Ruxolitinib

Uses

Myelofibrosis (MF): Ruxolitinib is used for the treatment of disease-related splenomegaly or symptoms in adult patients with primary myelofibrosis (also known as chronic idiopathic myelofibrosis), post polycythaemia vera myelofibrosis or post essential thrombocythaemia myelofibrosis.

Polycythaemia vera (PV): Ruxolitinib is used for the treatment of adult patients with polycythaemia vera who are resistant to or intolerant of hydroxyurea
Renal impairment: No specific dose adjustment is needed in patients with mild or moderate renal impairment.

Hepatic impairment: In patients with any hepatic impairment the recommended starting dose based on platelet count should be reduced by approximately 50% to be administered twice daily.

Elderly patients (≥65 years): No additional dose adjustments are recommended for elderly patients.

Paediatric population: The safety and efficacy of Ruxolitinib in children and adolescents aged up to 18 years have not been established. No data are available

Ruxolitinib is also used to associated treatment for these conditions: Graft Versus Host Disease, Acute, Post Essential Thrombocythaemia Myelofibrosis, Post Polycythemia Vera Myelofibrosis, Primary Myelofibrosis, High risk Myelofibrosis, Intermediate risk Myelofibrosis, Refractory Polycythemia vera

How Ruxolitinib works

The Janus kinase (JAK) family of protein tyrosine kinases comprises JAK1, JAK2, JAK3, and non-receptor tyrosine kinase 2 (TYK2). JAKs play a pivotal role in intracellular signalling pathways of various cytokines and growth factors essential to hematopoiesis, such as interleukin, erythropoietin, and thrombopoietin. JAKs have diverse functions: JAK1 and JAK3 promote lymphocyte differentiation, survival, and function, while JAK2 promotes signal transduction of erythropoietin and thrombopoietin. JAKs are in close proximity to the cytokine and growth factor receptor’s cytoplasmic region. Upon binding of cytokines and growth factors, JAKs are activated, undergoing cross-phosphorylation and tyrosine phosphorylation. This process also reveals selective binding sites for STATs, which are DNA-binding proteins that also bind to the cytoplasmic region of cytokine or growth factor receptors. Activated JAKs and STATs translocate to the nucleus as transcription factors to regulate gene expression of pro-inflammatory cytokines such as IL-6, IL-10, and nuclear factor κB (NF-κB). They also activate downstream pathways that promote erythroid, myeloid, and megakaryocytic development.

The molecular pathogenesis of myeloproliferative neoplasms is not fully understood; however, JAK2 is constitutively activated and the JAK-STAT signalling pathway becomes deregulated and aberrant. Ruxolitinib is a selective and potent inhibitor of JAK2 and JAK1, with some affinity against JAK3 and TYK2. Anticancer effects of ruxolitinib are attributed to its inhibition of JAKs and JAK-mediated phosphorylation of STAT3. By downregulating the JAK-STAT pathway, ruxolitinib inhibits myeloproliferation and suppresses the plasma levels of pro-inflammatory cytokines such as IL-6 and TNF-α.

Activated JAKs are also implicated in graft-versus-host-disease (GVHD), which is a severe immune complication of allogeneic hematopoietic cell transplantation GVHD is associated with significant morbidity and mortality, especially for patients who do not respond well to corticosteroid therapy. Activated JAKS stimulate T-effector cell responses, leading to increased proliferation of effector T cells and heightened production of pro-inflammatory cytokines. By blocking JAK1 and JAk2, ruxolitinib inhibits donor T-cell expansion and suppresses pro-inflammatory responses.

Dosage

Ruxolitinib dosage

The recommended starting dose of ruxolitinib in MF is 15 mg twice daily for patients with a platelet count between 100,000/mm 3 and 200,000/mm 3 and 20 mg twice daily for patients with a platelet count of >200,000/mm 3 . The recommended starting dose of ruxolitinib in PV is 10 mg given orally twice daily.

There is limited information to recommend a starting dose for patients with platelet counts between 50,000/mm 3 and <100,000/mm 3 . The maximum recommended starting dose in these patients is 5 mg twice daily and the patients should be titrated cautiously.

Ruxolitinib is to be taken orally, 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.

Toxicity

The oral LD₅₀ was 250 mg/kg.

