Ruxolitinib
Class: Antineoplastic Agents
VA Class: AN900
Chemical Name: (βR)-β-Cyclopentyl-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazole-1-propanenitrile phosphate
Molecular Formula: C17H18N6•H3PO4
CAS Number: 1092939-17-7
Brands: Jakafi
Medically reviewed by Drugs.com. Last updated on Oct 26, 2020.
Introduction
Antineoplastic agent; selective inhibitor of Janus kinase (JAK) 1 and 2.1 2 3 6 9 10
Uses for Ruxolitinib
Intermediate- or High-Risk Myelofibrosis
Treatment of intermediate- or high-risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis (designated an orphan drug by FDA for this use).1 2 3 7 11
Ruxolitinib Dosage and Administration
General
-
Perform CBC, including platelet count, prior to initiating therapy, every 2–4 weeks until dosage is stabilized, and then as clinically indicated.1
Restricted Distribution Program
-
Must be obtained through the Incyte Connecting to Access, Reimbursement, Education, and Support (IncyteCARES) program.8
-
Clinician and patient must jointly complete a prescription and reimbursement application.8 Following verification of prescription information and review of healthcare benefits, an authorized specialty pharmacy ships ruxolitinib directly to the patient.8
-
To enroll in this program, call 855-452-5234 or visit [Web].8
Administration
Oral Administration
Administer orally; take with or without food.1 5
NG Tube
Disperse in approximately 40 mL of water, stir for approximately 10 minutes, and administer within 6 hours through an NG tube (8 French or larger) using an appropriate syringe.1 Following administration, rinse tube with approximately 75 mL of water.1
Dosage
Available as ruxolitinib phosphate; dosage expressed in terms of ruxolitinib.1
Adults
Intermediate- or High-Risk Myelofibrosis
Oral
Platelet count >200,000/mm3: Initially, 20 mg twice daily.1
Platelet count 100,000–200,000/mm3: Initially, 15 mg twice daily.1
Titrate dosage based on efficacy and safety.1 (See Dosage Modification for Thrombocytopenia and also Dosage Modification for Insufficient Clinical Response under Dosage and Administration.)
Dosage adjustment required if used concomitantly with a potent CYP3A4 inhibitor.1 (See Drugs Affecting Hepatic Microsomal Enzymes under Interactions.)
When discontinuing ruxolitinib for reasons other than thrombocytopenia, taper dosage gradually (e.g., by 5 mg twice daily on a weekly basis).1
Dosage Modification for Thrombocytopenia
Interrupt treatment in patients with platelet counts <50,000/mm3.1
Restart therapy or increase dosage following recovery of platelet counts to acceptable levels.1 When restarting therapy, use dosage at least 5 mg twice daily below the original dosage.1 For maximum dosages when restarting ruxolitinib, see Table 1.1
Current Platelet Count (per mm3) |
Maximum Dosage for Restarting Therapy |
---|---|
≥125,000 |
20 mg twice daily1 |
100,000 to <125,000 |
15 mg twice daily1 |
75,000 to <100,000 |
10 mg twice daily for at least 2 weeks; if stable, may increase to 15 mg twice daily1 |
50,000 to <75,000 |
5 mg twice daily for at least 2 weeks; if stable, may increase to 10 mg twice daily1 |
<50,000 |
Continue to withhold therapy1 |
To avoid interruptions for thrombocytopenia, monitor patients for declining platelet counts and consider dosage reductions (see Table 2).1
Ruxolitinib Dosage at Time of Platelet Decline |
25 mg twice daily |
20 mg twice daily |
15 mg twice daily |
10 mg twice daily |
5 mg twice daily |
---|---|---|---|---|---|
Current Platelet Count (per mm3) |
Modified Ruxolitinib Dosage |
||||
100,000 to <125,000 |
20 mg twice daily1 |
15 mg twice daily1 |
Maintain dosage level1 |
Maintain dosage level1 |
Maintain dosage level1 |
75,000 to <100,000 |
10 mg twice daily1 |
10 mg twice daily1 |
10 mg twice daily1 |
Maintain dosage level1 |
Maintain dosage level1 |
50,000 to <75,000 |
5 mg twice daily 1 |
5 mg twice daily1 |
5 mg twice daily1 |
5 mg twice daily1 |
Maintain dosage level1 |
<50,000 |
Withhold therapy1 |
Withhold therapy1 |
Withhold therapy1 |
Withhold therapy1 |
Withhold therapy1 |
Dosage Modification for Insufficient Clinical Response
Increase dosage in increments of 5 mg twice daily (e.g., from 15 mg twice daily to 20 mg twice daily) up to maximum of 25 mg twice daily if response is insufficient and both platelet counts and ANC are adequate.1 Consider dosage increases in patients who meet all of the following conditions: failure to achieve a reduction from pretreatment baseline spleen size of either 50% in palpable length or 35% in volume (measured by CT or MRI); platelets >125,000/mm3 at 4 weeks and never <100,000/mm3; ANC >750/mm3.1
