Indicated for treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential thrombocythemia myelofibrosis.
Ruxolitinib, a kinase inhibitor, inhibits Janus Associated Kinases (JAKs) JAK1 and JAK2 which mediate the signaling of a number of cytokines and growth factors that are important for hematopoiesis and immune function. JAK signaling involves recruitment of STATs (signal transducers and activators of transcription) to cytokine receptors, activation and subsequent localization of STATs to the nucleus leading to modulation of gene expression. Myelofibrosis (MF) is a myeloproliferative neoplasm (MPN) known to be associated with dysregulated JAK1 and JAK2 signaling. Oral administration of ruxolitinib prevented splenomegaly, preferentially decreased JAK2V617F mutant cells in the spleen and decreased circulating inflammatory cytokines (eg, TNF-α, IL-6).
Absorption: Ruxolitinib is rapidly absorbed after oral Ruxolitinib administration with maximal plasma concentration (Cmax) achieved within 1 to 2 hours post-dose. Oral absorption of ruxolitinib was estimated to be at least 95%. Distribution: The mean volume of distribution of ruxolitinib at steady-state is 72 L in patient with MF and PV in myelofibrosis patients.
Half-life: the mean half-life of ruxolitinib & metabolites is approximately 5.8 hours. Elimination half-life: The mean elimination half-life of ruxolitinib is approximately 3 hours AUC: Mean ruxolitinib Cmax and total exposure (AUC) increased proportionally over a single dose range of 5 to 200 mg.
The plasma protein binding: 97%, mostly to albumin. Metabolism: Ruxolitinib is metabolized by CYP3A4 and to a lesser extent by CYP2C9.
Excretion: Following a single oral dose of radio labeled ruxolitinib in healthy adult subjects, elimination was predominately through metabolism with 74% of radioactivity excreted in urine and 22% excretion via feces. Unchanged drug accounted for less than 1% of the excreted total radioactivity.
The starting dose of it is 20 mg given orally twice daily for patients with a platelet count greater than 200 X 109 /L, and 15 mg twice daily for patients with a platelet count between 100 X 109 /L and 200 X 109 /L. ? Perform a complete blood count before initiating therapy with Jakafi. Monitor complete blood counts every 2 to 4 weeks until doses are stabilized, and then as clinically indicated. Modify dose for thrombocytopenia. ? Increase dose based on response and as recommended to a maximum of 25 mg twice daily. Discontinue after 6 months if no spleen reduction or symptom improvement
Fluconazole: Concomitant administration of Ruxolitinib with fluconazole greater than 200 mg daily may increase ruxolitinib exposure due to inhibition of both the CYP3A4 and CYP2C9 metabolic pathways. Increased exposure may increase the risk of exposure-related adverse reactions. Avoid the concomitant use of Ruxolitinib with fluconazole doses of greater than 200 mg daily except in patients with acute GVHD.
Strong CYP3A4 Inhibitors: Concomitant administration of Ruxolitinib with strong CYP3A4 inhibitors increases ruxolitinib exposure. Increased exposure may increase the risk of exposure-related adverse reactions. Consider dose reduction when administering Ruxolitinib with strong CYP3A4 inhibitors. In patients with acute GVHD, reduce Ruxolitinib dose as recommended only when coadministered with ketoconazole, and monitor blood counts more frequently for toxicity and adjust the dose if necessary when coadministered with itraconazole.
Strong CYP3A4 Inducers: Concomitant administration of Ruxolitinib with strong CYP3A4 inducers may decrease ruxolitinib exposure. No dose adjustment is recommended; however, monitor patients frequently and adjust the Ruxolitinib dose based on safety and efficacy.
The most common side effect (incidence > 20%) are thrombocytopenia and anemia. The most common non-hematologic adverse reactions (incidence >10%) are bruising, dizziness and headache.
Pregnancy Category C There are no adequate and well-controlled studies of itin pregnant women. In embryofetal toxicity studies, treatment with ruxolitinib resulted in an increase in late resorptions and reduced fetal weights at maternally toxic doses. itshould be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
There is no known antidote for overdoses with Ruxolitinib. Single doses up to 200 mg have been given with acceptable acute tolerability. Higher than recommended repeat doses are associated with increased myelosuppression including leukopenia, anemia and thrombocytopenia. Appropriate supportive treatment should be given. Hemodialysis is not expected to enhance the elimination of Ruxolitinib.
Store below 30°C in a dry place, away from sunlight. Keep out of reach of children.
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