ruxolitinib

Therapeutic Classification: antineoplastics

Pharmacologic Classification: kinase inhibitors

REMS

Intermediate or high-risk myelofibrosis (including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential thrombocytopenia fibrosis).
Polycythemia vera in patients who have had an inadequate response to or are intolerant of hydroxyurea
Steroid-refractory acute graft-versus-host disease (GVHD).

Inhibits kinases involved in the signaling of hematopoiesis and immune processes.

Therapeutic effects:

Decreased spleen size.
Hematocrit control.
Reduction in organ involvement.

Absorption: Well absorbed (95%) following oral administration.

Distribution: Unknown.

Protein Binding: 97%.

Metabolism/Excretion: Mostly metabolized (99%) the liver (CYP3A4 enzyme system). Some metabolites have pharmacologic activity and account for 18% of action. Metabolites are excreted in urine (74%) and feces (22%).

Half-Life: Ruxolitinib—3 hr; Ruxolitinib plus metabolites—5.8 hr.

(blood levels)

ROUTE	ONSET	PEAK	DURATION
PO	unknown	1–2 hr	12 hr

Contraindicated in:

End-stage renal disease (CCr <15 mL/min) not requiring dialysis;
Concurrent use of fluconazole at doses >200 mg/day (for myelofibrosis and polycythemia vera);
Lactation: Lactation.

Use Cautiously in:

Hepatic/moderate renal impairment (dose ↓ recommended);
OB: Use during pregnancy only if potential maternal benefit justifies potential fetal risk;
Pedi: Safety and effectiveness not established in children.

Drug-drug:

Concurrent use of strong inhibitors of the CYP3A4 enzyme system including clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole. lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, and voriconazole may ↑ blood levels and effects; initial dose may need to be ↓ (depends on indication).
Fluconazole (a combined CYP3A4 and CYP2C9 inhibitor) may ↑ blood levels and effects; initial dose should be ↓; avoid concomitant use of fluconazole doses >200 mg/day in patients with myelofibrosis or polycythemia vera.

Concurrent use with grapefruit juice may ↑ levels and effects; initial dose should be ↓.

Myelofibrosis

PO (Adults ): Platelet count >200 × 10⁹/L—20 mg twice daily initially, ↑ dose based on response to a maximum of 25 mg twice daily; Platelet count between 100 × 10⁹/L and 200 × 10⁹/L—15 mg twice daily initially; ↑ dose based on response to a maximum of 25 mg twice daily; Platelet count between 50 × 10⁹/L and 99 × 10⁹/L—5 mg twice daily initially; ↑ dose based on response to a maximum of 25 mg twice daily; Concurrent use of strong CYP3A4 inhibitors or fluconazole (≤200 mg/day) and platelet count ≥ 100 × 10⁹/L—10 mg twice daily initially; ↑ dose based on safety and efficacy; Concurrent use of strong CYP3A4 inhibitors or fluconazole (≤200 mg/day) and platelet count 50–100 × 10⁹/L—5 mg once daily initially; ↑ dose based on safety and efficacy; Concurrent use of strong CYP3A4 inhibitors or fluconazole (≤200 mg/day) and already on stable dose of ≥10 mg twice daily—↓ dose by 50%; ↑ dose based on safety and efficacy; Concurrent use of strong CYP3A4 inhibitors or fluconazole (≤200 mg/day) and already on stable dose of 5 mg twice daily—↓ dose to 5 mg once daily; ↑ dose based on safety and efficacy; Concurrent use of strong CYP3A4 inhibitors or fluconazole (≤200 mg/day) and already on stable dose of 5 mg once daily—Avoid concomitant use.

Hepatic Impairment

PO (Adults ): Mild, moderate, or severe hepatic impairment with platelet count between 100 × 10⁹/L and 150 × 10⁹/L—10 mg twice daily initially.

Renal Impairment

PO (Adults ): CCr 15–59 mL/min and platelet count between 100 × 10⁹/L and 150 × 10⁹/L—10 mg twice daily initially; CCr 15–59 mL/min and platelet count <100 × 10⁹/L—Avoid; CCr <15 mL/min (not on dialysis)—Avoid; CCr <15 mL/min (on dialysis) and platelet count between 100 × 10⁹/L and 200 × 10⁹/L——15 mg after dialysis; CCr <15 mL/min (on dialysis) and platelet count between >200 × 10⁹/L —20 mg after dialysis.

