Ruxolitinib Phosphate (Monograph)

Brand name: Jakafi
Drug class: Antineoplastic Agents

Medically reviewed by Drugs.com on Jul 10, 2024. Written by ASHP.

Introduction

Antineoplastic agent; selective inhibitor of Janus kinase (JAK) 1 and 2.

Uses for Ruxolitinib Phosphate

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).

Some experts recommend use of ruxolitinib as second-line therapy after hydroxyurea in patients with low-risk myelofibrosis, and as first-line therapy in patients with intermediate or high-risk myelofibrosis who are not eligible for allogenic stem cell transplantation.

Polycythemia Vera

Treatment of polycythemia vera in adults with a history of inadequate response to or intolerance to hydroxyurea. Designated an orphan drug by FDA for this use.

Some experts recommend use of ruxolitinib as second-line therapy for the treatment of polycythemia vera following failure of first-line therapies.

Acute Graft-Versus-Host Disease

Treatment of acute graft-versus-host disease (GVHD) that is refractory to corticosteroids in adults and pediatric patients ≥12 years of age (designated an orphan drug by the FDA for use in this condition).

Some experts recommend ruxolitinib as a second-line therapy option in patients with acute GVHD who are resistant to or dependent on corticosteroids.

Chronic Graft-Versus-Host Disease

Treatment of chronic GVHD in adults and pediatric patients ≥12 years of age who have failed 1 or 2 prior lines of systemic therapy (designated an orphan drug by the FDA for use in this condition).

Some experts recommend ruxolitinib as a second-line therapy option in patients with chronic GVHD who are already receiving corticosteroids.

Ruxolitinib Phosphate Dosage and Administration

General

Pretreatment Screening

• Perform a complete blood count (CBC) prior to initiation of therapy.

• Inquire about past infections including tuberculosis, herpes simplex, herpes zoster, and hepatitis B prior to treatment.

• Acute and chronic GVHD: Perform CBC, including platelet count and ANC, and measure serum bilirubin concentrations prior to initiation of therapy.

• Evaluate patients for tuberculosis infection risk factors; test for latent infection in patients at higher risk for tuberculosis infection (e.g., prior residence in or travel to countries with a high prevalence of tuberculosis, close contact with a person with active tuberculosis, history of active or latent tuberculosis where adequate course of treatment cannot be confirmed).

• Consider the benefits of ruxolitinib and risks of major adverse cardiovascular events (MACE) prior to initiating or continuing therapy with the drug, particularly in patients who are current or past smokers and patients with other cardiovascular risk factors.

• Consider the benefits of ruxolitinib and risks of developing secondary malignancies prior to initiating or continuing therapy with the drug, particularly in patients with a known secondary malignancy (other than a successfully treated nonmelanoma skin cancer), patients who develop a malignancy, and patients who are current or past smokers.

Patient Monitoring

• Perform a CBC every 2 to 4 weeks until a stable dosage and then as clinically indicated.

• Acute and chronic GVHD: Perform CBC, including platelet count and ANC, and measure serum bilirubin concentrations every 2–4 weeks until a stable dosage is achieved and then as clinically indicated.

• Monitor closely for signs or symptoms of infection, including herpes zoster and herpes simplex, during treatment with ruxolitinib.

• Perform skin examinations periodically during therapy.

• Assess lipid parameters approximately 8–12 weeks after initiation of ruxolitinib.

Administration

Oral Administration

Administer orally; take with or without food.

NG Tube

Disperse tablet 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. Following administration, rinse tube with approximately 75 mL of water.

Dosage

Available as ruxolitinib phosphate; dosage expressed in terms of ruxolitinib.

Pediatric Patients

Acute Graft-Versus-Host Disease

Oral

≥12 years of age: Initially, 5 mg twice daily; may increase dosage to 10 mg twice daily after at least 3 days of treatment if ANC and platelet count do not decrease by ≥50% relative to the first ruxolitinib dosage.

In patients who achieve a response and discontinue therapeutic doses of corticosteroids, consider tapering ruxolitinib after 6 months of therapy; taper dosage should by one dose level approximately every 8 weeks (e.g., 10 mg twice daily to 5 mg twice daily; 5 mg twice daily to 5 mg once daily). If acute GVHD recurs during or following tapering of the ruxolitinib dosage, consider retreatment with the drug.

