DRUG INTERACTIONS-(summary)

 Avoid use with moderate CYP3A4 inhibitors or inducers 

Coadministration of VONJO can alter the concentration of drugs that are Pgp, BCRP, or OCT1 substrates. Avoid use with sensitive substrates 

DRUG INTERACTIONS-(details)

1. Effect of Other Drugs on VONJO Strong and Moderate CYP3A4 inhibitors VONJO is predominantly metabolized by CYP3A4.

In a clinical drug interaction study, a single-dose of VONJO 400 mg was administered following treatment with clarithromycin, a strong CYP3A4 inhibitor. Clarithromycin was administered as 500 mg twice daily for 5 days, which is a submaximal regimen for CYP3A4 inhibition.

Compared to VONJO administered alone, the area under the concentration curve (AUC) and maximal concentration (Cmax) of pacritinib increased by 80% and 30%, respectively, upon coadministration with clarithromycin 

 The increase in exposure to pacritinib may be even higher when tested following a longer treatment with clarithromycin that results in maximal CYP3A4  inhibition.

The impact of moderate CYP3A4 inhibitors on the pharmacokinetics of VONJO has not been investigated in clinical studies.

Co-administration of VONJO with strong CYP3A4 inhibitors is contraindicated.

Avoid concomitant use of VONJO with moderate CYP3A4 inhibitors

1.Strong and Moderate CYP3A4 inducers In a clinical drug interaction study, a single-dose of VONJO 400 mg was administered following treatment with rifampin, a strong CYP3A4 inducer, at 600 mg once daily for 10 days.

Compared to VONJO administered alone, the AUC and Cmax of pacritinib decreased by 87% and 51%, respectively, upon coadministration with rifampin 

The impact of moderate CYP3A4 inducers on the pharmacokinetics of VONJO has not been investigated in clinical studies.

Co-administration of VONJO with strong CYP3A4 inducers is contraindicated.

Avoid concomitant use of VONJO with moderate CYP3A4 inducers .

2 Effect of VONJO on Other Drugs CYP1A2 or CYP3A4 substrates VONJO is an inhibitor of CYP1A2 and CYP3A4 in vitro. Concomitant administration of VONJO with CYP1A2 or CYP3A4 substrates may increase the plasma concentrations of these substrates.

Avoid co-administration of VONJO with drugs that are sensitive substrates of CYP1A2 or CYP3A4]. P-gp, BCRP, or OCT1 Substrates VONJO is an inhibitor of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and organic cation transporter 1 (OCT1) in vitro.

Concomitant administration of VONJO with P-gp, BCRP, or OCT1 substrates may increase the plasma concentrations of these substrates. Avoid co-administration of VONJO with drugs that are sensitive substrates of P-gp, BCRP, or OCT1 

BRIEF SUMMARY-

PACRITIB-(Feb 2022)

Indn- To treat Intermediate or High Risk Primary or  Secondary myeloFibrosis in Adults with low  Platelet                                                                                                                    

 Dosage-  Capsules: 100 mg • Recommended dosage is 200 mg orally twice daily.   May be taken with or without food 

ADR-  The most common (=20% of patients) adverse reactions are diarrhea, thrombocytopenia, nausea, anemia, and peripheral edema 

CI- Concomitant use of strong CYP3A4 inhibitors or inducers

 WARNINGS--

 Hemorrhage: Avoid use in patients with active bleeding and hold prior to any planned surgical procedures.

May require dose interruption, dose reduction or permanent discontinuation depending on severity.                                                                                                                 Diarrhea: Manage significant diarrhea with anti-diarrheals, dose reduction, or dose interruption

Pat inform-

Current therapy with another kinase inhibitor-  Advise patients who are currently taking a kinase inhibitor that they must taper or discontinue their current kinase inhibitor therapy according to the package insert for that drug prior to starting the drug

Hemorrhage-  Advise patients that VONJO can cause hemorrhage and instruct them to consult their healthcare provider right away if bleeding occurs.

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U.S. FDA APPROVED DRUGS SURING 2022                                        

Serial No 7

Name of the Drug-    VONJO

Active Ingredient -   Pacritinib

Pharmacological Classification- To treat Intermediate or High Risk Primary or                                                                Secondary myeloFibrosis in Adults with low                                                                  Platelet                                                                                                                                                                                               

 Date of Approval-          2/28/22  

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use                                      VONJO safely and effectively.   See full prescribing information for VONJO.         VONJO™ (pacritinib) capsules, for oral use

Initial U.S. Approval: 2022

INDICATIONS AND USAGE

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 × 109 /L 

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).

