Ruxolitinib

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Jakafi: 5 mg, 10 mg, 15 mg, 20 mg, 25 mg

Pharmacology

Mechanism of Action

Ruxolitinib is a kinase inhibitor which selectively inhibits Janus Associated Kinases (JAKs), JAK1 and JAK2. JAK1 and JAK2 mediate signaling of cytokine and growth factors responsible for hematopoiesis and immune function; JAK mediated signaling involves recruitment of STATs (signal transducers and activators of transcription) to cytokine receptors which leads to modulation of gene expression. In myelofibrosis and polycythemia vera, JAK1/2 activity is dysregulated; ruxolitinib modulates the affected JAK1/2 activity. JAK-STAT signaling is involved with the regulation of the development, proliferation, and activation of immune cell types important to GVHD pathogenesis; an animal model suggests that ruxolitinib may lead to decreased expression of inflammatory cytokines in colon homogenates and decreased immune cell infiltration in the colon.

Pharmacokinetics/Pharmacodynamics

Absorption

Rapid

Distribution

V_d: Myelofibrosis: 72 L; Polycythemia vera: 75 L

Metabolism

Hepatic, primarily via CYP3A4 (and minimally CYP2C9); forms active metabolites responsible for 20% to 50% of activity

Excretion

Urine (74%, <1% as unchanged drug); feces (22%, <1% as unchanged drug)

Onset of Action

Acute graft-versus-host disease (GVHD): Median time to response: 1.5 weeks (range: 1 to 11 weeks) (Zeiser 2015)

Chronic GVHD: Median time to response: 3 weeks (range: 1 to 25 weeks) (Zeiser 2015); responses were observed within 2 weeks of ruxolitinib initiation in another study (Khoury 2018)

Half-Life Elimination

Ruxolitinib: ~3 hours (hepatic impairment: 4.1 to 5 hours); Ruxolitinib + metabolites: ~5.8 hours

Protein Binding

~97%; primarily to albumin

Use in Specific Populations

Special Populations: Renal Function Impairment

Following a single 25 mg ruxolitinib dose, the total AUC of ruxolitinib (and active metabolites) increased by 1.3-, 1.5-, and 1.9-fold in subjects with mild, moderate, or severe renal impairment, respectively, compared to those with CrCl ≥90 mL/minute. Total AUC of ruxolitinib and active metabolites increased 1.6-fold in subjects with ESRD requiring dialysis (compared to those with CrCl ≥90 mL/minute).

Special Populations: Hepatic Function Impairment

Following a single 25 mg ruxolitinib dose, the AUC increased by 1.9-, 1.3-, and 1.7-fold in subjects with Child-Pugh class A, Child-Pugh class B, or Child-Pugh class C hepatic impairment, respectively, compared to those with normal hepatic function.

Use: Labeled Indications

Graft-versus-host disease, acute: Treatment of steroid-refractory acute graft-versus-host disease (GVHD) in adult and pediatric patients ≥12 years

Myelofibrosis: Treatment of intermediate or high-risk myelofibrosis in adults, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential thrombocythemia myelofibrosis

Polycythemia vera: Treatment of polycythemia vera in adults with an inadequate response to or intolerance to hydroxyurea

Use: Off Label

Graft-versus-host disease, treatment (chronic)c

Data from a retrospective survey reporting outcomes in patients with steroid-refractory acute or chronic graft-versus-host disease (GVHD) support the use of ruxolitinib for salvage treatment of this condition Zeiser 2015. Data from a small case series of patients with acute or chronic GVHD who had failed extracorporeal photopheresis (in addition to corticosteroids) further support the use of ruxolitinib in the management of chronic refractory GVHD Sarmiento Maldonado 2017. Data from a small retrospective study in patients with steroid dependent chronic GVHD showed success in discontinuing or reducing steroids and demonstrated responses (mostly partial response) with salvage ruxolitinib treatment Khoury 2018.

Contraindications

There are no contraindications listed in the manufacturer's US labeling.

Canadian labeling: Hypersensitivity to ruxolitinib or any component of the formulation or container; history of or current progressive multifocal leukoencephalopathy

Dosage and Administration

Dosing: Adult

Graft-versus-host disease (acute; treatment), steroid-refractory: Oral: Initial: 5 mg twice daily. Consider increasing the dose to 10 mg twice daily after at least 3 days of treatment (if ANC and platelets are not decreased by ≥50% compared to baseline [first day of ruxolitinib]).