When discontinuing ruxolitinib for reasons other than thrombocytopenia, taper dosage gradually (e.g., by 5 mg twice daily on a weekly basis).

Dosage Modification for Toxicity in Pediatric Patients with Acute GVHD

Oral

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

If an adverse reaction occurs, modify dosage accordingly (see Table 2).

Dosage Modification for Concomitant Use with Drugs Affecting Hepatic Microsomal Enzymes in Pediatric Patients ≥12 Years of Age with Acute GVHD

Oral

Dosage adjustment is recommended in patients receiving concomitant ruxolitinib with a potent inhibitor of CYP3A4 or fluconazole at dosage of ≤200 mg daily. Avoid concomitant use of ruxolitinib with fluconazole dosage >200 mg daily.

If coadministration with fluconazole ≤200 mg daily is necessary in patients with acute GVHD, reduce the starting dosage of ruxolitinib to 5 mg once daily.

If coadministration with a potent CYP3A4 inhibitor (other than fluconazole) is necessary in patients with acute GVHD, monitor CBCs more frequently and adjust ruxolitinib dosage for adverse effects, if necessary.

Chronic Graft-Versus-Host Disease

Oral

≥12 years of age: Initially, 10 mg twice daily.

In patients who achieve a response and discontinue therapeutic doses of corticosteroids, consider tapering ruxolitinib after 6 months of therapy; the dosage should be tapered by one dose level approximately every 8 weeks (e.g., 10 mg twice daily to 5 mg twice daily; 5 mg twice daily to 5 mg once daily). If chronic GVHD recurs during or following tapering of the ruxolitinib dosage, consider retreatment with the drug.

Dosage Modification for Toxicity in Pediatric Patients ≥12 Years of Age with Chronic GVHD

Oral

If adverse reactions occur during ruxolitinib therapy, temporary interruption of therapy and/or dosage reduction of the drug may be necessary. If dosage reduction is required, reduce dosage as described in Table 3.

If an adverse reaction occurs, modify dosage accordingly (see Table 4).

Dosage Modification for Concomitant Use with Drugs Affecting Hepatic Microsomal Enzymes in Pediatric Patients ≥12 Years of Age with Chronic GVHD

Oral

Dosage adjustment is recommended in patients receiving concomitant ruxolitinib with a potent inhibitor of CYP3A4 or fluconazole ≤200 mg daily. Avoid concomitant use of ruxolitinib with fluconazole >200 mg daily.

If coadministration with fluconazole ≤200 mg daily is necessary in patients with chronic GVHD, reduce the starting dosage of ruxolitinib to 5 mg twice daily.

If coadministration with a potent CYP3A4 inhibitor (other than fluconazole) is necessary in patients with chronic GVHD, CBCs should be monitored more frequently for toxicity and the dosage of ruxolitinib should be modified for adverse effects, if they occur.

Adults

Intermediate- or High-Risk Myelofibrosis

Oral

The recommended initial dosage of ruxolitinib is based on platelet count.

Platelet count >200,000/mm³: Initially, 20 mg twice daily.

Platelet count 100,000–200,000/mm³: Initially, 15 mg twice daily.

Platelet count of 50,000/mm³ to <100,000/mm³: Initially, 5 mg twice daily.

Individualize dosage to optimize response and manage cytopenias associated with the drug.

When discontinuing ruxolitinib for reasons other than thrombocytopenia, taper dosage gradually (e.g., by 5 mg twice daily on a weekly basis).

Dosage Modification for Hematologic Parameters in Patients with Myelofibrosis

Oral

Dosage reductions may be considered based on platelet count without interrupting therapy in patients with a baseline platelet count ≥100,000/mm³ (see Table 5) and in patients with a baseline platelet count of 50,000 to <100,000/mm³ (see Table 6). However, temporary interruption of therapy is necessary in patients with a baseline platelet count of ≥100,000/mm³ if platelet count decreases to <50,000/mm³ or ANC decreases to <500/mm³.

In patients with a baseline platelet count of ≥100,000/mm³, temporarily interrupt ruxolitinib therapy if platelet count decreases to <50,000/mm³ or ANC decreases to <500/mm³. When platelet counts improve to >50,000/mm³ and ANC improves to >750/mm³, ruxolitinib may be resumed. When restarting, begin with a dosage at least 5 mg twice daily below the dosage at interruption and follow the manufacturer's guideline for the maximum allowable dosage that may be used when restarting treatment (see Table 7).