Polycythemia Vera

PO (Adults ): 10 mg twice daily, ↑ dose based on response to a maximum of 25 mg twice daily; Concurrent use of strong CYP3A4 inhibitors or fluconazole (≤200 mg/day)—5 mg twice daily initially; ↑ dose based on safety and efficacy; Concurrent use of strong CYP3A4 inhibitors or fluconazole (≤200 mg/day) and already on stable dose of ≥10 mg twice daily—↓ dose by 50%; ↑ dose based on safety and efficacy; Concurrent use of strong CYP3A4 inhibitors or fluconazole (≤200 mg/day) and already on stable dose of 5 mg twice daily—↓ to 5 mg once daily; ↑ dose based on safety and efficacy; Concurrent use of strong CYP3A4 inhibitors or fluconazole (≤200 mg/day) and already on stable dose of 5 mg once daily—Avoid concomitant use.

Hepatic Impairment

PO (Adults ): Mild, moderate, or severe hepatic impairment—5 mg twice daily initially.

Renal Impairment

PO (Adults ): CCr 15–59 mL/min—5 mg twice daily initially; CCr <15 mL/min (not on dialysis)—Avoid; CCr <15 mL/min (on dialysis)——10 mg after dialysis.

Acute GVHD

PO (Adults and Children ≥12 yr): 5 mg twice daily initially; ↑ dose to 10 mg twice daily after ≥3 days of treatment if ANC and platelet counts are not ↓ by ≥50% (compared to baseline). Concurrent use of ketoconazole—5 mg once daily initially; ↑ dose based on safety and efficacy.

Hepatic Impairment

PO (Adults and Children ≥12 yr): Stage 3 or 4 liver GVHD—Monitor blood counts more frequently for toxicity; consider adjustment to 5 mg once daily.

Renal Impairment

PO (Adults and Children ≥12 yr): CCr 15–59 mL/min—5 mg twice daily initially; CCr <15 mL/min (on dialysis)—5 mg after dialysis

Tablets: 5 mg; 10 mg; 15 mg; 20 mg; 25 mg

Assess for signs and symptoms of infections (fever, dyspnea, chills, sore throat) including tuberculosis and hepatitis B virus (HBV), prior to and periodically during therapy.
Assess for new signs or symptoms suggestive of PML, an opportunistic infection of the brain caused by the JC virus, leading to death or severe disability; withhold dose and notify health care professional promptly. Monitor during therapy and for at least 6 mo following discontinuation. PML symptoms may begin gradually but usually worsen rapidly. Symptoms vary depending on which part of the brain is infected (mental function declines rapidly and progressively, causing dementia; speaking becomes increasingly difficult; partial blindness; difficulty walking; rarely, headaches and seizures occur). Diagnosis is usually made via gadolinium-enhanced MRI and CSF analysis. Risk of PML increases with the number of infusions. Withhold ruxolitinib at first sign of PML.
Assess patient for latent tuberculosis with a tuberculin skin test prior to initiation of therapy.
Monitor for signs and symptoms of herpes zoster infection (skin lesions, tingling and burning of skin) prior to and periodically during therapy.

Lab Test Considerations:

Monitor CBC and platelet count prior to initiating therapy, every 2–4 wks until doses are stabilized, and then as clinically indicated. Patients with platelet counts of <200 × 10⁹ at start of therapy are more likely to develop thrombocytopenia.
Myelofibrosis:
Polycythemia Vera
May cause anemia requiring blood transfusions and/or dose modification.
- If platelet count <50 × 10⁹ or ANC <0.5 x 10⁹, hold ruxolitinib. May restart therapy if platelet count >50 × 10⁹ or ANC <0.75 x 10⁹ with dose of 5 mg once daily or 5 mg twice daily below largest dose in wk prior to treatment interruption. Maximum restart doses: If platelet count returns to ≥125 × 10⁹/L, restart at 20 mg twice daily. If platelet count returns to 100 to <125 × 10⁹/L, restart at 15 mg twice daily. If platelet count returns to 75 to 100 × 10⁹/L, restart at 10 mg twice daily for at least 2 wks; if stable, may increase to 15 mg twice daily. If platelet count returns to 50 to 75 × 10⁹/L, restart at 5 mg twice daily for at least 2 wks; if stable, may increase to 10 mg twice daily. If platelet count returns at <50 × 10⁹/L, continue to hold ruxolitinib. Follow manufacturer's recommendations for additional dose modifications.
- If hemoglobin ≥12 g/dL AND platelet count ≥100 x 10⁹/L, continue therapy. If hemoglobin 10 to <12 g/dL AND platelet count 75 to <100 X 10⁹/L, consider dose reductions with the goal of avoiding dose interruptions for anemia and thrombocytopenia. If hemoglobin 8 to <10 g/dL OR platelet count 50 to <75 X 10⁹/L, reduce dose by 5 mg twice daily. For patients on 5 mg twice daily, decrease dose to 5 mg once daily. If hemoglobin <8 g/dL OR platelet count <50 X 10⁹/L OR ANC <1.0 X 10⁹/L, hold dose. Follow manufacturer's recommendations for additional dose modifications.
Acute Graft-Versus-Host Disease: If clinically significant thrombocytopenia remains after supportive measures, reduce dose by 1 dose level. Return to prior dose level when platelets recover to previous values. If ANC <1 X 10⁹/L related to ruxolitinib, hold therapy for up to 14 days; resume at 1 dose level lower upon recovery. If total bilirubin ↑ with no liver enzyme ↑ occurs: If bilirubin ↑ 3.0-5.0 x ULN, continue therapy at 1 dose level lower until recovery. If bilirubin >5.0-10.0 x ULN, hold ruxolitinib for up to 14 days until bilirubin ≤1.5 x ULN; resume at current dose upon recovery. If total bilirubin >10.0 x ULN, hold therapy for up to 14 days until bilirubin ≤1.5 x ULN; resume at 1 dose level lower upon recovery. If total bilirubin elevation with liver elevations occurs, If bilirubin >3.0 x ULN, continue ruxolitinib at 1 dose level lower until recovery.
May cause neutropenia; usually reversible by temporarily stopping therapy.
- Monitor for HBV blood tests periodically during therapy. May cause Hepatitis B viral load (HBV-DNA titer) increases.
- Monitor total cholesterol, low-density lipoprotein (LDL), and triglyceride levels periodically during therapy; may increase blood cholesterol. Assess 8–12 wks after starting therapy. Treat as needed.

