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Ruxolitinib

Pronunciation

(rux oh LI ti nib)

Index Terms

  • INCB 18424
  • INCB018424
  • INCB424
  • Ruxolitinib Phosphate

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

Brand Names: U.S.

  • Jakafi

Pharmacologic Category

  • Antineoplastic Agent, Janus Associated Kinase Inhibitor
  • Antineoplastic Agent, Tyrosine Kinase Inhibitor
  • Janus Associated Kinase Inhibitor

Pharmacology

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.

Absorption

Rapid

Distribution

Vd: 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)

Half-Life Elimination

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

Protein Binding

~97%; primarily to albumin

Special Populations: Renal Function Impairment

Plasma AUC values of ruxolitinib metabolites increased with increasing severity of renal impairment. This was most marked in the subjects with ESRD requiring hemodialysis.

Special Populations: Hepatic Function Impairment

The mean AUC for ruxolitinib was increased by 87%, 28%, and 65%, in patients with mild, moderate, and severe hepatic impairment, respectively, and the half-life of rituximab was increased from 2.8 hours (in patients with normal function) to 4.1 to 5 hours in patients with hepatic impairment.

Special Populations: Gender

In women, clearance was 17.7 L/hour and in men clearance was 22.1 L/hour with 39% intersubject variability.

Use: Labeled Indications

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

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

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

Dosing: Adult

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

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: US labeling: 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

Polycythemia vera: Oral: Initial dose:

US labeling: 10 mg twice daily (titrate dose based on efficacy and safety)

Canadian labeling:

Platelets ≥100,000/mm3: 10 mg twice daily (titrate dose based on efficacy and safety). Discontinue therapy if no benefit observed within 16 months.

Platelets 50,000 to <100,000/mm3: 5 mg twice daily (titrate dose based on efficacy and safety). Discontinue therapy if no benefit observed within 16 months.

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 (US labeling) or first 8 weeks of treatment (Canadian labeling) 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

Dosage adjustment with concomitant strong CYP3A4 inhibitors (eg, azole antifungals, clarithromycin, conivaptin, grapefruit juice, mibefradil, nefazodone, protease inhibitors, telithromycin) and fluconazole (≤200 mg):

US labeling: Note: Avoid concomitant use with fluconazole doses >200 mg daily.

Myelofibrosis: Initial dose:

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

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

Polycythemia vera: Initial dose: 5 mg twice daily

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

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

Patients 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.

Dosage adjustment with concomitant strong CYP3A4 inhibitors or concomitant moderate CYP2C9 and CYP3A4 inhibitors (Canadian labeling): Initial dose: ~50% of the dose, rounded to the closest available strength; monitor hematologic parameters more frequently (eg, twice weekly) and titrate dose based on safety and efficacy. If used concomitantly with fluconazole, do not exceed fluconazole 200 mg/day. If platelets <100,000/mm3, avoid concomitant use with strong CYP3A4 inhibitors or concomitant moderate CYP2C9 and CYP3A4.

Dosing: Renal Impairment

US labeling:

Myelofibrosis:

CrCl 15 to 59 mL/minute and platelets >150,000/mm3: No dosage adjustment is necessary.

CrCl 15 to 59 mL/minute and platelets 100,000 to 150,000/mm3: Initial dose: 10 mg twice daily; additional dose adjustments should be made with careful monitoring.

CrCl 15 to 59 mL/minute and platelets 50,000 to <100,000/mm3: Initial dose: 5 mg once daily; additional dose adjustments should be made with careful monitoring.

CrCl 15 to 59 mL/minute and platelets <50,000/mm3: Avoid use.

End-stage renal disease (ESRD) on dialysis and platelets 100,000 to 200,000/mm3: Initial dose: 15 mg once after dialysis; administer subsequent doses after dialysis on dialysis days. Additional dose adjustments should be made with frequent monitoring.

ESRD on dialysis and platelets >200,000/mm3: Initial dose: 20 mg once after dialysis; administer subsequent doses after dialysis on dialysis days. Additional dose adjustments should be made with frequent monitoring.

ESRD not requiring dialysis: Avoid use.

Polycythemia vera:

CrCl 15 to 59 mL/minute and any platelet count: Initial: 5 mg twice daily. Additional dose adjustments should be made with frequent monitoring.

End-stage renal disease (ESRD) on dialysis: Initial dose: 10 mg once after dialysis; additional dose adjustments should be made with careful monitoring

ESRD not requiring dialysis: Avoid use.