If ANC <500/mm³ occurs, temporarily interrupt ruxolitinib therapy; when ANC improves to ≥750/mm³, resume ruxolitinib at the higher of the following dosages: 5 mg once daily; or 5 mg twice daily below the highest dosage during the week prior to the treatment interruption.

In patients with a baseline platelet count of 50,000/mm³ to <100,000/mm³, temporarily interrupt ruxolitinib therapy if platelet count decreases to <25,000/mm³ or ANC decreases to <500/mm³. When platelet counts improve to >35,000/mm³ and ANC improves to >750/mm³, resume ruxolitinib at the higher of the following dosages: 5 mg once daily; or 5 mg twice daily below the highest dosage during the week prior to the treatment interruption.

Dosage Modification for Insufficient Clinical Response in Patients with Myelofibrosis

Oral

If clinical response is considered insufficient in patients with a baseline platelet count of ≥100,000/mm³, increase ruxolitinib dosage in increments of 5 mg twice daily up to a maximum of 25 mg twice daily if all the following conditions have been met: failure to achieve a reduction from pretreatment baseline spleen size of either 50% in palpable length or 35% in volume as measured by CT or MRI; platelet count >125,000/mm³ at 4 weeks; platelet count never reduced to <100,000/mm³; ANC >750/mm³.

Continued long-term use of ruxolitinib at a dosage of 5 mg twice daily should be limited to patients in whom the benefit outweighs the potential risk.

If clinical response is considered insufficient in patients with a baseline platelet count of 50,000/mm³ to <100,000/mm³, the dosage of ruxolitinib may be increased in increments of 5 mg daily up to a maximum of 10 mg twice daily if the following conditions have been met: platelet count has remained ≥40,000/mm³ and has not decreased by >20% in the prior 4 weeks; ANC is >1000/mm³; and the dosage of ruxolitinib has not been reduced or withheld due to an adverse event or hematologic toxicity in the prior 4 weeks. Continuation of ruxolitinib for a duration >6 months should be limited to patients in whom the benefit outweighs the potential risk.

Do not increase the ruxolitinib dosage during the first 4 weeks of therapy or more frequently than every 2 weeks.

If spleen size does not reduce or symptoms do not improve following 6 months of therapy with ruxolitinib, discontinue drug.

Dosage Modification for Hemorrhagic Events in Patients with Myelofibrosis

Oral

If a hemorrhagic event requiring intervention occurs during ruxolitinib therapy in patients with myelofibrosis, interrupt treatment regardless of the current platelet count.

If the hemorrhagic event resolves and the underlying cause of bleeding is controlled, consider resuming ruxolitinib at the dosage used prior to treatment interruption.

If the hemorrhagic event resolves but the underlying cause persists, consider resuming ruxolitinib at a reduced dosage.

Dosage Modification for Concomitant Use with Drugs Affecting Hepatic Microsomal Enzymes in Patients with Myelofibrosis

Oral

Dosage adjustment is recommended in patients receiving concomitant ruxolitinib with a potent inhibitor of CYP3A4 or fluconazole ≤200 mg daily. Reduce initial dosage of ruxolitinib based on baseline platelet count. (See Table 8.) Avoid concomitant use of ruxolitinib with fluconazole >200 mg daily.

If a stable dosage of ruxolitinib has been achieved in patients with myelofibrosis receiving concomitant potent CYP3A4 inhibitors or fluconazole ≤200 mg daily, the dosage of ruxolitinib should be reduced as described in Table 9.

Polycythemia Vera

Initially, 10 mg twice daily.

Individualize dosage to optimize response and manage cytopenias associated with the drug.

Dosage Modification for Hematologic Parameters in Patients with Polycythemia Vera

Oral

Dosage reduction should be considered for hemoglobin concentration <12 g/dL or platelet count <100,000/mm³ to avoid interruption of therapy (see Table 10).

If hemoglobin <8 g/dL, platelet count <50,000/mm³, or ANC <1000/mm³ occurs, temporarily interrupt ruxolitinib therapy until hematologic parameters recover to acceptable levels; may then resume ruxolitinib at a reduced dosage as described in Table 11.

The most severe hematologic parameter should be used to determine the corresponding maximum dosage.

Continue therapy for at least 2 weeks; if stable, the dosage of ruxolitinib may be increased by 5 mg twice daily.

