Ruxolitinib (Jakafi, Jakavi) belongs to the class of drugs called kinase inhibitors. It is used in the treatment of myelofibrosis and patients with polycythemia who have an inadequate response to hydroxyurea.

Ruxolitinib (Jakafi, Jakavi) Uses:

• Acute Graft-versus-host disease:

  • Treatment of steroid-refractory acute graft-versus-host disease (GVHD) in both 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

• Off Label Use of Ruxolitinib in Adults:

  • Treatment of chronic graft vs host disease

Ruxolitinib (Jakafi, Jakavi) Dose in Adults

Ruxolitinib Dosage recommendations by the Manufacturer:

Ruxolitinib (Jakafi, Jakavi) dose in the treatment of steroid-refractory acute Graft-versus-host disease:

• Oral: start with 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 reduced by ≥50% from baseline [first day of ruxolitinib]).
• Consider tapering ruxolitinib after 6 months of therapy if a response occurs and therapeutic corticosteroid doses have been discontinued; taper by one dose level every 8 weeks (10 mg twice daily to 5 mg twice daily and then to 5 mg once daily).
• Consider retreatment if acute graft-versus-host disease (GVHD) signs/symptoms reappear during or after tapering ruxolitinib.

Ruxolitinib (Jakafi, Jakavi) Dose in the treatment of chronic steroid-refractory Graft-versus-host disease  (off-label):

• Oral: 5 to 10 mg twice daily.

Ruxolitinib (Jakafi, Jakavi) Dose in the treatment of 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

Ruxolitinib (Jakafi, Jakavi) dosage modification based on the response in patients with baseline platelet count ≥100,000/mm³ prior to initial treatment with ruxolitinib:

• • For inadequate response (with normal 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 the first 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 slowly tapering by ~5 mg twice daily each 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/mm at 4 weeks (and never <100,000/mm³)
  • Absolute neutrophil count (ANC) >750/mm³

• Dosage modification for bleeding requiring intervention (regardless of platelet count):

  • Withhold treatment until bleeding resolved; may consider restarting at the previous 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 the response in patients with baseline platelet 50,000 to <100,000/mm³ prior to initial treatment with ruxolitinib:

  • For inadequate response (with normal 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 the first 4 weeks and not more than every 2 weeks.
  • Stop 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 fall more than 20% in the previous 4 weeks
  • Absolute neutrophil count (ANC) >1,000/mm³
  • No side effect or hematological toxicity leading to dose reduction or interruption occurred in the previous 4 weeks

• Therapy discontinuation:

  • Consider slowly tapering off (by 5 mg twice daily each week) if withheld for reasons other than thrombocytopenia.

Ruxolitinib (Jakafi, Jakavi) Dose in the treatment of Polycythemia vera:

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

• Dose modification due to insufficient response:

  • If the response is not satisfactory 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 the dose in the initial 4 weeks of treatment and not more than every 2 weeks.

  • Consider dose increases in patients who meet all of the following conditions:

    • Unsatisfactory efficacy demonstrated by one or more of the following:
      • The continued need for phlebotomy, WBC >ULN of the normal range, platelet count >ULN of the normal range, or palpable spleen that is decreased by <25% from baseline.
      • Platelet count ≥140,000/mm³
      • Hemoglobin ≥12 g/dL
      • ANC ≥1,500/mm³

  • Therapy discontinuation:

    • Consider slowly tapering off (by 5 mg twice daily each week) if interrupting for reasons other than thrombocytopenia.

Ruxolitinib (Jakafi, Jakavi) Dosage adjustment with concomitant therapy

• Acute treatment of steroid-refractory Graft-versus-host disease: CYP3A4 inhibitors:

  • Ketoconazole:
    • ruxolitinib 5 mg once daily
  • Other CYP3A4 inhibitors:
    • No ruxolitinib dose adjustment required.
    • If using concurrently with itraconazole, monitor blood counts more frequently and adjust ruxolitinib dosage as needed.

• Myelofibrosis and polycythemia vera:

  • Strong CYP3A4 inhibitors and fluconazole (≤200 mg):

Note: Avoid concurrent 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/mm to <100,000/mm³:
    • 5 mg once daily.
    • Observe 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:
    • decrease dose by 50% (rounded up to the closest available tablet strength).
  • Stabilized on ruxolitinib 5 mg twice daily:
    • decrease dose to 5 mg once daily.
  • Stabilized on ruxolitinib 5 mg once daily:
    • Avoid strong CYP3A4 inhibitors or fluconazole or withhold treatment for the duration of strong CYP3A4 inhibitor or fluconazole use.
    • Monitor closely and further adjust the dose according to safety and efficacy.