Single doses of ruxolitinib up to 200 mg were tolerated well. Higher doses than recommended repeat doses are associated with myelosuppression, including leukopenia, anemia, and thrombocytopenia. There is no known antidote for overdoses with ruxolitinib: it is recommended that patients are given appropriate supportive treatment. Hemodialysis is not expected to enhance the elimination of ruxolitinib.

Food Interaction

• Avoid grapefruit products. Grapefruit inhibits CYP3A4 metabolism, which may increase the serum concentration of ruxolitinib.
• Exercise caution with St. John's Wort. This herb induces CYP3A4 metabolism, which may reduce the serum levels of ruxolitinib.
• Take with or without food. A high-fat, high-calorie meal had negligible effects on the pharmacokinetics of ruxolitinib.

[Moderate] GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of ruxolitinib.

The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits.

MANAGEMENT: Patients treated with ruxolitinib should avoid consumption of grapefruit, grapefruit juice, and any supplement containing grapefruit extract.

Ruxolitinib may be administered with or without food.

Ruxolitinib Cholesterol interaction

[Moderate] The use of ruxolitinib may increase total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides.

It is recommended to assess lipid parameters approximately 8-12 weeks following initiation of therapy and to monitor and treat per clinical guidelines for the management of hyperlipidemia.

Care should be exercised when using this agent in patients with lipids disorders.

Ruxolitinib Drug Interaction

Moderate: escitalopramUnknown: zolpidem, diphenhydramine, sulfamethoxazole / trimethoprim, ubiquinone, ubiquinone, dorzolamide / timolol ophthalmic, warfarin, heparin, bimatoprost ophthalmic, pregabalin, morphine, acetaminophen, bioflavonoids, vitamin a topical, bioflavonoids, montelukast, sotalol, sildenafil, cholecalciferol

Ruxolitinib Disease Interaction

Major: cardiovascular risk, malignancy, thrombosisModerate: lung toxicity, cytopenia, hepatic impairment, Hepatitis B, infections, lipid elevations, PML, renal impairment, tuberculosis

Volume of Distribution

The mean volume of distribution (%coefficient of variation) at steady-state is 72 L (29%) in patients with myelofibrosis and 75 L (23%) in patients with polycythemia vera. It is not known whether ruxolitinib crosses the blood-brain barrier.

Elimination Route

Following oral administration, ruxolitinib undergoes rapid absorption and the peak concentrations are reached within one hour after administration. Over a single-dose range of 5 mg to 200 mg, the mean maximal plasma concentration (C_max) increases proportionally. C_max ranged from 205 nM to 7100 nM and AUC ranged from 862 nM x hr to 30700 nM x hr. T_max ranges from one to two hours following oral administration. Oral bioavailability is at least 95%.

Half Life

The mean elimination half-life of ruxolitinib is approximately 3 hours and the mean half-life of its metabolites is approximately 5.8 hours.

Clearance

Ruxolitinib clearance (% coefficient of variation) is 17.7 L/h in women and 22.1 L/h in men with myelofibrosis. Drug clearance was 12.7 L/h (42%) in patients with polycythemia vera and 11.9 L/h (43%) in patients with acute graft-versus-host disease.

Elimination Route

Following oral administration of a single radiolabeled dose of ruxolitinib, the drug was mainly eliminated through metabolism. About 74% of the total dose was excreted in urine and 22% was excreted in feces, mostly in the form of hydroxyl and oxo metabolites of ruxolitinib. The unchanged parent drug accounted for less than 1% of the excreted total radioactivity.

Pregnancy & Breastfeeding use

Contraindicated in pregnancy & lactation. There are no data from the use of ruxolitinib in pregnant women. Animal studies have shown that ruxolitinib is embryotoxic and foetotoxic. 

ruxolitinib must not be used during breast-feeding and breast-feeding should therefore be discontinued when treatment is started. It is unknown whether ruxolitinib and/or its metabolites are excreted in human milk. A risk to the breast-fed child cannot be excluded. Available pharmacodynamic/toxicological data in animals have shown excretion of ruxolitinib and its metabolites in milk

Fertility: There are no human data on the effect of ruxolitinib on fertility. In animal studies, no effect on fertility was observed.

Contraindication

Hypersensitivity to the active substance or to any of the excipients

Acute Overdose

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, anaemia and thrombocytopenia. Appropriate supportive treatment should be given. Haemodialysis is not expected to enhance the elimination of ruxolitinib.

Storage Condition

Do not store above 30°C.

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