If dosage interruption is necessary on a reduced dosage of 5 mg twice daily, resume ruxolitinib at a dosage of 5 mg twice daily or 5 mg once daily, but not higher, once hemoglobin concentration improves to ≥10 g/dL, platelet count improves to ≥75,000/mm³, and ANC improves to ≥1500/mm³.

Dosage of ruxolitinib may be titrated following treatment interruption; however, maximum total daily dosage should not exceed 5 mg less than the dosage that resulted in the dosage interruption. The manufacturer states that the maximal total daily dosage of ruxolitinib is not limited in patients who required treatment interruption following phlebotomy-associated anemia.

Dosage Modification for Insufficient Clinical Response in Patients with Polycythemia Vera

Oral

If clinical response is considered insufficient and platelet, hemoglobin, and neutrophil counts are adequate, increase ruxolitinib dosage in increments of 5 mg twice daily up to a maximum of 25 mg twice daily if all the following conditions have been met: inadequate efficacy (demonstrated by one or more of the following: continued need for phlebotomy, WBC or platelet count above the ULN, or spleen size reduced by <25% in palpable length from baseline); platelet count ≥140,000/mm³; hemoglobin concentration ≥12 g/dL; ANC ≥1500/mm³.

Do not increase the ruxolitinib dosage during the first 4 weeks of therapy or more frequently than every 2 weeks.

Dosage Modification for Concomitant Use with Drugs Affecting Hepatic Microsomal Enzymes in Patients with Polycythemia Vera

Oral

In patients receiving concomitant ruxolitinib with a potent inhibitor of CYP3A4 or fluconazole ≤200 mg daily, reduce initial dosage of ruxolitinib to 5 mg twice daily. Avoid concomitant use of ruxolitinib with fluconazole >200 mg daily.

If a stable dosage of ruxolitinib has been achieved in patients with polycythemia vera receiving concomitant potent CYP3A4 inhibitors of fluconazole ≤200 mg daily, reduce dosage of ruxolitinib as described in Table 12.

Acute Graft-Versus-Host Disease

Oral

Initially, 5 mg twice daily; may increase dosage to 10 mg twice daily after ≥3 days of treatment if ANC and platelet count do not decrease by ≥50% relative to the first ruxolitinib dosage.

In patients who achieve a response and discontinue therapeutic doses of corticosteroids, consider tapering ruxolitinib after 6 months of therapy; taper dosage should by one dose level approximately every 8 weeks (e.g., 10 mg twice daily to 5 mg twice daily; 5 mg twice daily to 5 mg once daily). If acute GVHD recurs during or following tapering of the ruxolitinib dosage, consider retreatment with the drug.

When discontinuing ruxolitinib for reasons other than thrombocytopenia, taper dosage gradually (e.g., by 5 mg twice daily on a weekly basis).

Dosage Modification for Toxicity in Patients with Acute GVHD

Oral

If adverse reactions occur during ruxolitinib therapy, temporary interruption of therapy and/or dosage reduction of the drug may be necessary. If dosage reduction is required, reduce dosage as described in Table 13.

If an adverse reaction occurs, modify dosage accordingly (see Table 14).

Dosage Modification for Concomitant Use with Drugs Affecting Hepatic Microsomal Enzymes in Patients with Acute GVHD

Oral

Dosage adjustment is recommended in patients receiving concomitant ruxolitinib with a potent inhibitor of CYP3A4 or fluconazole ≤200 mg daily. Avoid concomitant use of ruxolitinib with fluconazole >200 mg daily.

If coadministration with fluconazole at dosages of up to 200 mg per day is necessary in patients with acute GVHD, reduce starting dosage of ruxolitinib to 5 mg once daily.

If coadministration with a potent CYP3A4 inhibitor (other than fluconazole) is necessary in patients with acute GVHD, monitor CBCs more frequently and adjust ruxolitinib dosage for adverse effects, if necessary.

Chronic Graft-Versus-Host Disease

Oral

Initially, 10 mg twice daily.

In patients who achieve a response and discontinue therapeutic doses of corticosteroids, consider tapering ruxolitinib after 6 months of therapy; the dosage should be tapered by one dose level approximately every 8 weeks (e.g., 10 mg twice daily to 5 mg twice daily; 5 mg twice daily to 5 mg once daily). If chronic GVHD recurs during or following tapering of the ruxolitinib dosage, consider retreatment with the drug.

