ruxolitinib

ruxolitinib

Pharmacologic class: Kinase inhibitor

Therapeutic class: Antineoplastic

Pregnancy risk category C

Action

Inhibits Janus-associated kinases (JAKs) JAK1 and JAK2, which mediate the signaling of a number of cytokines and growth factors important for hematopoiesis and immune function. Myelofibrosis, a myeloproliferative neoplasm, is known to be associated with dysregulated JAK1 and JAK2 signaling.

Availability

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

Indications and dosages

Patients with intermediate- or high-risk myelofibrosis (including primary myelofibrosis, postpolycythemia vera myelofibrosis and post-essential thrombocythemia myelofibrosis)

Adults: 20 mg P.O. b.i.d. for patients with platelet count greater than 200 × 109/L, and 15 mg P.O. b.i.d for patients with platelet count between 100 × 109/L and 200 × 109/L. Increase dosage based on response and as recommended to maximum of 25 mg P.O. b.i.d. Discontinue after 6 months if no spleen reduction or symptom improvement.

Dosage adjustment

• Absolute neutrophil count (ANC) greater than 0.75 × 109/L
• Concomitant use of strong CYP3A4 inhibitors
• Decreased platelet count and thrombocytopenia
• Failure to achieve reduction from pretreatment baseline in either palpable spleen length of 50% or 35% reduction in spleen volume as measured by computed tomography scan or magnetic resonance imaging
• Platelet count greater than 125 × 109/L at 4 weeks and platelet count never below 100 × 109/L
• Renal and hepatic impairment

Contraindications

None

Precautions

Use cautiously in:
• renal or hepatic impairment
• end-stage renal disease (creatinine clearance less than 15 mL/minute) not requiring dialysis and patients with moderate or severe renal impairment and platelet count less than 100 × 109/L (avoid use)
• hepatic impairment in patients with platelet count less than 100 × 109/L (avoid use)
• patients with thrombocytopenia, anemia, neutropenia; patients at risk for infection
• ANC levels greater than 0.75 × 109/L
• concurrent use of strong CYP3A4 inhibitors in patients with platelet count less than 100 × 109/L (avoid use)
• pregnant or breastfeeding patients
• children (safety and efficacy not established).

Administration

• Administer with or without food but not with grapefruit juice.
• For patients unable to ingest tablets, give through nasogastric (NG) tube by suspending one tablet in approximately 40 ml of water, stirring for approximately 10 minutes, and administering within 6 hours after tablet has dispersed. Rinse NG tube with approximately 75 ml of water.
• Obtain CBC before start of therapy.
• Ensure that serious infections are resolved before start of therapy.

Be aware that thrombocytopenia, anemia, and neutropenia can occur. Manage by dosage reduction, dose interruption, or transfusion. After recovery of platelet count above 50 × 109/L, restart or increase dosing after recovery of platelet count to acceptable levels.
• When discontinuing drug for reasons other than thrombocytopenia, consider gradually tapering dosage, for example, by 5 mg b.i.d. weekly.

Adverse reactions

CNS: headache, dizziness

GI: flatulence

GU: urinary tract infections

Hematologic: anemia, neutropenia, thrombocytopenia

Skin: bruising

Other: weight gain, herpes zoster

Interactions

Drug-drug.CYP3A4 inducers (such as rifampin): decreased ruxolitinib Cmax and area under the curve (AUC)

Mild or moderate CYP3A4 inhibitors (such as erythromycin): increased ruxolitinib Cmax and AUC

Strong CYP3A4 inhibitors (such as boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole): increased ruxolitinib Cmax, AUC, and half-life

Drug-diagnostic tests.ALT, AST, cholesterol: increased levels

Hemoglobin, neutrophils, platelets, RBCs: decreased levels

Drug-food.Grapefruit juice: increased ruxolitinib Cmax, AUC, and half-life

Patient monitoring

• Monitor CBC with differential every 2 to 4 weeks until dosages are stabilized, then as clinically indicated.
• Monitor renal and hepatic function tests closely.
• Assess patient for risk of developing serious bacterial, mycobacterial, fungal, and viral infections and promptly initiate appropriate treatment.

Patient teaching

• Tell patient to take drug with or without food but not with grapefruit juice.
• For patient unable to ingest tablets, tell patient or caregiver to give through NG tube by suspending one tablet in approximately 40 ml of water, stirring for approximately 10 minutes, and administering within 6 hours after tablet has dispersed. Then rinse NG tube with approximately 75 ml of water.
• Inform patient of importance of having CBC before starting drug and regularly during teatment.

Instruct patient to immediately report signs and symptoms of low CBC (unusual bleeding, bruising, fatigue, shortness of breath) or infection (fever, chills, aches, weakness, painful rash or blisters).
• Instruct patient to tell prescriber about all drugs he's taking, because some drugs have potential for serious drug interactions and shouldn't be taken with ruxolitinib.
• Teach patient with end-stage renal disease to take drug on dialysis days after each dialysis session.
• Teach patient about early signs and symptoms of herpes zoster; advise patient to seek treatment as early as possible if these occur.
• Advise breastfeeding patient that she should decide whether to discontinue breastfeeding or discontinue drug, taking into account importance of drug for her treatment.
• As appropriate, review all other significant and life-threatening adverse reactions and interactions, especially those related to the drugs, tests, and food mentioned above.

ruxolitinib

(rux-oh-li-ti-nib) ,

Jakafi

(trade name),

Jakavi

(trade name)

Classification

Therapeutic: antineoplastics
Pharmacologic: kinase inhibitors
Pregnancy Category: C

Indications

Treatment of intermediate or high-risk myelofibrosis (including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential thrombocytopenia fibrosis).

