Introduction

Antineoplastic agent; selective inhibitor of Janus kinase (JAK) 2, mutant JAK2^V617F, and FMS-like tyrosine kinase (FLT) 3.

Uses for Pacritinib (Systemic)

Intermediate- or High-Risk Myelofibrosis

Treatment of adults with intermediate- or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis with a platelet count <50,000/mm³.

Approved under accelerated approval based on proportion of patients achieving ≥35% reduction from baseline in spleen volume; continued approval may be contingent upon verification and description of clinical benefit in confirmatory trials(s).

Designated an orphan drug by FDA for this use.

Myelofibrosis drug treatment is based upon prognostic risk models. Observation alone is advised for asymptomatic low-risk patients; for patients with higher-risk disease, allogeneic hematopoietic stem cell transplant (ASCT) is the preferred treatment. In patients who are not candidates for transplant, JAK inhibitors (i.e., ruxolitinib, pacritinib, fedratinib) may be used to provide symptom-based management and improve quality of life.

The first JAK inhibitors approved for myelofibrosis (e.g., ruxolitinib, feratinib) are associated with significant risks of hematologic toxicities. Pacritinib is an additional therapeutic option for patients with symptomatic myelofibrosis who have severe thrombocytopenia. Specific indications and toxicity profiles of the currently available JAK2 inhibitors differ; treatment should be individualized.

Pacritinib (Systemic) Dosage and Administration

General

Pretreatment Screening

• Perform CBC including WBC differential and platelet count.

• Perform coagulation testing (prothrombin time [PT], activated partial thromboplastin time [aPTT], thrombin time [TT], and international normalized ratio [INR]).

• Perform baseline ECG.

Patient Monitoring

• Monitor CBC including WBC differential and platelet count as clinically indicated during drug therapy.

• Monitor ECG as clinically indicated during drug therapy.

• Monitor for signs or symptoms of infection during drug therapy.

Other General Considerations

• Discontinue or taper other kinase inhibitors according to the specific prescribing information for that drug before pacritinib initiation.

• Discontinue pacritinib 7 days prior to elective surgery or invasive procedures because of the risk of hemorrhage; resume drug only after hemostasis is assured.

Administration

Oral Administration

Administer orally; take with or without food.

Swallow whole; do not open, break, or chew the capsules.

If a dose is missed, the dose should be taken at the next scheduled time. Do not take an additional dose.

Dosage

Available as pacritinib citrate; dosage expressed in terms of pacritinib.

Adults

Intermediate- or High-Risk Myelofibrosis

Oral

200 mg twice daily.

Dosage Modification for Toxicity

Oral

If adverse reactions occur during pacritinib therapy, temporary interruption of therapy, dosage reduction, and/or discontinuance of the drug may be necessary. If dosage reduction is required, the dosage of pacritinib should be reduced as described in Table 1.

The following table indicates the recommended dosage modification (i.e., temporary interruption of therapy, dosage reduction, discontinuance of therapy) for certain adverse effects according to severity.

Special Populations

Hepatic Impairment

No specific dosage recommendations for patients with hepatic impairment.

Patients with Child-Pugh class B: Avoid use.

Patients with Child-Pugh class C: Avoid use.

Renal Impairment

No specific dosage recommendations for patients with renal impairment.

Patients with eGFR (MDRD) <30 mL/minute: Avoid use.

Geriatric Use

No specific dosage recommendations for geriatric patients.

Contraindications

• Concomitant use of strong CYP3A4 inhibitors or inducers.

Warnings/Precautions

Hemorrhage

Serious and fatal hemorrhage reported in patients with platelet counts <100,000/mm³.

Dosage reduction, interruption, or permanent discontinuation may be required.

Avoid use in patients with active bleeding.

Hold 7 days prior to any planned surgical or invasive procedures.

Assess platelet counts periodically, as clinically indicated.

Manage hemorrhage using treatment interruption and medical intervention.

Diarrhea

Diarrhea occurs frequently; median time to resolution was 2 weeks. Incidence decreases over time; treatment interruption may be necessary.

Control pre-existing diarrhea before starting treatment. Manage with antidiarrheal medications, fluid replacement, and dosage modification.