Dosage Modification for Toxicity in Patients with Chronic GVHD

Oral

If adverse reactions occur during ruxolitinib therapy, temporary interruption of therapy and/or dosage reduction of the drug may be necessary. If dosage reduction is required, reduce dosage as described in Table 15.

If an adverse reaction occurs, modify dosage accordingly (see Table 16).

Dosage Modification for Concomitant Use with Drugs Affecting Hepatic Microsomal Enzymes in Patients with Chronic GVHD

Oral

Dosage adjustment is recommended in patients receiving concomitant ruxolitinib with a potent inhibitor of CYP3A4 or fluconazole ≤200 mg daily. Avoid concomitant use of ruxolitinib with fluconazole >200 mg daily.

If coadministration with fluconazole at dosages of up to 200 mg per day is necessary in patients with chronic GVHD, reduce the starting dosage of ruxolitinib to 5 mg twice daily.

If coadministration with a potent CYP3A4 inhibitor (other than fluconazole) is necessary in patients with chronic GVHD, CBCs should be monitored more frequently for toxicity and the dosage of ruxolitinib should be modified for adverse effects, if they occur.

Prescribing Limits

Adults

Intermediate- or High-Risk Myelofibrosis

Oral

Maximum recommended dosage is based on baseline platelet count and other parameters. (See Intermediate- or High-Risk Myelofibrosis under Dosage and Administration.)

Polycythemia Vera

Oral

Maximum recommended dosage is based on baseline platelet count and other parameters. (See Polycythemia Vera under Dosage and Administration.)

Special Populations

Hepatic Impairment

Intermediate- or High-Risk Myelofibrosis

In patients with myelofibrosis and preexisting mild, moderate, or severe hepatic impairment (Child-Pugh class A, B, or C), dosage adjustment of the initial dosage of ruxolitinib is determined by the patient's baseline platelet count.

In patients with a baseline platelet count >150,000/mm³, no dosage adjustment necessary.

In patients with a baseline platelet count 100,000–150,000/mm³, reduce initial ruxolitinib dosage to 10 mg twice daily.

In patients with a baseline platelet count 50,000 to <100,000/mm³, reduce initial ruxolitinib dosage to 5 mg once daily.

The manufacturer states that ruxolitinib should be avoided in patients with a baseline platelet count <50,000/mm³ and hepatic impairment.

Polycythemia Vera

In patients with polycythemia vera and preexisting mild, moderate, or severe hepatic impairment (Child-Pugh class A, B, or C), reduce initial ruxolitinib dosage to 5 mg twice daily.

Acute GVHD

In patients with acute GVHD (not of the liver) and preexisting mild, moderate, or severe hepatic impairment (based on National Cancer Institute [NCI] criteria), no dosage adjustment necessary.

In patients with grade 1, 2, or 3 acute GVHD of the liver, no dosage adjustment necessary.

In patients with grade 4 acute GVHD of the liver, reduce ruxolitinib dosage to 5 mg once daily.

Chronic GVHD

In patients with chronic GVHD (not of the liver) and preexisting mild, moderate, or severe hepatic impairment (based on NCI criteria), no dosage adjustment necessary.

In patients with grade 1 or 2 chronic GVHD of the liver, no dosage adjustment necessary.

In patients with grade 3 chronic GVHD of the liver, monitor CBCs more frequently and adjust ruxolitinib dosage for adverse effects, if necessary.

Renal Impairment

Intermediate- or High-Risk Myelofibrosis

In patients with myelofibrosis and preexisting mild, moderate, or severe renal impairment, dosage adjustment of the initial dosage of ruxolitinib is determined by the patient's baseline platelet count. (See Table 17.)

Polycythemia Vera

In patients with polycythemia vera and moderate to severe renal impairment (Cl_Cr15–59 mL/minute), reduce initial ruxolitinib dosage to 5 mg twice daily.

In patients with polycythemia vera and end-stage renal disease who are receiving dialysis, administer ruxolitinib 10 mg once after dialysis session only on days when hemodialysis is scheduled.

Acute GVHD

In patients with acute GVHD and moderate to severe renal impairment (Cl_Cr15–59 mL/minute), reduce initial ruxolitinib dosage to 5 mg once daily.

In patients with acute GVHD and end-stage renal disease who are receiving dialysis, administer ruxolitinib 5 mg once after dialysis session only on days when hemodialysis is scheduled.