Do not increase dosage during first 4 weeks of therapy or more frequently than every 2 weeks.1
Discontinue drug if there is no spleen size reduction or symptomatic improvement after 6 months of therapy.1
Long-term maintenance dosage of 5 mg twice daily not shown to produce adequate responses; limit continued use at this dosage to patients in whom benefits outweigh potential risks.1
Prescribing Limits
Adults
Intermediate- or High-Risk Myelofibrosis
Oral
Maximum 25 mg twice daily.1
Special Populations
Hepatic Impairment
Mild to severe hepatic impairment and platelet counts of 100,000–150,000/mm3: 10 mg twice daily.1 Carefully monitor safety and efficacy before additional dosage modifications.1
Avoid ruxolitinib in patients with hepatic impairment and platelet counts <100,000/mm3.1
Renal Impairment
Moderate or severe renal impairment (Clcr 15–59 mL/minute): Initially, 10 mg twice daily in patients with platelet counts of 100,000–150,000/mm3.1 Carefully monitor safety and efficacy before additional dosage modifications.1 Avoid use if platelet counts <100,000/mm3.1
End-stage renal disease (ESRD) (Clcr <15 mL/minute) requiring dialysis: Initially, 15 mg for patients with platelet counts of 100,000–200,000/mm3 and 20 mg for patients with platelet counts >200,000/mm3; administer dose following completion of each dialysis session only on days when hemodialysis is scheduled.1 14 Carefully monitor safety and efficacy before additional dosage modifications.1
ESRD not requiring dialysis: Avoid ruxolitinib.1
Geriatric Patients
Manufacturer makes no specific dosage recommendations in patients ≥65 years of age.1
Cautions for Ruxolitinib
Contraindications
-
Manufacturer states none known.1
Warnings/Precautions
Thrombocytopenia, Anemia, and Neutropenia
Can cause adverse hematologic reactions (e.g., thrombocytopenia, anemia, neutropenia).1 2 3 11 Perform CBCs before initiating therapy.1
Thrombocytopenia generally reversible; usually managed by reducing dosage or temporarily withholding therapy.1 2 3 11 Administer platelet transfusions if clinically indicated.1
Patients who develop anemia may require blood transfusions; consider dosage modification in such patients.1
Neutropenia (ANC <500/mm3) generally reversible; managed by temporarily withholding ruxolitinib.1
Monitor CBCs as clinically indicated and adjust dosage as required.1
Infectious Complications
Assess patients for risk of developing serious bacterial, mycobacterial, fungal, and viral infections.1 Resolve active serious infections prior to initiating ruxolitinib.1 Carefully observe patients for signs and/or symptoms of infection and promptly initiate appropriate treatment.1
Herpes zoster infection reported.1
Withdrawal of Therapy
Following interruption or discontinuance of therapy, disease symptoms generally return to pretreatment levels within approximately 1 week.1
In isolated cases, discontinuance of ruxolitinib during an acute concomitant illness was followed by worsening of clinical course; however, not established whether discontinuance of therapy contributed to clinical deterioration.1 Consider gradual tapering of dosage when discontinuing drug for reasons other than thrombocytopenia.1 (See Dosage under Dosage and Administration.)
Withdrawal manifestations (acute relapse of disease symptoms, accelerated splenomegaly, worsening of cytopenias, occasional hemodynamic decompensation) reported following discontinuance of ruxolitinib.10 12 Some experts recommend gradual (over 2 weeks) tapering of dosage under close medical supervision.10 13
Specific Populations
Pregnancy
Category C.1
Lactation
Distributed into milk in rats; not known whether distributed into human milk.1 Discontinue nursing or the drug.1
Pediatric Use
Safety and efficacy not established.1
Geriatric Use
No overall differences in safety or efficacy relative to younger adults.1
Hepatic Impairment
AUC increased and half-life prolonged in patients with mild to severe hepatic impairment.1 (See Absorption: Special Populations and Elimination: Special Populations, under Pharmacokinetics.) Dosage reduction recommended.1 (See Hepatic Impairment under Dosage and Administration.)