Consider tapering ruxolitinib after 6 months of therapy if response occurs and therapeutic corticosteroid doses have been discontinued; taper by one dose level approximately every 8 weeks (10 mg twice daily to 5 mg twice daily to 5 mg once daily). Consider retreatment if acute graft-versus-host disease (GVHD) signs/symptoms recur during or after tapering ruxolitinib.

Graft-versus-host disease (chronic; treatment), steroid-refractory (off-label use): Oral: 5 to 10 mg twice daily (Zeiser 2015)

Myelofibrosis: Oral: Initial dose (based on platelet count, titrate dose thereafter based on efficacy and safety):

Platelets >200,000/mm³: 20 mg twice daily

Platelets 100,000 to 200,000/mm³: 15 mg twice daily

Platelets 50,000 to <100,000/mm³: 5 mg twice daily

Dosage modification based on response in patients with baseline platelet count ≥100,000/mm³ prior to initial treatment with ruxolitinib: For insufficient response (with adequate platelet and neutrophil counts), may increase the dose in 5 mg twice daily increments to a maximum dose of 25 mg twice daily. Do not increase during initial 4 weeks and no more frequently than every 2 weeks. Discontinue treatment after 6 months if no reduction in spleen size or no improvement in symptoms. When discontinuing for reasons other than thrombocytopenia, consider gradually tapering by ~5 mg twice daily per week.

Dose increases may be considered if meet all of the following situations:

- Failure to achieve either a 50% reduction (from baseline) in palpable spleen length or a 35% reduction (from baseline) in spleen volume (measured by CT or MRI)

- Platelet count >125,000/mm³ at 4 weeks (and never <100,000/mm³)

- Absolute neutrophil count (ANC) >750/mm³

Dosage modification for bleeding requiring intervention (regardless of platelet count): Interrupt treatment until bleeding resolved; may consider resuming at the prior dose if the underlying cause of bleeding has resolved or at a reduced dose if the underlying cause of bleeding persists.

Dosage modification based on response in patients with baseline platelet 50,000 to <100,000/mm³ prior to initial treatment with ruxolitinib: For insufficient response (with adequate platelet and neutrophil counts), may increase the dose in 5 mg daily increments to a maximum dose of 10 mg twice daily. Do not increase during initial 4 weeks and no more frequently than every 2 weeks. Discontinue treatment after 6 months if no reduction in spleen size or no improvement in symptoms.

Dose increases may be considered if meet all of the following situations:

- Platelet count remains ≥40,000/mm³ and did not decrease more than 20% in prior 4 weeks

- Absolute neutrophil count (ANC) >1,000/mm³

- No adverse event or hematological toxicity resulting in dose reduction or interruption occurred in prior 4 weeks

Therapy discontinuation: Consider gradually tapering off (by 5 mg twice daily each week) if discontinuing for reasons other than thrombocytopenia.

Polycythemia vera: Oral: Initial dose: 10 mg twice daily (titrate dose based on efficacy and safety)

Dose modification due to insufficient response: If response is insufficient and platelet, hemoglobin, and neutrophil counts are adequate, the dose may be increased in 5 mg twice daily increments to a maximum of 25 mg twice daily. Do not increase dose in the first 4 weeks of treatment and not more frequently than every 2 weeks. Consider dose increases in patients who meet all of the following conditions:

- Inadequate efficacy demonstrated by one or more of the following: Continued need for phlebotomy, WBC >ULN of normal range, platelet count >ULN of normal range, or palpable spleen that is reduced by <25% from baseline.

- Platelet count ≥140,000/mm³

- Hemoglobin ≥12 g/dL

- ANC ≥1,500/mm³

Therapy discontinuation: Consider gradually tapering off (by 5 mg twice daily each week) if discontinuing for reasons other than thrombocytopenia.

Dosage adjustment with concomitant therapy

Graft-versus-host disease (acute; treatment), steroid-refractory: CYP3A4 inhibitors:

Ketoconazole: Administer ruxolitinib 5 mg once daily

Other CYP3A4 inhibitors: No ruxolitinib dosage adjustment necessary. If using concomitantly with itraconazole, monitor blood counts more frequently and adjust ruxolitinib dose if necessary.

Myelofibrosis and polycythemia vera: Strong CYP3A4 inhibitors and fluconazole (≤200 mg):

Note: Avoid concomitant use of fluconazole doses >200 mg daily with ruxolitinib (except in patients with acute GVHD).

