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.

• Overview
• Side Effects
• Dosage
• Professional
• Interactions
• More

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

To avoid interruptions for thrombocytopenia, monitor patients for declining platelet counts and consider dosage reductions (see Table 2).¹

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 (Cl_cr 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) (Cl_cr <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

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.)

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