Action

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

Therapeutic effects

Decrease in mutant cells in the spleen, decreased circulating inflammatory cells and decreased spleen size.

Pharmacokinetics

Absorption: Well absorbed (95%) following oral administration.
Distribution: Unknown.
Protein Binding: 97%.
Metabolism and 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.

Time/action profile (blood levels)

ROUTEONSETPEAKDURATION
POunknown1–2 hr12 hr

Contraindications/Precautions

Contraindicated in: Severe renal impairment (CCr <15 mL/min); Concurrent use of strong CYP3A4 inhibitors and platelet count of <100 × 109/L; Lactation: Breast feeding should be avoided.
Use Cautiously in: Hepatic/moderate renal impairment (dose ↓ recommended); Obstetric: Use during pregnancy only if potential benefit justifies potential fetal risk; Pediatric: Safe and effective use not established.

Adverse Reactions/Side Effects

Central nervous system

  • progressive multifocal leukoencephalopathy (life-threatening)
  • dizziness (most frequent)
  • headache (most frequent)
  • herpes zoster

Dermatologic

  • ecchymoses (most frequent)

Hematologic

  • anemia (most frequent)
  • thrombocytopenia (most frequent)
  • neutropenia

Interactions

Drug-Drug interaction

Concurrent use of strong inhibitors of the CYP3A4 enzyme system including boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole. lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, and voriconazole may ↑ blood levels and effects; initial dose should be ↓.Concurrent use with grapefuit juice may ↑ levels and effects; initial dose should be ↓.

Route/Dosage

Oral (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 and platelet count ≥ 100 × 109/L—10 mg twice daily initially; dose may be ↑ by 5 mg twice daily, no increments should be made in the first 4 wk and then may be made every 2 wk.

Renal Impairment

Oral (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.

Hepatic Impairment

Oral (Adults) Platelet count between 100 × 109/L and 150 × 109/L—10 mg twice daily initially.

Availability

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

Nursing implications

Nursing assessment

  • Assess for signs and symptoms of infections (fever, dyspnea, chills, sore throat) 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 months 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.
  • 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..
    • If platelet count <50 × 109 or ANC <0.5 x 109, interrupt therapy. 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 week 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.
    May cause anemia requiring blood transfusions and/or dose modification.
  • Lab Test Considerations: May cause neutropenia; usually reversible by temporarily stopping therapy.

Potential Nursing Diagnoses

Risk for infection (Adverse Reactions)

Implementation

  • Oral: Administer without regard to food.
    • Tablets may be suspended in 40 mL if water and stir for 10 min. Wait 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.

Patient/Family Teaching

  • 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.
  • Advise female patients to notify health care professional if pregnancy is planned or suspected, or if breastfeeding. Advise patient to avoid breastfeeding during therapy.
  • Inform patient of the need for frequent blood test to monitor for adverse reactions.

Evaluation/Desired Outcomes

  • Decrease in spleen size and/or spleen volume. 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.
References in periodicals archive ?
Long-Term Efficacy and Safety in COMFORT-II, a Phase 3 Study Comparing Ruxolitinib with Best Available Therapy for the Treatment of Myelofibrosis: 5-Year Final Study Results (Abstract #59, Oral Presentation, Saturday, December 5, 10:30 am EST)
Tenders are invited for Tablet/Capsule Ruxolitinib - 5 Mg
He was given ruxolitinib (kinase inhibitor) 6 months before symptom onset because of transfusion-dependent myelofibrosis despite splenectomy 4 years earlier (Table 1).
The new drug ruxolitinib was effective in fighting T-cells, which attacked hair follicles.
According to the report by Daily Mirror, all three patients experienced complete hair growth after four or five months of treatment with the drug ruxolitinib.
In fact, during the study period, a CNL patient was treated with the FDA-approved drug ruxolitinib, which inhibits the cancer cell growth initiated by the CSF3R mutation.
Another JAK inhibitor, ruxolitinib (Incyte's jakafi) was approved to treat myelofibrosis in November.
Drug Profiles discussed in this report include ACY-957, ALN-TMP, Antisense Oligonucleotides to Inhibit BCL11A and KLF1 for Hematological Disorders, BB-305, BtX-13, CNTO-530, Gene Therapy for Sickle Cell Disease and Beta Thalassemia, Gene Therapy for Sickle Cell Disease and Thalassemia, glutamine, luspatercept, NiCord, PB-04, Peptide Agonists of Hepcidin for Beta-Thalassemia and Juvenile Hemochromatosis, Project x-1450, ruxolitinib phosphate, Small Molecule to Inhibit Histone Deacetylase for Beta-Thalassemi, sotatercept, Stem Cell Therapy for Beta Thalassemia, Synthetic Peptides Hematological and Genetic Disorders, Thalagen.
Two FDA-approved JAK inhibitors tested separately by the researchers -- ruxolitinib and tofacitinib -- were able to block these immune pathways and stop the attack on the hair follicles.
Drugs that target mutations in these genes, including imatinib, ruxolitinib and sunitinib, while not approved for breast cancer, are already on the market for other cancers.
2011: Benlysta, Esbriet, Telaprevir, and Ruxolitinib.
The goal of this study is to learn if Pracinostat, when given in combination with ruxolitinib (marketed as Jakafi[sup.