Myelofibrosis: Initial dose:

Platelets ≥100,000/mm³: 10 mg twice daily.

Platelets 50,000/mm³ to <100,000/mm³: 5 mg once daily.

Monitor closely and further adjust dose based on safety and efficacy.

Polycythemia vera: Initial dose: 5 mg twice daily

Myelofibrosis and polycythemia vera: If on stable dose:

Stabilized on ruxolitinib ≥10 mg twice daily: Reduce dose by 50% (rounded up to the closest available tablet strength).

Stabilized on ruxolitinib 5 mg twice daily: Reduce dose to 5 mg once daily.

Stabilized on ruxolitinib 5 mg once daily: Avoid strong CYP3A4 inhibitors or fluconazole or interrupt treatment for the duration of strong CYP3A4 inhibitor or fluconazole use.

Monitor closely and further adjust dose based on safety and efficacy.

Dosing: Pediatric

Graft-versus-host disease (GVHD) (acute, steroid-refractory), treatment:

Fixed dosing: Children ≥12 years and Adolescents: Oral: Initial: 5 mg twice daily. Consider increasing the dose to 10 mg twice daily after at least 3 days of treatment if ANC and platelets are not decreased by ≥50% compared to baseline (first day of ruxolitinib).

Weight-directed dosing: Children and Adolescents: Limited data available: Oral: Note: Dosing based on a retrospective study of 13 patients (aged 1.6 to 16.5 years) receiving ruxolitinib for steroid-refractory GVHD. Ruxolitinib was associated with a high incidence of reversible adverse effects and fair overall response rate (Khandelwal 2017).

<25 kg: Initial: 2.5 mg twice daily; if tolerated, may double the dose on a weekly basis to a maximum dose of 10 mg twice daily.

≥25 kg: Initial: 5 mg twice daily; if tolerated, may double the dose on a weekly basis to a maximum dose of 10 mg twice daily.

Tapering of therapy: Consider tapering ruxolitinib after 6 months of therapy if response occurs and therapeutic corticosteroid doses have been discontinued; taper by 1 dose level approximately every 8 weeks (ie, 10 mg twice daily to 5 mg twice daily to 5 mg once daily). Consider retreatment if acute GVHD signs or symptoms recur during or after tapering ruxolitinib.

Dosage adjustment with concomitant strong CYP3A4 inhibitors: Children ≥12 years and Adolescents: Oral:

Ketoconazole: Administer ruxolitinib 5 mg once daily.

Other CYP3A4 inhibitors: No ruxolitinib dosage adjustment necessary. If using concomitantly with itraconazole, monitor blood counts more frequently and adjust ruxolitinib dose if necessary.

Dosage adjustment for toxicity: Children ≥12 years and Adolescents: Oral:

Dosage reduction levels:

Note: Dosage reduction is based on ruxolitinib regimen at time of toxicity.

10 mg twice daily: Reduce dose to 5 mg twice daily.

5 mg twice daily: Reduce dose to 5 mg once daily.

5 mg once daily: Interrupt ruxolitinib treatment until clinical and/or laboratory parameters recover.

Dosage modification for hematologic toxicity:

Clinically significant thrombocytopenia: Reduce dose by 1 dose level; when platelets recover to previous values, may increase dose to prior dose level.

ANC <1,000/mm³ related to ruxolitinib treatment: Interrupt treatment for up to 14 days; upon recovery, restart at 1 dose level lower.

Dosing: Adjustment for Toxicity

Graft-versus-host disease (acute; treatment), steroid-refractory:

Dosage reduction levels:

If dose is 10 mg twice daily, reduce dose to 5 mg twice daily.

If dose is 5 mg twice daily, reduce dose to 5 mg once daily.

If unable to tolerate 5 mg once daily, interrupt ruxolitinib treatment until clinical and/or laboratory parameters recover.

Dosage modification for hematologic toxicity:

Clinically significant thrombocytopenia (after supportive measures): Reduce dose by 1 dose level; when platelets recover to previous values, may increase dose to prior dose level.

ANC <1,000/mm³ (related to ruxolitinib treatment): Interrupt treatment for up to 14 days. Resume at 1 dose level lower when ANC recovers.