Chronic GVHD

In patients with chronic GVHD and moderate to severe renal impairment (Cl_Cr15–59 mL/minute), reduce initial ruxolitinib dosage to 5 mg twice daily.

In patients with chronic GVHD and end-stage renal disease who are receiving dialysis, administer ruxolitinib 10 mg once after dialysis session only on days when hemodialysis is scheduled.

Geriatric Patients

Manufacturer makes no specific dosage recommendations in patients ≥65 years of age.

Cautions for Ruxolitinib Phosphate

Contraindications

• Manufacturer states none known.

Warnings/Precautions

Thrombocytopenia, Anemia, and Neutropenia

Can cause adverse hematologic reactions (e.g., thrombocytopenia, anemia, neutropenia). Perform CBCs before initiating therapy and every 2 to 4 weeks until a stable dosage of the drug is reached. Once a stable dosage has been reached, monitor CBCs as clinically indicated.

Thrombocytopenia usually managed by reducing dosage or temporarily withholding therapy. Administer platelet transfusions if clinically indicated.

Patients who develop anemia may require blood transfusions; consider dosage modification in such patients.

Neutropenia (ANC <500/mm³) generally reversible; managed by temporarily withholding ruxolitinib.

Infectious Complications

Assess patients for risk of developing serious bacterial, mycobacterial, fungal, and viral infections. Resolve active serious infections prior to initiating ruxolitinib. Carefully observe patients for signs and/or symptoms of infection and promptly initiate appropriate treatment.

Tuberculosis infection reported. Evaluate patients for tuberculosis prior to initiating therapy and test patients at high risk for tuberculosis for latent infection. Risk factors for tuberculosis include a history of residence in or travel to an area with high tuberculosis prevalence, close contact with someone with active tuberculosis, or a history of latent or active tuberculosis without an ability to verify that adequate treatment was administered. Consult a tuberculosis specialist when deciding whether antimycobacterial therapy should be initiated in patients with active or latent tuberculosis.

Progressive multifocal leukoencephalopathy reported. If progressive multifocal leukoencephalopathy is suspected, discontinue treatment with ruxolitinib and evaluate patient.

Herpes zoster infection reported. Inform patients about the early signs and symptoms of herpes zoster and advise patients to seek treatment as soon as possible for this condition.

Herpes simplex virus reactivation and/or dissemination reported. Monitor patients for signs and symptoms of herpes simplex infection. If confirmed, consider therapy interruption and prompt treatment according to clinical guidelines.

Increases in hepatitis B viral load, both with and without concomitant elevations in alanine and aspartate aminotransferases, reported in patients with chronic hepatitis B virus infection. Effect of ruxolitinib on viral replication in patients with chronic hepatitis B virus infection is unknown. Treat patients with chronic hepatitis B virus infection and monitor according to current clinical guidelines.

Withdrawal of Therapy

Following interruption or discontinuance of therapy, symptoms of myeloproliferative neoplasms may return to pretreatment levels within approximately 1 week.

Some patients with myelofibrosis have reported adverse effects including fever, respiratory distress, hypotension, disseminated intravascular coagulation, and multiorgan failure following discontinuance of ruxolitinib.

Evaluate for adverse effects during tapering or discontinuance of ruxolitinib and consider restarting or increasing dosage if any of adverse effects associated with withdrawal occur. Consider gradual tapering of the dosage when ruxolitinib is discontinued for reasons other than thrombocytopenia or neutropenia.

Malignancies and Lymphoproliferative Disorders

Nonmelanoma skin cancers, including basal cell, squamous cell, and Merkel cell carcinoma, reported. Lymphoma and other malignancies reported in patients receiving other Janus kinase (JAK) inhibitors for the treatment of rheumatoid arthritis.

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

Periodically perform dermatologic examinations during therapy.

Metabolic Effects

Increases in total cholesterol, low-density lipoprotein (LDL)-cholesterol, and triglyceride concentrations observed. Potential effects of these elevations on cardiovascular morbidity and mortality not determined.

Monitor lipid concentrations 8–12 weeks after initiation of ruxolitinib therapy. Manage hyperlipidemia according to current standards of care.

Major Adverse Cardiovascular Events

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

Consider risks and benefits of ruxolitinib prior to initiating 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, pulmonary embolism, 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 ruxolitinib.

Specific Populations

Pregnancy

Adverse developmental outcomes, including decreased fetal weight, observed in animal studies.