Renal Impairment
Increased exposure to ruxolitinib metabolites observed with increasing severity of renal impairment.1 Dosage adjustment or avoidance of therapy may be required depending on degree of renal impairment and platelet count.1 (See Renal Impairment under Dosage and Administration.)
Common Adverse Effects
Thrombocytopenia,1 2 3 neutropenia,1 2 anemia,1 2 3 bruising,1 2 dizziness,1 2 headache.1 2 3
Interactions for Ruxolitinib
Metabolized mainly by CYP3A4.1 6
Ruxolitinib and its M18 metabolite do not inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4 in vitro.1
Ruxolitinib does not induce CYP1A2, 2B6, or 3A4 at clinically relevant concentrations.1
Not a substrate for P-glycoprotein (P-gp).1 6
Ruxolitinib and its M18 metabolite do not inhibit P-gp, breast cancer resistance protein (BCRP), organic anion-transporting polypeptides (OATP) 1B1 and 1B3, organic cation transporters (OCT) 1 and 2, and organic anion transporters (OAT) 1 and 3 in vitro at clinically relevant concentrations.1
Drugs Affecting Hepatic Microsomal Enzymes
Potent CYP3A4 inhibitors: Pharmacokinetic interaction (increased ruxolitinib peak plasma concentrations and AUC).1 6 Avoid concomitant use in patients with platelet counts <100,000/mm3.1 In patients with platelet counts ≥100,000/mm3, use reduced initial ruxolitinib dosage of 10 mg twice daily.1 Monitor patients closely; titrate dosage based on safety and efficacy.1
Weak or moderate CYP3A4 inhibitors: Pharmacokinetic interaction (increased ruxolitinib peak plasma concentrations and AUC).1 6 Not clinically important; dosage adjustment not recommended.1 6
CYP3A4 inducers: Pharmacokinetic interaction (decreased ruxolitinib peak plasma concentrations and AUC).1 6 Dosage adjustment not recommended.1 6 Monitor patients closely; titrate dosage based on safety and efficacy.1
Specific Drugs and Foods
Drug or Food |
Interaction |
Comments |
---|---|---|
Antifungals, azole (e.g., itraconazole, ketoconazole, posaconazole, voriconazole) |
Ketoconazole: Increased ruxolitinib peak plasma concentration (by 33%), AUC (by 91%),1 6 and half-life1 Itraconazole, posaconazole, voriconazole: Potential increased ruxolitinib peak plasma concentration and AUC1 |
Platelets ≥100,000/mm3: Initial ruxolitinib dosage of 10 mg twice daily; 1 6 titrate dosage based on careful monitoring of safety and efficacy1 Platelets <100,000/mm3: Avoid concomitant use1 |
Antiretrovirals, HIV protease inhibitors (PIs) (e.g., indinavir, lopinavir and ritonavir [lopinavir/ritonavir], nelfinavir, ritonavir, saquinavir) |
Possible increased ruxolitinib peak plasma concentration and AUC1 |
Platelets ≥100,000/mm3: Initial ruxolitinib dosage of 10 mg twice daily;1 titrate dosage based on careful monitoring of safety and efficacy1 Platelets <100,000/mm3: Avoid concomitant use1 |
Clarithromycin |
Possible increased ruxolitinib peak plasma concentration and AUC1 |
Platelets ≥100,000/mm3: Initial ruxolitinib dosage of 10 mg twice daily;1 titrate dosage based on careful monitoring of safety and efficacy1 Platelets <100,000/mm3: Avoid concomitant use1 |
Conivaptan |
Possible increased ruxolitinib peak plasma concentration and AUC1 |
Platelets ≥100,000/mm3: Initial ruxolitinib dosage of 10 mg twice daily;1 titrate dosage based on careful monitoring of safety and efficacy1 Platelets <100,000/mm3: Avoid concomitant use1 |
Erythromycin |
Increased ruxolitinib peak plasma concentration (by 8%) and AUC (by 27%)1 6 |
No dosage adjustment recommended1 |
Grapefruit juice |
Possible increased ruxolitinib peak plasma concentration and AUC1 |
Platelets ≥100,000/mm3: Initial ruxolitinib dosage of 10 mg twice daily;1 titrate dosage based on careful monitoring of safety and efficacy1 Platelets <100,000/mm3: Avoid concomitant use1 |
HCV protease inhibitors (e.g., boceprevir, telaprevir) |
Possible increased ruxolitinib peak plasma concentration and AUC1 |
Platelets ≥100,000/mm3: Initial ruxolitinib dosage of 10 mg twice daily;1 titrate dosage based on careful monitoring of safety and efficacy1 Platelets <100,000/mm3: Avoid concomitant use1 |
Mibefradil [no longer commercially available in US] |
Possible increased ruxolitinib peak plasma concentration and AUC1 |
Platelets ≥100,000/mm3: Initial ruxolitinib dosage of 10 mg twice daily;1 titrate dosage based on careful monitoring of safety and efficacy1 Platelets <100,000/mm3: Avoid concomitant use1 |
Nefazodone |
Possible increased ruxolitinib peak plasma concentration and AUC1 |