PO: Administer without regard to food.
- Tablets may be suspended in 40 mL if water and stir for 10 min. Within 6 hr after tablet is dispersed, suspension can be administered through an NG tube using a syringe. Rinse tube with 75 mL of water.
- Tablets should be administered following dialysis for patients receiving dialysis.
Acute Graft-Versus-Host Disease: Tapering of ruxolitinib may be considered after 6 months of treatment in patients with response who have discontinued therapeutic doses of corticosteroids. Taper by 1 dose level approximately every 8 wks (10 mg twice daily to 5 mg twice daily to 5 mg once daily). If acute GVHD signs or symptoms recur during or after taper, consider retreatment.

Instruct patient to take ruxolitinib as directed. If a dose is missed, omit and take next dose at prescribed time; do not double doses. When discontinuing therapy, unless for thrombocytopenia, decrease gradually by 5 mg twice daily each wk. If therapy is discontinued, signs and symptoms of myelofibrosis are expected to return.
Instruct patient to avoid drinking grapefruit juice during therapy; may affect blood levels of ruxolitinib.
Advise patient to notify health care professional promptly if signs and symptoms of infections, PML (progressive weakness on one side of the body or clumsiness of limbs; disturbance of vision; changes in thinking, memory, and orientation leading to confusion and personality changes), or herpes zoster occur.
Instruct patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and consult health care professional before taking any new medications.
Rep: Advise females of reproductive potential to notify health care professional if pregnancy is planned or suspected, and to avoid breastfeeding during and for 2 wk after final dose of therapy.
Inform patient of the need for frequent blood test to monitor for adverse reactions.

Decrease in spleen size and/or spleen volume. Discontinue ruxolitinib if there is no spleen size reduction or symptom improvement after 6 mos of therapy.
Hematocrit control. If efficacy is insufficient and platelet and neutrophil counts are adequate, doses may be increased by 5 mg twice daily increments to 25 mg twice daily.
Reduction in organ involvement.

Risk for infection(Adverse Reactions)

NDC Code

50881- Incyte Corporation
- 50881-005- JAKAFI
  - 50881-005-60- 60 TABLET in 1 BOTTLE, PLASTIC (50881-005-60)

50881- Incyte Corporation
- 50881-010- JAKAFI
  - 50881-010-01- 28 TABLET in 1 BOTTLE, PLASTIC (50881-010-01)

50881- Incyte Corporation
- 50881-010- JAKAFI
  - 50881-010-60- 60 TABLET in 1 BOTTLE, PLASTIC (50881-010-60)

50881- Incyte Corporation
- 50881-015- JAKAFI
  - 50881-015-60- 60 TABLET in 1 BOTTLE, PLASTIC (50881-015-60)

50881- Incyte Corporation
- 50881-020- JAKAFI
  - 50881-020-60- 60 TABLET in 1 BOTTLE, PLASTIC (50881-020-60)

50881- Incyte Corporation
- 50881-025- JAKAFI
  - 50881-025-60- 60 TABLET in 1 BOTTLE, PLASTIC (50881-025-60)

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