Myelofibrosis:

Dosage modification for treatment interruption:

If baseline platelet count ≥100,000/mm³ prior to initial treatment with ruxolitinib and:

Platelets <50,000/mm³ or ANC <500/mm³: Interrupt treatment; upon platelet recovery (to ≥50,000/mm³) or ANC recovery (to ≥750/mm³), dosing may be restarted or increased based on the following platelet or ANC levels:

Platelets ≥125,000/mm³: Dose should be at least 5 mg twice daily below the dose at treatment interruption, up to a maximum of 20 mg twice daily

Platelets 100,000 to <125,000/mm³: Dose should be at least 5 mg twice daily below the dose at treatment interruption, up to a maximum of 15 mg twice daily

Platelets 75,000 to <100,000/mm³: Dose should be at least 5 mg twice daily below the dose at treatment interruption, up to a maximum of 10 mg twice daily for at least 2 weeks; may increase to 15 mg twice daily if stable

Platelets 50,000 to <75,000/mm³: 5 mg twice daily for at least 2 weeks; may increase to 10 mg twice daily if stable

Platelets <50,000/mm³: Continue to withhold treatment

ANC ≥750/mm³: Resume at 5 mg once daily or 5 mg twice daily below the largest dose in the week prior to treatment interruption, whichever is greater

Note: Long-term maintenance at 5 mg twice daily has not demonstrated responses; limit use of the dose level to patients where the benefits outweigh risks

If baseline platelet count 50,000 to <100,000/mm³ prior to initial treatment with ruxolitinib and:

Platelets <25,000/mm³ or ANC <500/mm³: Interrupt treatment; upon platelet recovery (to ≥35,000/mm³) or ANC recovery (to ≥750/mm³), resume at 5 mg once daily or 5 mg twice daily below the largest dose in the week prior to treatment interruption, whichever is greater

Note: Long-term maintenance at 5 mg twice daily has not demonstrated responses; limit use of the dose level to patients where the benefits outweigh risks

Dosage reduction for thrombocytopenia in patients with baseline platelet count ≥100,000/mm³ prior to initial treatment with ruxolitinib:

Tablet has been converted to the following text:

Dosage reduction for thrombocytopenia in patients with baseline platelet count ≥100,000/mm³ prior to initial treatment with ruxolitinib:

Dose at time of thrombocytopenia: 25 mg twice daily

Platelets 100,000 to <125,000/mm³: Reduce dose to 20 mg twice daily

Platelets 75,000 to <100,000/mm³: Reduce dose to 10 mg twice daily

Platelets 50,000 to <75,000/mm³: Reduce dose to 5 mg twice daily

Platelets <50,000/mm³: Hold dose

Dose at time of thrombocytopenia: 20 mg twice daily

Platelets 100,000 to <125,000/mm³: Reduce dose to 15 mg twice daily

Platelets 75,000 to <100,000/mm³: Reduce dose to 10 mg twice daily

Platelets 50,000 to <75,000/mm³: Reduce dose to 5 mg twice daily

Platelets <50,000/mm³: Hold dose

Dose at time of thrombocytopenia: 15 mg twice daily

Platelets 100,000 to <125,000/mm³: No change

Platelets 75,000 to <100,000/mm³: Reduce dose to 10 mg twice daily

Platelets 50,000 to <75,000/mm³: Reduce dose to 5 mg twice daily

Platelets <50,000/mm³: Hold dose

Dose at time of thrombocytopenia: 10 mg twice daily

Platelets 100,000 to <125,000/mm³: No change

Platelets 75,000 to <100,000/mm³: No change

Platelets 50,000 to <75,000/mm³: Reduce dose to 5 mg twice daily

Platelets <50,000/mm³: Hold dose

Dose at time of thrombocytopenia: 5 mg twice daily

Platelets 100,000 to <125,000/mm³: No change

Platelets 75,000 to <100,000/mm³: No change

Platelets 50,000 to <75,000/mm³: No change

Platelets <50,000/mm³: Hold dose

Note: Long-term maintenance at 5 mg twice daily has not demonstrated responses; limit use of the dose level to patients where the benefits outweigh risks

Dosage reduction for thrombocytopenia in patients with baseline platelet 50,000 to <100,000/mm³ prior to initial treatment with ruxolitinib:

Platelets 25,000 to <35,000/mm³and platelet count decreased <20% during prior 4 weeks:

If current daily dose >5 mg: Reduce dose by 5 mg once daily

If current dose 5 mg once daily: Continue 5 mg once daily

Platelets 25,000 to <35,000/mm³and platelet count decreased ≥20% during prior four weeks:

If current daily dose >10 mg: Reduce dose by 5 mg twice daily

If current dose 5 mg twice daily: Reduce dose to 5 mg once daily

If current dose 5 mg once daily: Continue 5 mg once daily

Platelets <25,000 mm³: Continue to withhold treatment

Note: Long-term maintenance at 5 mg twice daily has not demonstrated responses; limit use of the dose level to patients where the benefits outweigh risks

Polycythemia vera:

Hematologic toxicity:

Hemoglobin ≥12 g/dL AND platelets ≥100,000/mm³: No dosage adjustment necessary.