Platelets ≥100,000/mm3: Initial ruxolitinib dosage of 10 mg twice daily;1 titrate dosage based on careful monitoring of safety and efficacy1 Platelets <100,000/mm3: Avoid concomitant use1 |
Rifampin |
Decreased ruxolitinib peak plasma concentration (by 32%) and AUC (by 61%)1 |
No dosage adjustment recommended1 6 Closely monitor patients; titrate dosage based on safety and efficacy1 |
Telithromycin |
Possible increased ruxolitinib peak plasma concentration and AUC1 |
Platelets ≥100,000/mm3: Initial ruxolitinib dosage of 10 mg twice daily;1 titrate dosage based on careful monitoring of safety and efficacy1 Platelets <100,000/mm3: Avoid concomitant use1 |
Ruxolitinib Pharmacokinetics
Absorption
Bioavailability
Rapidly absorbed following oral administration; peak plasma concentrations usually attained within 1–2 hours.1 5
About 80% of dose systemically available.5
Food
No clinically relevant changes in pharmacokinetics when administered with high-fat meal.1
Special Populations
In patients with mild, moderate, or severe hepatic impairment, AUC increased by 87, 28, or 65%, respectively.1
Pharmacokinetics of ruxolitinib not substantially altered by renal impairment; however, AUC of ruxolitinib metabolites increases with increasing severity of renal impairment.1
Distribution
Extent
Distributed into milk in rats; not known whether distributed into human milk.1
Plasma Protein Binding
Approximately 97% (mainly albumin).1
Elimination
Metabolism
CYP3A4 is the major enzyme responsible for metabolism.1
Elimination Route
Excreted in urine (74%) and feces (22%), mainly as metabolites (<1% excreted as unchanged drug).1 9
Half-life
Mean half-life following a single oral dose: approximately 3 hours.1 5
Mean half-life of ruxolitinib and its metabolites: approximately 5.8 hours.1
Special Populations
Terminal elimination half-life prolonged in patients with hepatic impairment (4.1–5 hours) compared with healthy individuals (2.8 hours).1
Ruxolitinib is not removed by dialysis; however, removal of some active metabolites by dialysis cannot be ruled out.1
Stability
Storage
Oral
Tablets
20–25°C (may be exposed to 15–30°C).1
Actions
-
Selectively inhibits JAK1 and 2, which mediate signaling of cytokines and growth factors important for hematopoiesis and immune function.1
-
Myelofibrosis is a myeloproliferative neoplasm known to be associated with dysregulated JAK1 and 2 signaling.1
-
JAK signaling involves recruitment of signal transducers and activators of transcription (STATs) to cytokine receptors, activation, and subsequent localization of STATs to the nucleus leading to modulation of gene expression.1
-
Demonstrated dose- and time-dependent inhibition of cytokine-induced phosphorylated STAT3 with maximal inhibition occurring 1–2 hours after single-dose administration (ranging from 5–200 mg) in healthy individuals at all dosage levels.5
Advice to Patients
-
Importance of informing patients that ruxolitinib is associated with thrombocytopenia, anemia, and neutropenia, and to have CBCs monitored before and during treatment.1 12 Advise patients to contact their clinicians if unusual bleeding, bruising, fatigue, shortness of breath, or fever occurs.1
-
Advise patients to notify clinician immediately if signs and/or symptoms of infection (e.g., chills, aches, fever, nausea, vomiting, weakness ) occur.1
-
Importance of informing patients about early signs and symptoms of herpes zoster (e.g., painful skin rash or blisters) and advising patients to seek treatment as soon as possible.1
-
Importance of informing patients with ESRD receiving dialysis to take their dose of ruxolitinib following completion of the dialysis session only on days when hemodialysis is scheduled.1
-
Inform patients of importance of adherence to dosing schedule; advise patients not to change dosage or discontinue drug without consulting their clinicians.1 Inform patients that myelofibrosis signs and symptoms are expected to return after treatment discontinuance.1
-
Importance of not drinking grapefruit juice while receiving ruxolitinib therapy.1
-
Importance of not doubling the next dose if a dose is missed; take next dose at the regularly scheduled time.1
-
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 Importance of advising women not to breast-feed during therapy with the drug.1
-
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses (e.g., fungal, bacterial, or HIV infection).