Treat with antidiarrheal medications promptly at the first onset of symptoms. Interrupt or reduce dosage in patients with significant diarrhea despite optimal supportive care.

Thrombocytopenia

Worsening thrombocytopenia reported. Pacritinib interruption and dosage reduction may be required.

Monitor platelet count prior to treatment and as clinically indicated during treatment.

Interrupt pacritinib in patients with clinically significant worsening of thrombocytopenia that lasts for >7 days. Once the toxicity has resolved, restart at 50% of the last given dosage.

If toxicity recurs, hold pacritinib; resume the drug at 50% of the last given dose once the toxicity has resolved.

Prolonged QT Interval

Can cause prolongation of the QT_c interval. QT_c prolongation of >500 msec or increase from baseline by ≥60 msec was higher in pacritinib-treated patients than patients in the control group.

Adverse reactions related to QT_c prolongation reported; no cases of torsades de pointes reported.

Avoid use in patients with a baseline QT_c of >480 msec. Avoid concomitant use of drugs with significant potential for QT_c prolongation.

Correct hypokalemia prior to and during treatment. Manage QT_c prolongation with dose interruption and electrolyte management.

Major Adverse Cardiac Events (MACE)

Increased risk of major adverse cardiovascular events (MACE), including cardiovascular death, MI, and stroke, reported in patients receiving other JAK inhibitors for the treatment of rheumatoid arthritis.

Consider risks and benefits of pacritinib prior to initiating or continuing therapy, particularly in patients who are current or past smokers and in those with other cardiovascular risk factors. Advise patient to seek immediate medical attention if symptoms of serious cardiovascular events occur.

Thromboembolic Events

Serious and sometimes fatal thromboembolic events, including DVT, PE, and arterial thrombosis in the extremities, reported in patients receiving other JAK inhibitors for the treatment of rheumatoid arthritis.

Promptly evaluate and treat any patients who develop symptoms of thrombosis during treatment with pacritinib.

Secondary Malignancies

Another JAK inhibitor increased risk of lymphoma and other malignancies, excluding non-melanoma skin cancer (NMSC), in patients with rheumatoid arthritis.

Consider risks and benefits of pacritinib prior to initiating therapy or when considering whether to continue pacritinib, particularly in patients with a known malignancy (other than successfully treated NMSC), in those who develop a malignancy, and those who are current or past smokers.

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.

Resolve active serious infections prior to initiating pacritinib. Observe patients for signs and/or symptoms of infection and promptly initiate appropriate treatment.

Employ active surveillance and prophylactic antibiotics according to clinical guidelines.

Interactions with CYP3A4 Inhibitors or Inducers

Concomitant use with strong CYP3A4 inhibitors or inducers contraindicated.

Avoid concomitant use with moderate CYP3A4 inhibitors or inducers.

Specific Populations

Pregnancy

Animal studies revealed maternal toxicity and embryonic and fetal loss at dosages considerably lower than the recommended human dose.

No available human data to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes related to the use of pacritinib.

Advise pregnant women of the potential risk to a fetus. Consider benefits and risks of pacritinib for the mother and possible risks to the fetus when prescribing pacritinib to a pregnant woman.

Lactation

No data on presence of pacritinib in either human or animal milk, effects on the breast-fed child, or effects on milk production.

Females should not breast-feed while receiving the drug, and for at least 2 weeks after the last dose.

Females and Males of Reproductive Potential

Reduced male mating and fertility in mice. Pacritinib may impair male fertility in humans.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

Experience in patients ≥65 years of age is insufficient to determine whether geriatric patients respond differently than younger individuals.

Hepatic Impairment

Mild (Child-Pugh class A): AUC decreased by 8.5%.

Moderate (Child-Pugh class B): AUC decreased by 36%. Avoid use.

Severe hepatic impairment (Child-Pugh class C): AUC decreased by 45%. Avoid use.

Renal Impairment

eGFR 15 to 29 mL/minute: Peak plasma concentration and AUC of pacritinib increased by approximately 30%. Avoid use.

eGFR <15 mL/minute on hemodialysis: Peak plasma concentration and AUC of pacritinib increased by approximately 30%. Avoid use.

Common Adverse Effects

Adverse effects (≥20%): Diarrhea, thrombocytopenia, nausea, anemia, peripheral edema.

