ruxolitinib (systemic)

RUX-oh-LI-ti-nib

Therapeutic Classification: antineoplastics

Pharmacologic Classification: kinase inhibitors

High Alert

Intermediate or high-risk myelofibrosis (including primary myelofibrosis, postpolycythemia vera myelofibrosis, and postessential 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).
Chronic GVHD after failure of one or two lines of systemic therapy.

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: Primarily metabolized by the liver via the CYP3A4 isoenzyme. 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.

(plasma concentrations)

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

Contraindicated in:

End-stage renal disease (CCr <15 mL/min) not requiring dialysis;
Lactation: Lactation.

Use Cautiously in:

Hepatic impairment (↓ dose);
Moderate renal impairment (↓ dose);
OB: Use during pregnancy only if potential maternal benefit justifies potential fetal risk;
Pedi: Safety and effectiveness not established in children <12 yr (acute or chronic GVHD) or <18 yr (all other indications).

Derm: ecchymoses, NON-MELANOMA SKIN CANCER

Hemat: anemia, thrombocytopenia, neutropenia

Metab: hyperlipidemia

Neuro: dizziness, headache, herpes zoster, PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML)

Misc: INFECTION (INCLUDING REACTIVATION TUBERCULOSIS AND OTHER OPPORTUNISTIC INFECTIONS DUE TO BACTERIAL, FUNGAL, VIRAL, AND MYCOBACTERIAL PATHOGENS)

Drug-drug:

Strong CYP3A4 inhibitors, including clarithromycin, conivaptan, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, and voriconazole, may ↑ levels and the risk of toxicity; initial dose may need to be ↓ (depends on indication).
Fluconazole may ↑ levels and the risk of toxicity; initial dose should be ↓; avoid concomitant use of fluconazole doses >200 mg/day in patients with myelofibrosis or polycythemia vera.

Natural-Food Products:

Grapefruit juice may ↑ levels and the risk of toxicity; 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 100–200 × 10⁹/L: 15 mg twice daily initially; ↑ dose based on response to a maximum of 25 mg twice daily; Platelet count 50–<100 × 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 concurrent use.

Hepatic Impairment

PO (Adults ): Mild, moderate, or severe hepatic impairment with platelet count 100–150 × 10⁹/L: 10 mg twice daily initially; Mild, moderate, or severe hepatic impairment with platelet count 50–<100 × 10⁹/L: 5 mg once daily initially; Mild, moderate, or severe hepatic impairment with platelet count <50 × 10⁹/L: Avoid use.

Renal Impairment

PO (Adults ): CCr 15–59 mL/min and platelet count 100–150 × 10⁹/L: 10 mg twice daily initially; CCr 15–59 mL/min and platelet count 50–<100 × 10⁹/L: 5 mg once daily; CCr 15–59 mL/min and platelet count <50 × 10⁹/L: Avoid use; CCr <15 mL/min (not on dialysis): Avoid use; CCr <15 mL/min (on dialysis) and platelet count >200 × 10⁹/L : 20 mg once after dialysis session; CCr <15 mL/min (on dialysis) and platelet count 100–200 × 10⁹/L: 15 mg once after dialysis session.

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 concurrent 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 use; CCr <15 mL/min (on dialysis): 10 mg once after dialysis session.

Acute Graft-Versus-Host Disease

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). Consider tapering therapy after 6 mo of treatment in patients who have experienced a response and have discontinued therapeutic doses of corticosteroids. When tapering, ↓ to 5 mg twice daily; then after 8 wk, ↓ to 5 mg once daily; then after 8 wk, discontinue therapy.Concurrent use of fluconazole (≤200 mg/day): 5 mg once daily initially; ↑ dose based on safety and efficacy.

Hepatic Impairment

PO (Adults and Children ≥12 yr): Stage 4 liver acute GVHD: 5 mg once daily initially.

Renal Impairment

PO (Adults and Children ≥12 yr): CCr 15–59 mL/min: 5 mg once daily initially; CCr <15 mL/min (not on dialysis): Avoid use; CCr <15 mL/min (on dialysis): 5 mg once after dialysis session.

Chronic Graft-Versus-Host Disease

PO (Adults and Children ≥12 yr): 10 mg twice daily initially. Consider tapering therapy after 6 mo of treatment in patients who have experienced a response and have discontinued therapeutic doses of corticosteroids. When tapering, ↓ to 5 mg twice daily; then after 8 wk, ↓ to 5 mg once daily; then after 8 wk, discontinue therapy. Concurrent use of fluconazole (≤200 mg/day): 5 mg twice daily initially; ↑ dose based on safety and efficacy.

Hepatic Impairment

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

Renal Impairment

PO (Adults and Children ≥12 yr): CCr 15–59 mL/min: 5 mg twice daily initially; CCr <15 mL/min (not on dialysis): Avoid use; CCr <15 mL/min (on dialysis): 10 mg once after dialysis session.