Ruxolitinib (Jakafi) Dose adjustment in patients with thrombocytopenia [Ref]:

Ruxolitinib (Jakafi, Jakavi) Dose in Childrens

Ruxolitinib (Jakafi, Jakavi) Dose in the treatment of Acute Steroid-refractory Graft-versus-host disease (GVHD):

• Fixed dosing:

  • Children ≥12 years and Adolescents:

    • Oral: start with 5 mg twice daily.
    • Consider increasing the dose to 10 mg twice daily after at least 3 days of treatment if ANC and platelets do not fall by ≥50% compared to baseline (first day of ruxolitinib).

• Weight-directed dosing:

  • Children and Adolescents: Limited data available:

    • Note:
      • Dosing based on a retrospective study of 13 patients (aged 1.6 to 16.5 years) receiving ruxolitinib for steroid-refractory GVHD.
      • Ruxolitinib has a high risk of reversible side effects and an overall average response rate.
    • <25 kg:
      • Initial: 2.5 mg orally twice daily;
      • if tolerated, may double the dose on a weekly basis to a maximum dose of 10 mg twice daily.
    • ≥25 kg:
      • start with 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 a response occurs and therapeutic corticosteroid doses have been stopped;
    • taper by 1 dose level every 8 weeks (ie, 10 mg twice daily to 5 mg twice daily and then to 5 mg once daily).
    • Consider retreatment if acute GVHD signs or symptoms develop again during or after tapering ruxolitinib.

Ruxolitinib (Jakafi, Jakavi) 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 dose adjustment required.
    • If using concurrently with itraconazole, monitor blood counts more frequently and adjust ruxolitinib dose as needed.

Ruxolitinib (Jakafi, Jakavi) Dosage adjustment for toxicity:

• Children ≥12 years and Adolescents: Oral:

  • Dosage reduction levels:

Note: Dose reduction is based on the ruxolitinib regimen at the 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:
      • withhold ruxolitinib treatment until clinical and/or laboratory parameters improve.

Ruxolitinib (Jakafi, Jakavi) Dosage modification for hematologic toxicity:

• Clinically significant thrombocytopenia:

  • Decrease dose by 1 dose level;
  • When platelets recover to previous values, may increase dose to the previous dose.

• ANC <1,000/mm³ related to ruxolitinib treatment:

  • Interrupt treatment for up to 14 days;
  • upon recovery, reinitiate at 1 dose level lower.

Ruxolitinib (Jakafi) Pregnancy Risk Category: C

• Human pregnancies have not been tested with the drug.
• When the drug was administered to the animals during organogenesis, there were no teratogenic effects.
• However, the fetal weight was significantly less than that of control subjects.

Use during breastfeeding:

• It is unknown if the drug is excreted from breastmilk.
• The drug and its metabolites, however, were 13 times more concentrated in the breastmilk of rats that their plasma.
• Manufacturers recommend that you stop using the drug and/or breastfeed to balance the benefits and risks.

Ruxolitinib (Jakafi, Jakavi) Dose in Kidney Disease:

• Acute treatment of steroid-refractory Graft-versus-host disease:

  • CrCl 15 to 59 mL/minute and any platelet count:
    • start with 5 mg once daily.
    • Additional dose adjustments should be made with frequent observation.
  • End-stage renal disease (ESRD) (CrCl <15 mL/minute) on dialysis and any platelet count:
    • starting dose: 5 mg once after dialysis;
    • additional dose adjustments should be made with close monitoring.
  • ESRD (CrCl <15 mL/minute) not requiring dialysis: 
    • donot use.

• Myelofibrosis:

  • CrCl 15 to 59 mL/minute and platelets >150,000/mm³:
    • No dose adjustment is needed.
  • CrCl 15 to 59 mL/minute and platelets 100,000 to 150,000/mm³:
    • starting dose: 10 mg twice daily;
    • further dose adjustments should be made with careful monitoring.
  • CrCl 15 to 59 mL/minute and platelets 50,000 to <100,000/mm³:
    • starting dose: 5 mg once daily;
    • additional dose adjustments should be made with close monitoring.
  • CrCl 15 to 59 mL/minute and platelets <50,000/mm³:  
    • use not recommended.
  • ESRD (CrCl <15 mL/minute) on dialysis and platelets 100,000 to 200,000/mm³:
    • starting dose: 15 mg once after dialysis;
    • administer subsequent doses after dialysis on dialysis days.
    • Further dose adjustments should be made with frequent monitoring.
  • ESRD (CrCl <15 mL/minute) on dialysis and platelets >200,000/mm³:
    • starting dose: 20 mg once after dialysis;
    • administer subsequent doses after dialysis on dialysis days.
    • Further dose adjustments should be made with frequent monitoring.
  • ESRD not requiring dialysis:
    • Use not recommended.