DOSAGE AND ADMINISTRATION

 • Recommended dosage is 200 mg orally twice daily 

• May be taken with or without food 

DOSAGE FORMS AND STRENGTHS-                                                                      Capsules: 100 mg

ADVERSE REACTIONS-

 The most common (=20% of patients) adverse reactions are diarrhea, thrombocytopenia, nausea, anemia, and peripheral edema 

 CONTRAINDICATIONS-

 Concomitant use of strong CYP3A4 inhibitors or inducers

 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

• Diarrhea: Manage significant diarrhea with anti-diarrheals, dose reduction, or dose interruption

• Thrombocytopenia: Manage by dose reduction or interruption

 • 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

 • 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

 • Thrombosis: Including deep venous thrombosis, pulmonary embolism, and arterial thrombosis may occur. Monitor for signs, evaluate and treat promptly

• Secondary Malignancies: Lymphoma and other malignancies may occur. Past/current smokers may be at increased risk

 • Risk of Infection: Delay starting VONJO until active serious infections have resolved. Observe for signs and symptoms of infection and manage promptly 

DOSAGE AND ADMINISTRATION

 • Recommended dosage is 200 mg orally twice daily 

• May be taken with or without food 

DOSAGE FORMS AND STRENGTHS-                                                                      Capsules: 100 mg

PATIENT COUNSELING INFORMATION

See FDA approved patient labeling (Patient Information)

 Discuss the following with the patient prior to and during treatment with VONJO:

Current therapy with another kinase inhibitor-                                                      Advise patients who are currently taking a kinase inhibitor that they must taper or discontinue their current kinase inhibitor therapy according to the package insert for that drug prior to starting VONJO.

Hemorrhage-                                                                                                            Advise patients that VONJO can cause hemorrhage and instruct them to consult their healthcare provider right away if bleeding occurs.

Advise patients about how to recognize bleeding and of the urgent need to report any unusual bleeding to their physician.

Patients should urgently seek emergency medical attention for any bleeding that cannot be stopped 

Diarrhea-                                                                                                                        Advise patients that VONJO can cause diarrhea.

Advise patients to stay hydrated while taking VONJO and to inform their physician if they experience diarrhea. Instruct patients to initiate anti-diarrheal medications (e.g., loperamide) if diarrhea occurs.

Advise patients to urgently seek emergency medical attention if diarrhea becomes severe.

Thrombocytopenia-                                                                                                 Advise patients that VONJO can cause thrombocytopenia, and of the need to monitor complete blood counts before and during treatment .

 Prolonged QT Interval-                                                                                           Advise patients to consult their healthcare provider immediately if they feel faint, lose consciousness, or have signs or symptoms suggestive of arrhythmia.

Advise patients with a history of hypokalemia of the importance of monitoring their electrolytes 

Major Adverse Cardiac Events -                                                                           (MACE) Advise patients that events of major adverse cardiac events (MACE) including myocardial infarction, stroke, and cardiovascular death, have been reported in clinical studies with another JAK-inhibitor used to treat rheumatoid arthritis, a condition for which VONJO is not indicated.

Advise patients, especially current or past smokers or patients with other cardiovascular risk  factors, to be alert for the development of signs and symptoms of cardiovascular events.

Thrombosis-                                                                                                             Advise patients that events of deep vein thrombosis and pulmonary embolism have been reported in clinical studies with another JAK-inhibitor used to treat rheumatoid arthritis, a condition for which VONJO is not indicated.

Advise patients to tell their healthcare provider if they develop any signs or symptoms of a DVT or PE 

Secondary Malignancies-                                                                                        Advise patients, especially current or past smokers and patients with a known secondary malignancy (other than a successfully treated NMSC), that lymphoma and other malignancies (excluding NMSC) have been reported in clinical studies with another JAK-inhibitor used to treat rheumatoid arthritis, a condition for which VONJO is not indicated.

Infections -                                                                                                                    Advise patients that treatment with another JAK-inhibitor has increased the risk of serious infections in patients with myeloproliferative neoplasms and that serious bacterial, mycobacterial, fungal and viral infections may occur in patients treated with VONJO.

