Dosing & Uses
Dosage Forms & Strengths
capsule
- 100mg
Myelofibrosis
Indicated for adults with intermediate or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis (MF) with a platelet count <50 x 109/L
200 mg PO BID
Dosage Modifications
Dose reductions for adverse reactions
- First dose reduction: Reduce to 100 mg BID
- Second dose reduction: Reduce to 100 mg qDay
- Unable to tolerate 100 mg qDay: Discontinue treatment
Planned surgical procedures or other interventions
- Discontinue 7 days before elective surgery or invasive procedures, owing to risk of hemorrhage, and restart only after hemostasis is assured
Diarrhea
- New onset: Initiate antidiarrheal medications; encourage adequate oral hydration
-
Grade 3 or 4
- Defined as increase of ≥7 stools/day over baseline, or hospitalization indicated, or severe increase in ostomy output over baseline, or if limiting self-care
- Hold until diarrhea resolves to Grade ≤1 or baseline (increase of <4 stools/day or mild increase in ostomy output compared with baseline), then restart at last given dose
- Intensify antidiarrheal regimen and provide fluid replacement
- If recurs, hold until diarrhea resolves to Grade ≤1 or baseline, then restart at 50% of last given dose
- Concomitant antidiarrheal treatment is required if restarting
Thrombocytopenia
- In clinically significant worsening of thrombocytopenia lasting >7 days
- Hold therapy until resolution; restart at 50% of last given dose once resolved
- If recurs, hold therapy until resolution, then restart at 50% of last given dose
Hemorrhage
- Moderate bleeding (intervention indicated): Hold until hemorrhage resolves, then restart at last given dose; if recurs, hold until resolution, then restart at 50% of last given dose
- Severe bleeding (transfusion, invasive intervention, or hospitalization indicated): Hold until hemorrhage resolves, then restart at 50% of last given dose; if recurs, discontinue therapy
- Life-threatening bleeding (urgent intervention indicated): Discontinue therapy
QTc prolongation
- QTc prolongation >500 msec or >60 msec from baseline: Hold until QTc interval resolves to ≤480 msec or baseline within 1 week, then restart at same dose
- If time to resolution >1 week, restart at reduced dose
Renal impairment
- eGFR ≥30 mL/min: No dosage adjustment necessary
- eGFR <30 mL/min: Avoid use
Hepatic impairment
- Mild (Child-Pugh A): Decreases AUC by 8.5%; no dosage adjustment necessary
- Moderate or severe (Child-Pugh B or C): Avoid use; decreases AUC by 36% and 45% respectively
Dosing Considerations
- Before initiating, patients who are on treatment with other kinase inhibitors must taper or discontinue according to the prescribing information for that drug
-
Monitor parameters at baseline and as clinically indicated
- Complete blood count (CBC; including white blood cell count differential and platelet count)
- Coagulation testing (prothrombin time [PT], partial thromboplastin time, thrombin time, and international normalized ratio [INR])
- Electrocardiogram (ECG)
Safety and efficacy not established
Interactions
Interaction Checker
No Results
Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor
Adverse Effects
>10%
All grades
- Diarrhea (48%)
- Thrombocytopenia (34%)
- Nausea (32%)
- Anemia (24%)
- Peripheral edema (20%)
- Vomiting (19%)
- Dizziness (15%)
- Pyrexia (15%)
- Epistaxis (12%)
Grade ≥3
- Thrombocytopenia (32%)
- Anemia (22%)
1-10%
All grades
- Dyspnea (10%)
- Pruritus (10%)
- Upper respiratory tract infection (10%)
- Cough (8%)
Grade ≥3
- Epistaxis (5%)
- Diarrhea (4%)
- Pruritus (2%)
- Cough (2%)
- Nausea (1%)
- Peripheral edema (1%)
- Dizziness (1%)
- Pyrexia (1%)
Warnings
Contraindications
Coadministration with strong CYP3A4 inhibitors or inducers
Cautions
May worsen thrombocytopenia; monitor platelet count before initiating and as clinically indicated during treatment
Manage QTc prolongation using interruption and electrolyte management
Serious bacterial, mycobacterial, fungal, and viral infections may occur with therapy; delay initiating therapy until active serious infections are resolved
Hemorrhage
- Serious and fatal hemorrhages have occurred in treated patients with platelet counts <50 x 109/L
- Avoid use in patients with active bleeding and hold therapy 7 days before any planned surgical or invasive procedures
- Assess platelet counts periodically, as clinically indicated
- Interrupt treatment and treat appropriately, if necessary
Diarrhea
- May cause diarrhea
- Median time to resolution was 2 weeks
- Incidence of reported diarrhea decreased over time
- Control preexisting diarrhea before starting treatment
- Manage diarrhea with antidiarrheal medications, fluid replacement, and dosage modification
- Treat diarrhea with antidiarrheal medications promptly at the first onset of symptoms
- Interrupt or reduce dose in patients with significant diarrhea despite optimal supportive care
QTc prolongation
- QTc prolongation may occur; no cases of torsade de pointes were reported
- Avoid use in patients with a baseline QTc of >480 msec
- Avoid coadministration with drugs that cause significant QTc prolongation
- Correct hypokalemia before and during treatment
- Advise patients to consult their healthcare provider immediately if they feel faint, lose consciousness, or have signs or symptoms suggestive of arrhythmia
- Manage QTc prolongation using interruption and electrolyte management