Hemodialysis is not expected to enhance the elimination of ruxolitinib.

Canadian labeling:

Preexisting renal impairment:

CrCl >50 mL/minute: No dosage adjustment necessary; refer to recommended dosages based on platelet count

CrCl ≤50 mL/minute: Initial dose: Reduce to ~50% of recommended initial dose based on platelet count (round up to the nearest available strength if necessary); additional dose adjustments should be made with careful monitoring. Avoid use if platelets <100,000/mm3.

Myelofibrosis:

ESRD on hemodialysis and platelets 100,000 to 200,000/mm3: Initial dose: 15 mg once daily administered after dialysis and only on dialysis days. Additional dose adjustments should be made with careful monitoring.

ESRD on hemodialysis and platelets >200,000/mm3: Initial dose: 20 mg once daily; administered after dialysis and only on dialysis days. Additional dose adjustments should be made with careful monitoring.

Peritoneal dialysis or continuous venous hemofiltration: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Polycythemia vera:

ESRD on hemodialysis and platelets ≥100,000/mm3: Initial dose: 10 mg once daily; administer after dialysis and only on dialysis days. Additional dose adjustments should be made with careful monitoring.

Peritoneal dialysis or continuous venous hemofiltration: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Moderate or severe renal impairment during therapy: There are no dosage adjustments provided in the manufacturer’s labeling; however, dosage adjustment may be necessary. Use caution and monitor closely.

Dosing: Hepatic Impairment

US labeling:

Myelofibrosis:

Mild to severe impairment (Child-Pugh class A, B, or C) and platelets >150,000/mm3: No dosage adjustment is necessary.

Mild to severe impairment (Child-Pugh class A, B, or C) and platelets 100,000 to 150,000/mm3: Initial dose: 10 mg twice daily; additional dose adjustments should be made with careful monitoring.

Mild to severe impairment (Child-Pugh class A, B, or C) and platelets 50,000 to <100,000/mm3: Initial dose: 5 mg once daily; additional dose adjustments should be made with careful monitoring.

Mild to severe impairment (Child-Pugh class A, B, or C) and platelets <50,000/mm3: Avoid use.

Polycythemia vera: Mild-to-severe impairment (Child-Pugh class A, B, or C) and any platelet count: Initial dose: 5 mg twice daily; additional dose adjustments should be made with careful monitoring.

Canadian labeling:

Preexisting hepatic impairment: Mild, moderate, or severe impairment (Child-Pugh class A, B, or C): Initial dose: Reduce to ~50% of recommended initial dose based on platelet count (round up to the nearest available strength if necessary); additional dose adjustments should be made with careful monitoring. Avoid use if platelets <100,000/mm3.

Hepatic impairment during therapy: There are no specific dosage adjustments provided in the manufacturer’s labeling (regardless of indication); however a dosage adjustment may be necessary. Use caution and monitor closely.

Dosing: Adjustment for Toxicity

Myelofibrosis:

Dosage modification for treatment interruption:

US labeling:

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

Platelets <50,000/mm3 and 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 and 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

Canadian labeling: Platelets <50,000/mm3 or ANC <500 mm3: Interrupt treatment; upon recovery of platelets to ≥50,000/mm3 or ANC to ≥500/mm3, dosing may be restarted at 5 mg twice daily and then gradually titrated based on blood cell counts.

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

Dose at Time of Thrombocytopenia

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

25 mg twice/day

20 mg twice/day

15 mg twice/day

10 mg twice/day

5 mg twice/day

Platelet Count

New Dose

New Dose

New Dose

New Dose

New Dose

100,000 to <125,000/mm3

20 mg twice/day

15 mg twice/day

No change

No change

No change

75,000 to <100,000/mm3

10 mg twice/day

10 mg twice/day

10 mg twice/day

No change

No change

50,000 to <75,000/mm3

5 mg twice/day

5 mg twice/day

5 mg twice/day

5 mg twice/day

No change

<50,000/mm3

Hold dose

Hold dose

Hold dose

Hold dose

Hold dose

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: US labeling:

Platelets 25,000 to <35,000/mm3 and 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/mm3 and 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:

US labeling:

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.

Canadian labeling:

Hemoglobin ≥12 g/dL: No dosage adjustment necessary.

Hemoglobin 10 to <12 g/dL: There are no specific dosage adjustments provided in the manufacturer’s labeling, however a reduction should be considered.

