RUXOLITINIB MECHANISM OF ACTION
It is a potent and selective oral inhibitor of JAK1 and JAK2. The Janus kinase (JAK) family consists of four intracellular, nonreceptor tyrosine kinases: JAK1, JAK2, JAK3, and TYK2. JAKs are constitutively bound to cytokine receptors. Upon binding of ligand, JAKs are activated and thereby phosphorylate and activate downstream targets such as signal transducers and activators of transcription (STAT). Ruxolitinib is an oral, reversible class I inhibitor and competes with ATP in the catalytic site of the JAK tyrosine kinases.
Accordingly, ruxolitinib is not specific for the JAK2 V617F mutation. Its efficacy in
myelofibrosis has been primarily attributed to attenuation of the inflammatory state caused by constitutive JAK/STAT activation and a nonspecific myelosuppression.
Maximal plasma concentration (Cmax) achieved within 1 to 2 hours post-dose.
• No clinically relevant changes in the pharmacokinetics of ruxolitinib upon administration of Jakafi with a high-fat meal.
• CYP3A4 is the major enzyme responsible for metabolism of ruxolitinib.
• Elimination was predominately through metabolism with 74% of excreted in urine and 22% excretion via feces.
• Mean elimination half-life of ruxolitinib is approximately 3 hours.
INDICATIONS AND USAGE
• Patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential thrombocythemia myelofibrosis.
Platelets Greater than 200 X 109/L
• 20 mg orally twice daily
Platelets 100 X 109/L to 200 X 109/L
• 15 mg orally twice daily
• A complete blood count (CBC) and platelet count must be performed before initiating
therapy, every 2 to 4 weeks until doses are stabilized, and then as clinically indicated.
• Can be administered with or without food.
• If a dose is missed, the patient should not take an additional dose, but should take the next usual prescribed dose.
• When discontinuing therapy for reasons other than thrombocytopenia, gradual tapering of
the dose may be considered, for example by 5 mg twice daily each week.
• For patients unable to ingest tablets, Jakafi can be administered through a nasogastric tube (8 French or greater) as follows:
• Suspend one tablet in approximately 40 mL of water with stirring for approximately 10
• Within 6 hours after the tablet has dispersed, the suspension can be administered through a nasogastric tube using an appropriate syringe.
• The tube should be rinsed with approximately 75 mL of water.
• 5 mg, 10 mg, 15 mg, 20 mg and 25 mg, round and white tablets.
– Interrupt treatment for platelet counts less than 50 X 109/L.
– After recovery of platelet counts above this level, dosing may be restarted or increased following recovery of platelet counts.
– Greater than or equal to 125 X 109/L
• 20 mg twice daily
– 100 to less than 125 X 109/L
• 15 mg twice daily
– 75 to less than 100 X 109/L
• 10 mg twice daily for at least 2 weeks; if stable, may increase to 15 mg twice daily
– 50 to less than 75 X 109/L
• 5 mg twice daily for at least 2 weeks; if stable, may increase to 10 mg twice
Dose Modification Based on Response
• Consider dose increases in patients who meet all of the following conditions:
– Failure to achieve a reduction from pretreatment baseline in either palpable spleen
length of 50% or a 35% reduction in spleen volume as measured by CT or MRI
– Platelet count greater than 125 X 109/L at 4 weeks and platelet count never below
100 X 109/L
– ANC levels greater than 0.75 X 109/L.
– Should be avoided in patients with end stage renal disease (CrCl less than 15
mL/min) and in patients with moderate or severe renal impairment with platelet
counts less than 100 X 109/L.
– In rest of the patients with mild or moderate renal impairment starting dose of
ruxolitinib should be 5 mg lesser than that in normal patients with the same platelet
RUXOLITINIB Side Effects
• The most common hematologic adverse reactions are thrombocytopenia and anemia.
• The most common non-hematologic adverse reactions are bruising, dizziness and headache.
• Should be assessed for the risk of developing serious bacterial, mycobacterial, fungal and
• Active serious infections should have resolved before starting therapy .