No studies of ruxolitinib in pregnant women exist to inform a drug-associated risk.

Lactation

Ruxolitinib and/or its metabolites distributed into milk in rats; not known whether distributed into human milk. Discontinue breast-feeding during ruxolitinib therapy and for 2 weeks after the final dose of the drug.

Pediatric Use

Safety and efficacy not established in pediatric patients <12 years of age with acute or chronic GVHD or in pediatric patients <18 years of age for the treatment of myelofibrosis and polycythemia vera.

Geriatric Use

No overall differences in safety or efficacy relative to younger adults.

Clinical studies of patients with acute GVHD did not include sufficient numbers of subjects ≥65 years of age to determine whether they respond different relative to younger adults.

Hepatic Impairment

Acute or chronic GVHD: No clinically significant effects on pharmacokinetics observed in patients with mild to severe hepatic impairment as defined by National Cancer Institute (NCI) criteria. In patients with mild to severe hepatic impairment according to Child-Pugh criteria, mean area under the plasma concentration-time curve (AUC) for the drug was increased in patients with mild (Child-Pugh class A), moderate (Child-Pugh class B), or severe (Child-Pugh class C) hepatic impairment compared with patients with normal hepatic function. In patients with GVHD of the liver, no clinically significant effects on pharmacokinetics of ruxolitinib observed in patients with grade 1, 2, or 3 acute GVHD or grade 1 or 2 chronic GVHD; however, clearance of the drug was reduced in patients with grade 4 acute GVHD of the liver compared with patients without acute GVHD of the liver. The effect of grade 3 chronic GVHD on the pharmacokinetics of ruxolitinib is not known.

Dosage adjustment in patients with hepatic impairment may be necessary.

Renal Impairment

Total AUC of ruxolitinib and its active metabolites increased in patients with mild, moderate, or severe renal impairment compared with patients with normal renal function.

Total AUC increased in patients with end-stage renal disease after dialysis.

Dosage reduction of ruxolitinib recommended in patients with end-stage renal disease requiring dialysis and in patients with moderate or severe renal impairment (Cl_cr 15–59 mL/minute).

Common Adverse Effects

Myelofibrosis and polycythemia vera: Most common adverse hematologic reactions (reported in >20%) include thrombocytopenia and anemia. Most common nonhematologic adverse reactions (reported in ≥15%) include bruising, dizziness, headache, and diarrhea.

Acute GVHD: Most common adverse hematologic reactions (reported in >50%) include anemia, thrombocytopenia, and neutropenia. Most common nonhematologic adverse reactions (reported in >50%) include infections and edema.

Chronic GVHD: Most common adverse hematologic reactions (reported in >35%) include anemia and thrombocytopenia. Most common nonhematologic adverse reactions (reported in ≥20%) include infections and viral infections.

Drug Interactions

Metabolized mainly by CYP3A4.

Ruxolitinib and its M18 metabolite do not inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4 in vitro.

Ruxolitinib does not induce CYP1A2, 2B6, or 3A4 at clinically relevant concentrations.

Not a substrate for P-glycoprotein (P-gp).

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.

Drugs Affecting Hepatic Microsomal Enzymes

Potent CYP3A4 inhibitors: Pharmacokinetic interaction (increased ruxolitinib peak plasma concentrations and AUC). Dosage modification of ruxolitinib may be necessary.

Weak or moderate CYP3A4 inhibitors: Pharmacokinetic interaction (increased ruxolitinib peak plasma concentrations and AUC). Not clinically important; dosage adjustment not recommended.

Potent CYP3A4 inducers: Pharmacokinetic interaction (decreased ruxolitinib peak plasma concentrations and AUC). Dosage adjustment not recommended. Monitor patients closely; titrate dosage based on safety and efficacy.

Specific Drugs

Ruxolitinib Phosphate Pharmacokinetics

Absorption

Bioavailability

Rapidly absorbed following oral administration; peak plasma concentrations usually attained within 1–2 hours.

About 80% of dose systemically available.

Food

No clinically relevant changes in pharmacokinetics when administered with high-fat meal.