Hemoglobin 10 to <12 g/dL AND platelets 75,000 to <100,000/mm³: Consider dosage adjustment to avoid dose interruptions due to anemia and thrombocytopenia.

Hemoglobin 8 to <10 g/dL OR platelets 50,000 to <75,000/mm³: Reduce dose by 5 mg twice daily; for patients currently receiving 5 mg twice daily, reduce dose to 5 mg once daily.

Hemoglobin <8 g/dL OR platelets <50,000/mm³ OR ANC <1,000/mm³: Interrupt dosing.

Dosage reduction following treatment interruption (use the most severe category of hemoglobin, platelets or ANC to determine reinitiation dose):

Hemoglobin <8 g/dL OR platelets <50,000/mm³ OR ANC <1,000/mm³: Continue to hold.

Hemoglobin 8 to <10 g/dL OR platelets 50,000 to <75,000/mm³ OR ANC 1,000 to <1,500/mm³: Restart at a maximum of 5 mg twice daily (continue treatment for at least 2 weeks, if stable, then may increase dose by 5 mg twice daily) or no more than 5 mg twice daily less than the dose that resulted in dose interruption

Hemoglobin 10 to <12 g/dL OR platelets 75,000 to <100,000/mm³ OR ANC 1,500 to <2,000/mm³: Restart at a maximum of 10 mg twice daily (continue treatment for at least 2 weeks, if stable, then may increase dose by 5 mg twice daily) or no more than 5 mg twice daily less than the dose that resulted in dose interruption

Hemoglobin ≥12 g/dL OR platelets ≥100,000/mm³ OR ANC ≥2,000/mm³: Restart at a maximum of 15 mg twice daily (continue treatment for at least 2 weeks, if stable, then may increase dose by 5 mg twice daily) or no more than 5 mg twice daily less than the dose that resulted in dose interruption

Note: If dose interruption was required while receiving 5 mg twice daily, may restart at 5 mg twice daily or 5 mg once daily (but not higher) once hemoglobin is ≥10 g/dL, platelets are ≥75,000/mm³, and ANC is ≥1,500/mm³

Dose management after restarting treatment: After restarting following a dose interruption, the dose may be titrated, although the maximum total daily dose should not exceed 5 mg less than the dose resulting in the interruption (unless dose interruption following phlebotomy-associated anemia, in which case the maximum total daily dose is not limited).

Extemporaneously Prepared

A suspension for nasogastric administration may be prepared with tablets. Place one tablet into ~40 mL water; stir for approximately 10 minutes. Administer within 6 hours after preparation.

Jakafi (ruxolitinib) [prescribing information]. Wilmington, DE: Incyte Corporation; May 2019.

Administration

Oral: May be administered orally with or without food. If a dose is missed, return to the usual dosing schedule and do not administer an additional dose.

If unable to ingest tablets, may administer through a nasogastric (NG) tube (≥8 Fr): Suspend 1 tablet in ~40 mL water and stir for ~10 minutes and administer (within 6 hours after dispersion) with appropriate syringe; rinse NG tube with ~75 mL water (effect of enteral tube feeding on ruxolitinib exposure has not been evaluated).

Dietary Considerations

Avoid grapefruit juice (may increase the effects of ruxolitinib).

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F).

