59 as a free base. The molecular formula is C 28H 32N 4O 3•C 6H 8O 7and the structural formula is:
VONJO capsule is for oral administration. Each capsule contains 100 mg of pacritinib equivalent to 140.65 mg of pacritinib citrate and the inactive ingredients are microcrystalline cellulose NF, polyethylene glycol 8000 (PEG 8000) NF, and magnesium stearate NF. The gelatin capsule is bovine derived. The capsule shell contains gelatin, titanium dioxide, black iron oxide, erythrosine, red iron oxide, and printing ink containing shellac, propylene glycol, titanium dioxide, sodium hydroxide, and povidone.
11CLINICAL PHARMACOLOGY
11.1Mechanism of Action
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.
11.2Pharmacodynamics
Pacritinib inhibited the phosphorylation of signal transducer and activator of transcription 5 (STAT5) protein in a dose-dependent manner (ex vivo) in expanded erythroid progenitor cells derived from healthy subjects. Administration of single doses of 400 mg pacritinib resulted in modest inhibition of interleukin-6-induced STAT3 phosphorylation in whole blood derived from healthy subjects.
11.3Pharmacokinetics
Pacritinib steady-state mean (CV%) C maxis 8.4 mg/L (32.4%) and AUC 0-12is 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.
12NONCLINICAL TOXICOLOGY
12.1Carcinogenesis, Mutagenesis, and Impairment of Fertility
Pacritinib was not carcinogenic in the 6-month Tg.rasH2 transgenic mouse model. Pacritinib was not carcinogenic in a 2-year carcinogenicity study in rats at 0.004 times and 0.014 times, in males and females, respectively, the recommended human dose (AUC-based). Pacritinib exposures achieved in mice and rats during the carcinogenicity assessments were considerably lower than the exposure observed at the recommended human dose.
Pacritinib was not mutagenic in a bacterial mutagenicity assay (Ames test) or clastogenic in vitro in a chromosomal aberration assay (Chinese hamster ovary cells) or in vivo in a micronucleus test in mice.
In a fertility study in male BALB/c mice, pacritinib was administered for at least 70 days prior to cohabitation with untreated partners. Pacritinib had no effects at any dose level on uterine implantation, macroscopic findings, reproductive organ weights, and sperm evaluations. At 213.4 mg/kg/day (3.0 times, the recommended human dose, based on body surface area), reduced mating and fertility indices were observed in male BALB/c mice. In a fertility and early embryonic development study in CD-1 mice, no effects on male or female reproductive performance, including assessments of mating, fertility, estrous cyclicity, and intrauterine survival, were observed at doses up to 250 mg/kg/day (3.0 times, the recommended human dose, based on body surface area).
13CLINICAL STUDIES
14HOW SUPPLIED/STORAGE AND HANDLING
14.1How Supplied
VONJO is supplied in the following strength and package configuration:
14.2Storage
Store at room temperature, below 30°C (86°F). Keep the bottle tightly closed and protect from light. Store in original package. Dispense in original package or in a light-resistant container.
15PATIENT COUNSELING INFORMATION
Discuss the following with the patient prior to and during treatment with VONJO:
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