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

Assess for latent tuberculosis with a tuberculin skin test prior to initiation of therapy.
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 ≥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 ↑ with the number of infusions. Withhold ruxolitinib at first sign of PML.
Assess and monitor for herpes simplex and herpes zoster (skin lesions, tingling and burning of skin) before and during therapy.

Lab Test Considerations:

Monitor baseline CBC before starting therapy, every 2–4 wk until doses are stabilized, and then as clinically indicated. Patients with platelet counts <200 × 10⁹ at start of therapy are more likely to develop thrombocytopenia.
Myelofibrosis: Polycythemia VeraMay cause anemia requiring blood transfusions and/or dose modification.
- If platelet count <50 × 10⁹ or ANC <0.5 × 10⁹, hold ruxolitinib. May restart therapy if platelet count >50 × 10⁹ or ANC <0.75 × 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 wk; if stable, may ↑ to 15 mg twice daily. If platelet count returns to 50 to <75 × 10⁹/L, restart at 5 mg twice daily for ≥2 wk; if stable, may ↑ 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 × 10⁹/L, continue therapy. If hemoglobin 10 to <12 g/dL AND platelet count 75 to <100 × 10⁹/L, consider dose ↓ with the goal of avoiding dose interruptions for anemia and thrombocytopenia. If hemoglobin 8 to <10 g/dL OR platelet count 50 to <75 × 10⁹/L,↓ dose by 5 mg twice daily. For patients on 5 mg twice daily, ↓ dose to 5 mg once daily. If hemoglobin <8 g/dL OR platelet count <50 × 10⁹/L OR ANC <1.0 × 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, ↓dose by one dose level. Return to prior dose level when platelets recover to previous values. If ANC <1 × 10⁹/L, hold therapy for up to 14 days; resume at one dose level lower upon recovery. If total bilirubin ↑ with no liver enzyme ↑ occurs and if bilirubin ↑ 3–5 times upper limit of normal (ULN), continue therapy at one dose level lower until recovery. If bilirubin >5–10 times ULN, hold dose for up to 14 days until bilirubin ≤1.5 times ULN; resume at current dose upon recovery. If total bilirubin >10 times ULN, hold therapy for up to 14 days until bilirubin ≤1.5 times ULN; resume at one dose level lower upon recovery. If total bilirubin ↑ with liver enzyme ↑ occurs and if bilirubin >3 times ULN, continue therapy at one dose level lower until recovery.
Chronic Graft-Versus-Host Disease:If platelet count <20 × 10⁹/L, ↓by one dose level. If resolved within 7 days, start at initial dose level. If takes >7 days to resolve, resume at one dose level lower. If ANC <0.75 × 10⁹/L,↓ by one dose level; resume at initial dose once recovered. If ANC <0.5 × 10⁹/L,hold therapy for 14 days. Resume at one dose level lower once recovered. May resume initial dose level when ANC >1 × 10⁹/L. If total bilirubin 3–5 times ULN,continue at one dose level lower until recovered. If resolved within 14 days, ↑ by one dose level. If takes >14 days to recovery, resume at one dose level lower. If total bilirubin >5–10 times ULN,hold therapy for 14 days; resume current dose once recovered. If takes >14 days to recover, resume at one dose level lower. If total bilirubin >10 times ULN,hold therapy for 14 days until recovered; resume at one dose level lower. If >14 days with no recovery, discontinue therapy. For Grade 3 adverse reactions, continue therapy at one dose level lower until recovery.For Grade 4 adverse reactions,discontinue therapy.
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).
- Monitor total cholesterol, LDL-C, and triglyceride levels periodically during therapy; may ↑ blood cholesterol. Assess 8–12 wk after starting therapy. Treat as needed.

PO: Administer without regard to food.
- Tablets may be suspended in 40 mL of water and stirred 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/Chronic Graft-Versus-Host Disease: Tapering of ruxolitinib may be considered after 6 mo of treatment in patients with response who have discontinued therapeutic doses of corticosteroids. Taper by one dose level approximately every 8 wk (10 mg twice daily to 5 mg twice daily to 5 mg once daily). If acute/chronic GVHD signs or symptoms recur during or after taper, consider retreatment.

Explain purpose and side effects of medication to patient. Advise patient to read Patient Information before starting therapy. Instruct patient to take 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, ↓ gradually by 5 mg twice daily each wk. If therapy is discontinued, signs and symptoms of myelofibrosis are expected to return. Emphasize on the need for frequent blood test.
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.
Instruct patient to avoid drinking grapefruit juice during therapy.
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/simplex occur.
Rep: Advise women 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.

Decrease in spleen size and/or spleen volume.
Hematocrit control.
Reduction in organ involvement.

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