Hemoglobin <10 g/dL: There are no specific dosage adjustments provided in the manufacturer’s labeling, however a reduction is recommended.

Platelets ≥75,000/mm3: No dosage adjustment necessary.

Platelets 50,000 to <75,000/mm3: Reduce dose to 5 mg twice daily; if already receiving 5 mg twice daily, no dosage adjustment required.

Hemoglobin <8 g/dL OR platelets <50,000/mm3 OR ANC <500/mm3: Interrupt dosing.

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

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

Hazardous agent; use appropriate precautions for handling and disposal (meets NIOSH 2014 criteria). When compounding an oral liquid or suspension, NIOSH recommends double gloving, a protective gown, and preparation in a controlled device; if not prepared in a controlled device, respiratory and eye protection as well as ventilated engineering controls are recommended (NIOSH 2014).

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 hour after preparation.

Jakafi (ruxolitinib) [prescribing information]. Wilmington, DE: Incyte Corporation; December 2014.

Administration

Oral:

US labeling: 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)

Canadian labeling: May be administered orally with or without food. Tablet should be swallowed whole and not be cut, broken, dissolved, crushed, or chewed. If a dose is missed, return to the usual dosing schedule and do not administer an additional dose.

Hazardous agent; use appropriate precautions for handling and disposal (meets NIOSH 2014 criteria). NIOSH recommends single gloving for administration of intact tablets; if administering an oral suspension via NG tube, NIOSH recommends double gloving, a protective gown, eye protection, and respiratory protection (NIOSH 2014).

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. Monitor therapy

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

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

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

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. Avoid combination

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. 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

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination

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

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

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates. Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

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. Monitor therapy

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

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

Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Ivacaftor: May increase the serum concentration of CYP3A4 Substrates. 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

Luliconazole: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Mifepristone: May increase the serum concentration of CYP3A4 Substrates. 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

Mitotane: May decrease the serum concentration of CYP3A4 Substrates. Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. 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. Monitor therapy

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

Osimertinib: May increase the serum concentration of CYP3A4 Substrates. Osimertinib may decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Palbociclib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

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

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

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

St John's Wort: May decrease the serum concentration of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

Stiripentol: May increase the serum concentration of CYP3A4 Substrates. 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

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. 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. Avoid combination

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

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. 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 ALT (25%; grade 3: <1%), increased serum AST (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%), vomiting

Genitourinary: Urinary tract infection (≤9%)

Infection: Herpes zoster (2% yo 6%)

Neuromuscular & skeletal: Weakness (7%)

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

<1% (Limited to important or life-threatening): Bradycardia, disseminated intravascular coagulation, fever, hemorrhagic diathesis, hypotension, multi-organ failure, myelofibrosis (symptom exacerbation), progressive multifocal leukoencephalopathy, prolonged Q-T interval on ECG, respiratory distress, systolic hypertension, tuberculosis, withdrawal syndrome

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. 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). The Canadian labeling recommends avoiding use (regardless of indication) when platelets are <100,000/mm3 in patients with hepatic impairment.

• 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. The Canadian labeling recommends avoiding use in moderate or severe impairment (regardless of indication) when platelets are <100,000/mm3. 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.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (meets NIOSH 2014 criteria).

Other warnings/precautions:

• Appropriate use: Discontinue treatment in myelofibrosis patients after 6 months if no reduction in spleen size or no improvement in symptoms. The Canadian labeling recommends discontinuing therapy in polycythemia vera patients if clinical benefit is not observed within 16 months. 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), 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. Additional Canadian labeling recommendations include tuberculin skin test and/or interferon-gamma release assay prior to initiation, ECG at baseline and then periodically during therapy, and heart rate and blood pressure during therapy.

Pregnancy Risk Factor

C

Pregnancy Considerations

Increased resorptions (late) and reduced fetal weights were observed in animal reproduction studies. The Canadian labeling recommends avoiding use during pregnancy and that women of childbearing potential and male patients use effective contraception during therapy.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience diarrhea, constipation, dizziness, headache, muscle spasms, dyspepsia, asthenia, weight gain, or flatulence. Have patient report immediately to prescriber signs of infection, nausea, dyspnea, asthenia, ecchymosis, hemorrhaging, mole changes, skin growths, or signs of progressive multifocal leukoencephalopathy (HCAHPS).

• Educate patient about signs of a significant reaction (eg, 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. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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