Janus-associated kinase (JAK) inhibitor–associated adverse effects
-
Another JAK inhibitor has increased the risk of the following
- Major adverse cardiac events (MACE; eg, cardiovascular death, myocardial infarction, stroke) in patients with rheumatoid arthritis (RA), a condition for which pacritinib is not indicated
- Thrombosis (eg, deep venous thrombosis, pulmonary embolism, arterial thrombosis) in patients with RA
- Secondary malignancies, such as lymphoma and other malignancies, excluding non-melanoma skin cancer (NMSC), in patients with RA
- Serious infections in patients with myeloproliferative neoplasms
- Consider the benefits and risks before initiating or continuing therapy, particularly in patients who are current or past smokers, patients with other cardiovascular risk factors, and patients with a developed or known malignancy (other than a successfully treated NMSC)
- Consult about symptoms of serious cardiovascular events and the necessary steps to take if they occur
- Monitor for signs and symptoms of infection and manage promptly
- Use active surveillance and prophylactic antibiotics according to clinical guidelines
Drug interaction overview
- Substrate of CYP3A4
- Inhibitor of CYP1A2, CYP3A4, P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and organic cation transporter 1 (OCT1)
-
CYP3A4 inhibitors
- Strong inhibitors: Contraindicated
- Moderate inhibitors: Avoid use
- Coadministration with clarithromycin (a strong CYP3A4 inhibitor) increases AUC and peak plasma concentration of pacritinib by 80% and 30%, respectively; exposure to pacritinib may increase following a longer treatment with clarithromycin that results in maximal CYP3A4 inhibition
- Impact of moderate CYP3A4 inhibition not studied
-
CYP3A4 inducers
- Strong inducers: Contraindicated
- Moderate inducers: Avoid use
- Coadministration with rifampin (a strong CYP3A4 inducer) decreases AUC and peak plasma concentration of pacritinib by 87% and 51%, respectively
- Impact of moderate CYP3A4 inducers not studied
-
Sensitive CYP1A2 or CYP3A4 substrates
- Avoid coadministration
- Pacritinib may increase plasma concentrations of sensitive CYP1A2 or CYP3A4 substrates
-
Sensitive P-gp, BCRP, or OCT1 substrates
- Avoid coadministration
- Pacritinib may increase plasma concentrations of sensitive P-gp, BCRP, or OCT1 substrates
Pregnancy & Lactation
Pregnancy
No data are available on use in pregnant females to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes
Advise pregnant females of potential risk to a fetus
Consider benefits and risks for mother and possible risks to the fetus when prescribing to pregnant females
Infertility
- May reduced male mating and fertility indices in BALB/c mice
- Therefore, may impair male fertility in humans
Animal data
- Pregnant mice: Orally administered doses of 30, 100, or 250 mg/kg/day from gestation day 6 to day 15; the high dose was associated with an increased incidence of an external malformation (cleft palate) in presence of maternal toxicity
- Pregnant rabbits: Orally administered doses of 15, 30, or 60 mg/kg/day from gestation day 7 to day 20
- In both species, pacritinib was associated with maternal toxicity, which resulted in postimplantation loss in mice, abortions in rabbits, and reduced fetal body weights in mice and rabbits at exposures 0.1x (mice) and 0.3x (rabbits) the exposure at the recommended human dose (AUC-based)
Lactation
There are no data on presence in either human or animal milk, effects on breastfed children, or effects on milk production
Unknown whether pacritinib is excreted in human milk
Advise patients that breastfeeding is not recommended during treatment, and for 2 weeks after last dose
Pregnancy Categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk. C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk. X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist. NA: Information not available.Pharmacology
Mechanism of Action
Oral kinase with activity against wild-type JAK2, mutant JAK2V617F, and FMS-like tyrosine kinase 3, which contribute to signaling of cytokines and growth factors that are important for hematopoiesis and immune function
MF is often associated with dysregulated JAK2 signaling
Also exhibits inhibitory activity against additional cellular kinases (eg, CSF1R, IRAK1), clinical relevance of which is unknown
Absorption
Peak plasma concentration: 8.4 mg/mL
Peak plasma time: 4-5 hr
AUC: 95.6 mg·hr/L
Accumulation: 386%
Steady-state reached at 1 week
Distribution
Vd (steady-state): 229 L
Protein bound: 98.8%
Metabolism
Primarily metabolized by CYP3A4
Major circulating component and pharmacologic activity are mainly attributed to parent molecule
Major metabolites: M1 (9.6%) and M2 (10.5%), in human whole plasma of parent drug exposure
Elimination
Clearance: 2.09 L/hr
Half-life: 27.7 hr
Excretion: 87% (feces); 6% (urine; 0.12% [unchanged])
Administration
Oral Administration
May take with or without food
Swallow capsules whole; do not open, break, or chew
Missed dose: Take next prescribed dose at its scheduled time; do not take extra capsules to make up for missed dose
Storage
Store at room temperature (<30ºC [<86ºF])
Keep bottle tightly closed and protect from light
Store in original package; dispense in original package or in light-resistant container
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Formulary
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