• Polycythemia vera:

  • CrCl 15 to 59 mL/minute and any platelet count:
    • start with: 5 mg twice daily. Further dose adjustments should be made with frequent monitoring.
  • ESRD (CrCl <15 mL/minute) on dialysis and any platelet count:
    • starting dose: 10 mg once after dialysis; further dose adjustments should be made with close monitoring
  • ESRD (CrCl <15 mL/minute) not requiring dialysis:
    • use not recommended.
    • Hemodialysis is not expected to increase the elimination of ruxolitinib.

Ruxolitinib (Jakafi, Jakavi) Dose in Liver disease:

• Acute treatment of Steroid-refractory Graft-versus-host disease:

  • Preexisting hepatic impairment:

    • Mild to severe impairment (based on NCI criteria) and any platelet count:
      • No dose adjustment needed.
  • Stage 3 or 4 liver graft-versus-host disease (GVHD) and any platelet count:
    • Monitor blood counts more frequently and consider dosing at 5 mg once daily.

• Hepatoxicity during treatment (refer to Dosing – Adjustment for Toxicity for acute GVHD dosage reduction levels):

  • Total bilirubin elevation without liver GVHD:

    • Total bilirubin 3 to 5 times ULN:
      • Continue ruxolitinib at 1 dose level lower until recovery.
    • Total bilirubin >5 to 10 times ULN:
      • Interrupt ruxolitinib treatment for up to 14 days. When bilirubin recovers to ≤1.5 times ULN, may restart at the current dose.
    • Total bilirubin >10 times ULN:
      • withhold ruxolitinib treatment for up to 2 weeks. When bilirubin recovers to ≤1.5 times ULN, may restart at 1 dose level lower.
    • Total bilirubin elevation with liver GVHD:
      • Total bilirubin >3 times ULN: Continue ruxolitinib at 1 dose level lower until recovery.

• Myelofibrosis:

  • Mild to severe impairment (Child-Pugh class A, B, or C) and platelets >150,000/mm³:
    • No dose adjustment is needed.
  • Mild to severe impairment (Child-Pugh class A, B, or C) and platelets 100,000 to 150,000/mm³:
    • starting 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:
    • starting 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:
    • use not recommended.

• Polycythemia vera:

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

Common Side Effects of Ruxolitinib (Jakafi, Jakavi):

• Central Nervous System:

  • Dizziness
  • Headache
  • Fatigue
  • Insomnia

• Dermatologic:

  • Bruise
  • Pruritus

• Endocrine & Metabolic:

  • Increased Serum Cholesterol
  • Hypertriglyceridemia

• Gastrointestinal:

  • Diarrhea
  • Abdominal Pain

• Hematologic & Oncologic:

  • Anemia
  • Thrombocytopenia
  • Neutropenia

• Hepatic:

  • Increased Serum Alanine Aminotransferase
  • Increased Serum Aspartate Aminotransferase

• Neuromuscular & Skeletal:

  • Muscle Spasm

• Respiratory:

  • Dyspnea

Less Common Side Effects Of Ruxolitinib (Jakafi, Jakavi):

• Cardiovascular:

  • Edema
  • Hypertension

• Endocrine & Metabolic:

  • Weight Gain

• Gastrointestinal:

  • Constipation
  • Nausea
  • Flatulence

• Genitourinary:

  • Urinary Tract Infection

• Infection:

  • Herpes Zoster Infection

• Neuromuscular & Skeletal:

  • Arthralgia
  • Asthenia

• Respiratory:

  • Nasopharyngitis
  • Cough
  • Epistaxis

Contraindications to Ruxolitinib (Jakafi, Jakavi):

The US labeling of the manufacturer does not list any contraindications. Canadian labeling:

• Hypersensitivity to ruxolitinib and any component of the formula or container
• A history of progressive multifocal or current leukoencephalopathy

Warnings and precautions

• Hematologic toxicities:

  • Hematologic toxicities, such as anemia, thrombocytopenia, and neutropenia, may occur. It may be necessary to adjust the dosage. 
  • Complete blood counts should be monitored at baseline and every 2 to 4 weeks during dose stabilization. Follow-up appointments may be necessary if clinically indicated.
  • Treatment interruption or dose reduction is usually enough to reverse thrombocytopenia. If necessary, platelet transfusions can be administered during treatment.
  • Anemia can require blood transfusions; you may also consider dose modification.
  • Neutropenia (ANC 500/mm3) can be reversible. It is managed by withholding treatment.