Drug Interactions

Aprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Baricitinib: Immunosuppressants may enhance the immunosuppressive effect of Baricitinib. Management: Use of baricitinib in combination with potent immunosuppressants such as azathioprine or cyclosporine is not recommended. Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted. Consider therapy modification

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Bradycardia-Causing Agents: Ruxolitinib may enhance the bradycardic effect of Bradycardia-Causing Agents. Management: Ruxolitinib Canadian product labeling recommends avoiding use with bradycardia-causing agents to the extent possible. Monitor therapy

Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Monitor therapy

Cladribine: May enhance the immunosuppressive effect of Immunosuppressants. Avoid combination

Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Avoid combination

Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

CYP3A4 Inducers (Strong): May decrease the serum concentration of Ruxolitinib. Monitor therapy

CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Ruxolitinib. Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Ruxolitinib. Management: This combination should be avoided under some circumstances. See monograph for details. Consider therapy modification

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Consider therapy modification

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Duvelisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Erdafitinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Fluconazole: May increase the serum concentration of Ruxolitinib. Management: This combination should be avoided under some circumstances. See monograph for details. Consider therapy modification

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fosnetupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Idelalisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Larotrectinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Mesalamine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

MiFEPRIStone: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Consider therapy modification

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Netupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy

Palbociclib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Pidotimod: Immunosuppressants may diminish the therapeutic effect of Pidotimod. Monitor therapy

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Simeprevir: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Siponimod: Immunosuppressants may enhance the immunosuppressive effect of Siponimod. Monitor therapy

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Management: Evaluate patients to see if it is medically appropriate to reduce or discontinue therapy with immunosuppressants prior to initiating sipuleucel-T therapy. Consider therapy modification

Smallpox and Monkeypox Vaccine (Live): Immunosuppressants may diminish the therapeutic effect of Smallpox and Monkeypox Vaccine (Live). Monitor therapy

Stiripentol: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Consider therapy modification

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Upadacitinib: Immunosuppressants may enhance the immunosuppressive effect of Upadacitinib. Avoid combination

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Exceptions: Smallpox and Monkeypox Vaccine (Live). Avoid combination

Adverse Reactions

>10%:

Central nervous system: Dizziness (15% to 18%), headache (15% to 16%), fatigue (15%), insomnia (12%) (Verstovsek 2012)

Dermatologic: Bruise (23%), pruritus (14%)

Endocrine & metabolic: Increased serum cholesterol (17% to 35%), hypertriglyceridemia (15%)

Gastrointestinal: Diarrhea (15%), abdominal pain (15%)

Hematologic & oncologic: Anemia (72% to 96%; grade 3: ≤34%; grade 4: ≤11%), thrombocytopenia (27% to 70%; grade 3: 5% to 9%; grade 4: ≤4%), neutropenia (3% to 19%; grade 3: 5%; grade 4: ≤2%)

Hepatic: Increased serum alanine aminotransferase (25%), increased serum aspartate aminotransferase (17% to 23%)

Neuromuscular & skeletal: Muscle spasm (12%)

Respiratory: Dyspnea (13%)

1% to 10%:

Cardiovascular: Edema (8%), hypertension (<6%)

Endocrine & metabolic: Weight gain (≤7%)

Gastrointestinal: Constipation (8%), nausea (6%), flatulence (5%)

Genitourinary: Urinary tract infection (≤9%)

Infection: Herpes zoster infection (2% to 6%)

Neuromuscular & skeletal: Arthralgia (7%), asthenia (7%)

Respiratory: Nasopharyngitis (9%), cough (8%), epistaxis (6%)

<1%, postmarketing, and/or case reports: Exacerbation of hepatitis B, increased LDL cholesterol, progressive multifocal leukoencephalopathy, skin carcinoma, tuberculosis

Warnings/Precautions

Concerns related to adverse effects:

• Hematologic toxicity: Hematologic toxicity, including thrombocytopenia, anemia and neutropenia may occur; may require dosage modification. Monitor complete blood counts at baseline, every 2 to 4 weeks during dose stabilization, and then as clinically necessary. Thrombocytopenia is generally reversible with treatment interruption or dose reduction; platelet transfusions may be administered during treatment if clinically indicated. Anemia may require blood transfusion; may consider dose modification. Neutropenia (ANC <500/mm³) is generally reversible and managed by treatment interruption.
• Infections: Serious bacterial, mycobacterial (including tuberculosis), fungal, or viral infections have occurred. Active serious infections should be resolved prior to treatment initiation. Monitor for infections (including signs/symptoms of active tuberculosis and herpes zoster) during treatment; utilize prophylactic antibiotics according to clinical practice guidelines. Prompt treatment is recommended if symptoms of active tuberculosis and/or herpes zoster infection develop. Evaluate for tuberculosis risk factors prior to treatment initiation; patients at higher risk for tuberculosis (prior residence/travel to countries with a high tuberculosis prevalence, close contacts with active tuberculosis, or history of latent or active tuberculosis where adequate treatment course cannot be confirmed) should be tested for latent infection. For patients with evidence of tuberculosis (active or latent), decide risk-benefit of continuing treatment. Progressive multifocal leukoencephalopathy (PML) has been reported; discontinue and evaluate if suspected. Hepatitis B viral load (HBV-DNA titer) increases (with and without associated ALT or AST elevations) have been reported with ruxolitinib in patients with chronic hepatitis B infection, although the effect of ruxolitinib is unknown; monitor and manage appropriately.
• Lipid abnormalities: Ruxolitinib has been associated with increases in lipid parameters (eg, total cholesterol, LDL cholesterol, and triglycerides). Assess lipid parameters 8 to 12 weeks after ruxolitinib initiation; monitor and manage hyperlipidemia accordingly.
• Non-melanoma skin cancer: Non-melanoma skin cancers (basal cell, squamous cell, and Merkel cell carcinoma) have been reported in patients who have received ruxolitinib. Periodic skin examinations should be performed.