Special Populations

In patients with acute or chronic GVHD, no clinically significant effects on pharmacokinetics observed in patients with mild to severe hepatic impairment as defined by National Cancer Institute (NCI) criteria. In patients with mild to severe hepatic impairment according to Child-Pugh criteria, mean AUC for the drug increased by 1.9-, 1.3-, or 1.7-fold in patients with mild (Child-Pugh class A), moderate (Child-Pugh class B), or severe (Child-Pugh class C) hepatic impairment, respectively, compared with patients with normal hepatic function. In patients with GVHD of the liver, no clinically significant effect on pharmacokinetics of ruxolitinib observed in patients with grade 1, 2, or 3 acute GVHD or grade 1 or 2 chronic GVHD; however, clearance was reduced in patients with grade 4 acute GVHD of the liver compared with patients without acute GVHD of the liver. Effect of grade 3 chronic GVHD on pharmacokinetics of ruxolitinib is not known.

In patients with renal impairment, total AUC of ruxolitinib and its active metabolites increased by 1.3-, 1.5-, or 1.9-fold in patients with mild, moderate, or severe renal impairment, respectively, compared with patients with normal renal function; total AUC increased by 1.6-fold in patients with end-stage renal disease after dialysis.

Distribution

Extent

Distributed into milk in rats; not known whether distributed into human milk.

Plasma Protein Binding

Approximately 97% (mainly albumin).

Elimination

Metabolism

CYP3A4 is the major enzyme responsible for metabolism.

Elimination Route

Excreted in urine (74%) and feces (22%), mainly as metabolites (<1% excreted as unchanged drug).

Half-life

Mean half-life following a single oral dose: approximately 3 hours.

Mean half-life of ruxolitinib and its metabolites: approximately 5.8 hours.

Special Populations

Ruxolitinib is not removed by dialysis; however, removal of some active metabolites by dialysis cannot be ruled out.

Stability

Storage

Oral

Tablets

20–25°C (excursions permitted between 15–30°C).

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• Selectively inhibits JAK1 and 2, which mediate signaling of cytokines and growth factors important for hematopoiesis and immune function.

• Myelofibrosis and polycythemia vera are myeloproliferative neoplasms known to be associated with dysregulated JAK1 and 2 signaling.

• 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.

• JAK-STAT signaling pathways play a role in regulating the development, proliferation, and activation of several immune cell types important for pathogenesis of graft-versus-host disease (GVHD).

• 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.

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. Advise patients to contact their clinicians if unusual bleeding, bruising, fatigue, shortness of breath, or fever occurs.

• Advise patients to notify clinician immediately if signs and/or symptoms of infection (e.g., chills, aches, fever, nausea, vomiting, weakness) occur.

• Importance of informing patients about early signs and symptoms of herpes zoster (e.g., painful skin rash or blisters), herpes simplex, and progressive multifocal leukoencephalopathy. Advise patients to seek treatment as soon as possible if signs and/or symptoms of herpes zoster, herpe simplex, or progressive multifocal leukoencephalopathy occur.

• Inform patients that after discontinuance of treatment, signs and symptoms from myeloproliferative neoplasms are expected to return. Instruct patients not to interrupt or discontinue ruxolitinib without consulting their clinician.

• Inform patients that ruxolitinib may increase their risk of certain nonmelanoma skin cancers (NMSC). Advise patients to inform their healthcare provider if they have ever had any type of skin cancer or if they observe any new or changing skin lesions.

• Inform patients that ruxolitinib may increase blood cholesterol, and of the need to monitor blood cholesterol levels.

• Advise patients that major adverse cardiovascular events (MACE), including myocardial infarction, stroke, and cardiovascular death, have been reported in clinical studies with another Janus kinase (JAK) inhibitor when used in patients with rheumatoid arthritis. 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.

• Advise patients that deep-vein thrombosis (DVT) and pulmonary embolism (PE) have been reported in clinical studies with another JAK inhibitor when used in patients with rheumatoid arthritis. Advise patients to tell their clinician if they develop any signs or symptoms of a DVT or PE.

• 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 when used in patients with rheumatoid arthritis.

• 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.

• Inform patients of importance of adherence to dosing schedule and that ruxolitinib is a long-term therapy; advise patients not to change dosage or discontinue drug without consulting their clinicians. Inform patients that signs and symptoms of myeloproliferative neoplasms are expected to return after treatment discontinuance.

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed. Importance of advising women not to breast-feed during therapy with the drug and for 2 weeks after the final dose.

• 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. (See Cautions.)

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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 of ruxolitinib is restricted. Patients must obtain ruxolitinib through the Incyte Connecting to Access, Reimbursement, Education, and Support (IncyteCARES) program.

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Frequently asked questions

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