General

Pretreatment Screening

• Perform CBC including WBC differential and platelet count.

• Perform coagulation testing (prothrombin time [PT], activated partial thromboplastin time [aPTT], thrombin time [TT], and international normalized ratio [INR]).

• Perform baseline ECG.

Patient Monitoring

• Monitor CBC including WBC differential and platelet count as clinically indicated during drug therapy.

• Monitor ECG as clinically indicated during drug therapy.

• Monitor for signs or symptoms of infection during drug therapy.

Other General Considerations

• Discontinue or taper other kinase inhibitors according to the specific prescribing information for that drug before pacritinib initiation.

• Discontinue pacritinib 7 days prior to elective surgery or invasive procedures because of the risk of hemorrhage; resume drug only after hemostasis is assured.

Administration

Oral Administration

Administer orally; take with or without food.

Swallow whole; do not open, break, or chew the capsules.

If a dose is missed, the dose should be taken at the next scheduled time. Do not take an additional dose.

Dosage

Available as pacritinib citrate; dosage expressed in terms of pacritinib.

Adults

Intermediate- or High-Risk Myelofibrosis

Oral

200 mg twice daily.

Dosage Modification for Toxicity

Oral

If adverse reactions occur during pacritinib therapy, temporary interruption of therapy, dosage reduction, and/or discontinuance of the drug may be necessary. If dosage reduction is required, the dosage of pacritinib should be reduced as described in Table 1.

The following table indicates the recommended dosage modification (i.e., temporary interruption of therapy, dosage reduction, discontinuance of therapy) for certain adverse effects according to severity.

Special Populations

Hepatic Impairment

No specific dosage recommendations for patients with hepatic impairment.

Patients with Child-Pugh class B: Avoid use.

Patients with Child-Pugh class C: Avoid use.

Renal Impairment

No specific dosage recommendations for patients with renal impairment.

Patients with eGFR (MDRD) <30 mL/minute: Avoid use.

Geriatric Use

No specific dosage recommendations for geriatric patients.

Metabolized mainly by CYP3A4.

Pacritinib inhibits CYP1A2, 2C19 and 3A4 and to a lesser extent CYP1A2, 2B6, 2C8, 2C9, and 2D6.

Pacritinib is an inducer of CYP1A2 and 3A4.

Pacritinib is not a substrate of breast cancer resistance protein (BCRP), multidrug resistance-associated protein (MRP) 2, organic anion-transporters (OAT) 1 and 3, organic anion-transporting polypeptides (OATP) 1B1 and 1B3, organic cation transporters (OCT) 1 and 2, or P-glycoprotein (P-gp).

Pacritinib is an inhibitor of BCRP, OCT1, OCT2, and P-gp, but not an inhibitor of bile salt export pump (BSEP), MRP2, OAT1, or OAT3.

Drugs Affecting Hepatic Microsomal Enzymes

Potent CYP3A4 inhibitors: Pharmacokinetic interaction (increased pacritinib peak plasma concentrations and AUC). Concomitant use is contraindicated.

Moderate CYP3A4 inhibitors: Pharmacokinetic interaction not studied. Avoid.

Potent CYP3A4 inducers: Pharmacokinetic interaction (decreased pacritinib peak plasma concentrations and AUC). Concomitant use is contraindicated.

Moderate CYP3A4 inducers: Pharmacokinetic interaction not studied. Avoid.

Drugs Metabolized by Hepatic Microsomal Enzymes

CYP1A2 substrates: Pharmacokinetic interaction (increased substrate plasma concentration). Avoid co-administration.

CYP 3A4 substrates: Pharmacokinetic interaction (increased substrate plasma concentration). Avoid co-administration.

Drugs Affecting or Affected by Transport Systems

P-gp substrates: Pharmacokinetic interaction (increased substrate plasma concentration). Avoid co-administration.

BCRP substrates: Pharmacokinetic interaction (increased substrate plasma concentration). Avoid co-administration.

OCT1 substrates: Pharmacokinetic interaction (increased substrate plasma concentration). Avoid co-administration.

Drugs Associated with QT Prolongation

Avoid co-administration of drugs with significant potential for QT_c prolongation with pacritinib.

Specific Drugs and Foods