-
Importance of informing patients of other important precautionary information.1 (See Cautions.)
Preparations
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Distribution is restricted. (See Restricted Distribution under Dosage and Administration.)
Routes |
Dosage Forms |
Strengths |
Brand Names |
Manufacturer |
---|---|---|---|---|
Oral |
Tablets |
5 mg (of ruxolitinib) |
Jakafi |
Incyte Corporation |
10 mg (of ruxolitinib) |
Jakafi |
Incyte Corporation |
||
15 mg (of ruxolitinib) |
Jakafi |
Incyte Corporation |
||
20 mg (of ruxolitinib) |
Jakafi |
Incyte Corporation |
||
25 mg (of ruxolitinib) |
Jakafi |
Incyte Corporation |
AHFS DI Essentials™. © Copyright 2021, Selected Revisions November 5, 2012. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.
References
1. Incyte Corporation. Jakafi (ruxolitinib) tablets prescribing information. Wilmington, DE; 2012 Jun.
2. Verstovsek S, Mesa RA, Gotlib J et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012; 366:799-807. http://www.ncbi.nlm.nih.gov/pubmed/22375971?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=4822164&blobtype=pdf
3. Harrison C, Kiladjian JJ, Al-Ali HK et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012; 366:787-98. http://www.ncbi.nlm.nih.gov/pubmed/22375970?dopt=AbstractPlus
4. Cervantes F, Dupriez B, Pereira A et al. New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment. Blood. 2009; 113:2895-901. http://www.ncbi.nlm.nih.gov/pubmed/18988864?dopt=AbstractPlus
5. Shi JG, Chen X, McGee RF et al. The pharmacokinetics, pharmacodynamics, and safety of orally dosed INCB018424 phosphate in healthy volunteers. J Clin Pharmacol. 2011; 51:1644-54. http://www.ncbi.nlm.nih.gov/pubmed/21257798?dopt=AbstractPlus
6. Shi JG, Chen X, Emm T et al. The Effect of CYP3A4 Inhibition or Induction on the Pharmacokinetics and Pharmacodynamics of Orally Administered Ruxolitinib (INCB018424 Phosphate) in Healthy Volunteers. J Clin Pharmacol. 2011; :.
7. US Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97 414). Rockville, MD. From FDA web site. Accessed 2012 Feb 17. http://www.accessdata.fda.gov/scripts/opdlisting/oopd/index.cfm
8. Incyte Corporation. How to Prescribe Jakafi. From Jakafi website. Accessed 2012 Feb 22. http://www.jakafi.com/
9. Shilling AD, Nedza FM, Emm T et al. Metabolism, excretion, and pharmacokinetics of [14C]INCB018424, a selective Janus tyrosine kinase 1/2 inhibitor, in humans. Drug Metab Dispos. 2010; 38:2023-31. http://www.ncbi.nlm.nih.gov/pubmed/20699411?dopt=AbstractPlus
10. Tefferi A, Pardanani A. Serious adverse events during ruxolitinib treatment discontinuation in patients with myelofibrosis. Mayo Clin Proc. 2011; 86:1188-91. http://www.ncbi.nlm.nih.gov/pubmed/22034658?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=3228619&blobtype=pdf
11. Verstovsek S, Kantarjian H, Mesa RA et al. Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis. N Engl J Med. 2010; 363:1117-27. http://www.ncbi.nlm.nih.gov/pubmed/20843246?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=5187954&blobtype=pdf
12. Tefferi A, Litzow MR, Pardanani A. Long-term outcome of treatment with ruxolitinib in myelofibrosis. N Engl J Med. 2011; 365:1455-7. http://www.ncbi.nlm.nih.gov/pubmed/21995409?dopt=AbstractPlus
13. Tefferi A. How I treat myelofibrosis. Blood. 2011; 117:3494-504. http://www.ncbi.nlm.nih.gov/pubmed/21200024?dopt=AbstractPlus
14. Incyte Corporation. Wilmington, DE: Personal communication.
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