Disease-related concerns:

• Hepatic impairment: May require initial dosage reduction. In patients with myelofibrosis, avoid use if platelets <50,000/mm³ and with hepatic impairment (any degree). Monitor blood counts more frequently and consider dosage reduction in patients with stage 3 or 4 liver graft-versus-host disease (GVHD).
• Renal impairment: May require initial dosage reduction. Avoid use in patients with ESRD not requiring dialysis; in patients with myelofibrosis, avoid use if platelets <50,000/mm³ and with moderate to severe renal impairment. Ruxolitinib is not removed by dialysis; however, some active metabolites may be removed. On dialysis days, patients are advised to take their dose following dialysis sessions.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Other warnings/precautions:

• Appropriate use: Discontinue treatment in myelofibrosis patients after 6 months if no reduction in spleen size or no improvement in symptoms. Consider gradually tapering off if discontinuing for reasons other than thrombocytopenia. Within ~1 week after discontinuation, symptoms of myelofibrosis generally return to pretreatment levels.
• Withdrawal syndrome: Acute relapse of myelofibrosis symptoms (eg, fever, respiratory distress, hypotension, DIC, multiorgan failure), splenomegaly, worsening cytopenias, hemodynamic compensation, and septic shock-like syndrome have been reported with treatment tapering or discontinuation (Tefferi 2011). Symptoms generally return over approximately 1 week. Evaluate and treat any intercurrent illness and consider restarting or increasing dose. Consider gradually tapering off if discontinuing for reasons other than thrombocytopenia or neutropenia. Patients should not interrupt/discontinue treatment without consulting healthcare provider.

Monitoring Parameters

CBC (baseline, every 2 to 4 weeks until dose stabilized, then as clinically indicated; monitor blood counts more frequently in patients with stage 3 or 4 liver graft-versus-host disease [GVHD]), lipid parameters (8 to 12 weeks after ruxolitinib initiation and as appropriate thereafter), renal function, hepatic function. Monitor hepatitis B viral load (HBV-DNA titer) in patients with chronic hepatitis B infection. Perform periodic skin examinations monitor for signs/symptoms of infection; Tuberculin skin test (prior to initiation). Monitor adherence.

Pregnancy

Pregnancy Considerations

Adverse events have been observed in animal reproduction studies. Use of ruxolitinib in pregnant females is not recommended; other agents are preferred for management of polycythemia vera and myeloproliferative disease (Gerds 2017; Kiladjian 2015).

Patient Education

What is this drug used for?

• It is used to treat myelofibrosis.
• It is used to treat polycythemia vera.
• It is used to treat graft-versus-host disease (GVHD).

Frequently reported side effects of this drug

• Diarrhea
• Constipation
• Dizziness
• Headache
• Muscle spasms
• Abdominal pain
• Weight gain
• Joint pain
• Stuffy nose
• Sore throat
• Passing gas

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Infection
• Urinary tract infection like blood in the urine, burning or painful urination, passing a lot of urine, fever, lower abdominal pain, or pelvic pain
• Bleeding like vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding
• Painful skin rashes with blisters
• Nausea
• Vomiting
• Shortness of breath
• Loss of strength and energy
• Swelling
• Mole changes
• Skin growths
• Progressive multifocal leukoencephalopathy like confusion, depression, trouble with memory, behavioral changes, change in strength on one side is greater than the other, difficulty speaking, change in balance, or vision changes.
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.