Inform patients of the signs and symptoms of infection and to report any such signs and symptoms promptly.

Nausea and Vomiting-                                                                                                Advise patients that nausea and vomiting may occur during treatment with VONJO. Instruct them on how to manage nausea and vomiting and to immediately inform their healthcare provider if nausea/vomiting become severe.

Drug–Drug Interactions-                                                                                                Advise patients to inform their healthcare providers of all medications they are taking, including prescription and over-the-counter medications, vitamins, herbal products, and dietary supplements [see Drug Interactions (7)].

Dosing Advise patients to take VONJO twice a day, with or without food or drink. VONJO should be taken at similar times each day.

Instruct patients to swallow the VONJO capsules whole and not to open, break, or chew the capsules [see Dosage and Administration (2.1)]. 18 Reference ID: 4944746

Instruct patients that if they miss a dose of VONJO, to skip the dose and take the next dose when it is due and return to the normal schedule .

Warn patients not to take 2 doses to make up for the missed dose. Instruct patients to discontinue VONJO 7 days prior to any surgery or invasive procedures (such as cardiac catheterization, coronary stenting or varicose vein ablation) due to the risk of bleeding and to only restart VONJO on the instruction of their healthcare provider.

Patients should not change or stop taking VONJO without first consulting their physician.

Lactation-                                                                                                                 Advise patients to avoid breastfeeding while taking VONJO and for 2 weeks after the final dose .

Manufactured and marketed by: CTI BioPharma Corp. 3101 Western Ave #800 Seattle, WA 98121 VONJO is a trademark of CTI BioPharma Corp. All rights reserved. ©2022 All rights reserved.

 CLINICAL PHARMACOLOGY

1. Mechanism of Action-                                                                                         Pacritinib is an oral kinase inhibitor with activity against wild type Janus associated kinase 2 (JAK2), mutant JAK2V617F, and FMS-like tyrosine kinase 3 (FLT3), which contribute to signaling of a number of cytokines and growth factors that are important for hematopoiesis and immune function. MF is often associated with dysregulated JAK2 signaling.

2. Pharmacodynamics-                                                                                              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.

Cardiac Electrophysiology -                                                                                           In a 24-week study of 54 patients with MF treated with VONJO 200 mg twice daily, the maximum mean (90% confidence interval) change in QTcF from baseline was 11 (90% CI: 5-17) msec.

3. Pharmacokinetics-                                                                                                    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.

Absorption-                                                                                                                   Pacritinib achieves Cmax within approximately 4 to 5 hours post-dose.

Effect of Food-                                                                                                           There was no significant effect of food on the pharmacokinetics of pacritinib following oral administration of VONJO 200 mg with a high-fat meal.

Distribution-                                                                                                                  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%.

Metabolism-                                                                                                                    Pacritinib is predominantly metabolized by the CYP3A4 isozyme. Pacritinib is the major circulating component and the pharmacologic activity is mainly attributed to the parent 12 Reference ID: 4944746 molecule.

Two major metabolites, M1 and M2, in human whole plasma represent 9.6% and 10.5% of parent drug exposure, respectively.

Elimination 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%).

Excretion-                                                                                                                        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.

Specific Populations-                                                                                                    No clinically significant differences in the pharmacokinetics of pacritinib were observed based on age, sex, body weight, or race.

Patients With Renal Impairment-                                                                                       Pacritinib Cmax and 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 Cmax and AUC increased approximately 30% in subjects with eGFR 15 to 29 mL/min and eGFR <15 mL/min on hemodialysis.

Patients With Hepatic Impairment-                                                                                   The effect of hepatic impairment on the pharmacokinetics of pacritinib was studied in 28 healthy subjects with normal or impaired hepatic function after a single VONJO 400 mg dose.

Compared to subjects with normal hepatic function, the geometric mean AUC of pacritinib decreased 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.

The geometric mean Cmax to pacritinib decreased by 22%, 47%, and 57% 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.

USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary-                                                                                   There are no available data on VONJO use in pregnant women to evaluate for a drug-associated

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.

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.

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 

Pacritinib may impair male fertility in humans.

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

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

6. Hepatic 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].

7. Renal Impairment -                                                                                          Administration of a single dose of VONJO 400 mg to subjects with renal impairment resulted in approximately 30% increase in Cmax 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.

OVERDOSAGE -

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.