• Infections

  • There have been serious bacterial, mycobacterial (including tuberculosis), and fungal or viral infections.
  • Before beginning treatment, it is important to get rid of any active serious infections.
  • During treatment, monitor for signs/symptoms of active tuberculosis or herpes zoster; prescribe prophylactic antibiotics in accordance with clinical practice guidelines.
  • If you notice symptoms of active tuberculosis or herpes zoster, it is important to get immediate treatment.
  • Before beginning treatment, assess for tuberculosis risk factors.
  • Patients at greater risk (previous travel to countries with high tuberculosis incidence, close contact with active tuberculosis or history of latent tuberculosis in which appropriate treatment cannot be confirmed) should be tested for latent infections.
  • Patients with active or latent tuberculosis should decide if continuing treatment is worth the risk.
  • Progressive multifocal Leukoencephalopathy (PML), has been reported. Stop and have your symptoms assessed if you suspect.
  • Patients with chronic hepatitis A have reported an increase in HBV-DNA titer (with or without associated ALT/AST elevations). However, the effects of ruxolitinib are not known.

• Lipid abnormalities

  • The increase in lipid parameters, such as total cholesterol and LDL cholesterol, has been linked to Ruxolitinib.
  • Assess your lipid levels 8-12 weeks after you start ruxolitinib. Monitor and manage hyperlipidemia accordingly.

• Non-melanoma skin carcinoma:

  • Patients who received ruxolitinib have had non-melanoma skin tumors (basal, squamous, and Merkel cell carcinoma).
  • It is important to conduct periodic skin exams.

• Hepatic impairment

  • You may need to reduce your initial dose.
  • Patients with myelofibrosis should not be given if their platelets are below 50,000/mm3 or if they have any degree of hepatic impairment.
  • Patients with liver graft-versus-host disease (GVHD) stage 3 and 4 should be monitored more often.

• Renal impairment

  • You may need to reduce your initial dose.
  • Patients with ESRD should not be on dialysis. Avoid patients with myelofibrosis whose platelets are 50,000/mm3 or with severe to moderate renal impairment.
  • Ruxolitinib cannot be removed through dialysis. However, active metabolites can be removed. Patients are instructed to take their doses after dialysis.

Ruxolitinib: Drug Interaction

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 needed thereafter).
• renal function.
• hepatic function.
• hepatitis B viral load (HBV-DNA titer) in patients with chronic hepatitis B infection.
• Examine skin, periodically monitor for signs/symptoms of an infection; Tuberculin skin test (before starting treatment).
• Monitor compliance.

How to administer Ruxolitinib (Jakafi)?

Oral: It may be administered orally with or without meals. In case a dose is missed, continue the usual dosing schedule additional dose is not needed. If unable to ingest tablets, may administer via nasogastric (NG) tube (≥8 Fr):

• mix 1 tablet in ~40 mL water and stir for ~10 minutes and administer (within 6 hours after dissolution) with an appropriate syringe;
• rinse NG tube with ~75 mL water (effect of enteral tube feeding on ruxolitinib exposure has not been studied).

Mechanism of action of Ruxolitinib (Jakafi):

• Ruxolitinib, a kinase inhibitor, selectively inhibits Janus Associated Kinases JAK1 and JAK2.
• JAK1 & JAK2 mediate the signaling of cytokine growth factors and hematopoiesis-related growth factors
• JAK-mediated signaling involves the recruitment STATs (signal transmitters and activators transcription) to cytokine receivers, which results in modulation gene expression.
• Myelofibrosis, polycythemia vera and JAK1/2 activity are dysregulated.
• Ruxolitinib modifies the affected JAK1/2 activities. JAK-STAT signaling regulates the development, proliferation and activation immune cell types that are important for GVHD pathogenesis.
• A animal model suggests that ruxolitinib might cause a decrease in expression of inflammatory cytokines and decreased immune cell infiltration in the colon.

Onset:

• Acute graft-versus-host disease (GVHD):
  • The median time to response: 1.5 weeks (range: 1 to 11 weeks)
• Chronic GVHD:
  • The median time to response: 3 weeks (range: 1 to 25 weeks);
  • responses were observed within 2 weeks of ruxolitinib initiation in another study.

Absorption:

• Rapid

Protein binding:

• ~97%;
• primarily to albumin

Metabolism:

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

Half-life elimination:

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

Time to peak:

• Within 1 to 2 hours

Excretion:

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

International Brand Names of Ruxolitinib:

• Jakafi
• Jakavi

Ruxolitinib Brand Names in Pakistan:

• Jakafi
• Jakavi

Jakavi is available at a very low price in Pakistan. You can get it by contacting +923455440667