JAKAVI 15MG

Indications

• Disease-related spl

Mechanism of action

Ruxolitinib works by selectively inhibiting JAK1 and JAK2, which are protein tyrosine kinases that mediate intracellular signaling for cytokines critical for blood cell production and immune responses. Upon cytokine binding, JAKs become activated, leading to phosphorylation of STAT proteins, which then translocate to the nucleus to regulate gene expression. Ruxolitinib interrupts this pathway, thereby inhibiting the activation of pro-inflammatory cytokines and reducing the symptoms associated with myeloproliferative disorders.

Pharmacodynamics

As an antineoplastic agent, ruxolitinib inhibits cell proliferation and promotes apoptosis in malignant cells. It effectively reduces splenomegaly and alleviates symptoms of conditions like myelofibrosis and polycythemia vera. The inhibition of STAT3 phosphorylation occurs rapidly after dosing, indicating its action on JAK activity, and the effects can be observed within hours. In clinical settings, ruxolitinib has shown efficacy in extending survival in patients with myeloproliferative neoplasms, although resistance may occur in some cases, particularly in patients with the JAK2V617F mutation.

Pharmacokinetics

Ruxolitinib is administered orally and undergoes hepatic metabolism primarily via CYP3A4. Its bioavailability can be affected by food, thus dosing recommendations may include consideration of meal timing. The drug displays moderate plasma protein binding and has a half-life that supports twice daily dosing. Renal and hepatic impairments may require dose adjustments, and monitoring of blood counts is essential during therapy due to risks of cytopenias.

Adverse effects

• Anaemia
• Alopecia
• Arthralgia
• Bruising
• Constipation
• Dizziness
• Dyslipidaemia
• Flatulence
• Fatigue
• Headache
• Hypertension
• Increased risk of infection
• Neutropenia
• Sepsis
• Thrombocytopenia
• Weight increased
• Stomatitis
• Peripheral oedema
• Skin reactions
• Diarrhoea
• Heart failure
• Cough
• Hypophosphataemia
• Hypothyroidism
• Muscle weakness
• Nausea
• Pain
• Peripheral neuropathy
• Tachycardia
• Vomiting

Interactions

• Fluconazole (increases exposure)
• Cobicistat (increases exposure)
• Dabrafenib (decreases exposure)
• Bosentan (decreases exposure)
• Idelalisib (increases exposure)
• Clarithromycin (increases exposure)
• Mitotane (decreases exposure)
• Rifampicin (decreases exposure)
• St. John's Wort (decreases exposure)
• Dronedarone (unknown, increases exposure)

Precautions

• Assess risk of developing infection before treatment
• Monitor full blood count before treatment and regularly thereafter
• Evaluate for latent and active tuberculosis before starting treatment
• Assess left ventricular ejection fraction before treatment
• Caution advised on driving and skilled tasks due to increased risk of fatigue
• Perform skin examinations when starting treatment and routinely during treatment

Pregnancy

Avoid-toxicity in animal studies.

Breast-feeding

Avoid breastfeeding during treatment and for at least 1 week after last treatment-no information available.

Storage

Store at room temperature, away from moisture and heat.

Formulations

• Tablets

Mechanism of action

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. ... By directly targeting both JAK1 and JAK2 through small-molecule inhibition, ruxolitinib elicits a reduction in splenomegaly and disease-related symptoms in patients with intermediate- or high-risk myelofibrosis while maintaining an acceptable toxicity profile and a low treatment-discontinuation rate. Ruxolitinib phosphate, a selective inhibitor of Janus kinase (JAK) 1 and 2, is an antineoplastic agent. JAK1 and 2 mediate the signaling of cytokines and growth factors that are important for hematopoiesis and immune function. JAK signaling involves recruitment of signal transducers and activators of transcription (STAT) to cytokine receptors, activation, and subsequent localization of STATs to the nucleus leading to modulation of gene expression. Myelofibrosis is a myeloproliferative neoplasm known to be associated with dysregulated JAK1 and 2 signaling. Ruxolitinib demonstrated dose- and time-dependent inhibition of cytokine-induced phosphorylated STAT3 with maximal inhibition occurring 1-2 hours after single-dose administration (ranging from 5-200 mg) in healthy individuals at all dosage levels.

Pharmacodynamics

Ruxolitinib is an antineoplastic agent that inhibits cell proliferation, induces apoptosis of malignant cells, and reduces pro-inflammatory cytokine plasma levels by inhibiting JAK-induced phosphorylation of signal transducer and activator of transcription (STAT). Inhibition of STAT3 phosphorylation, which is used as a marker of JAK activity, by ruxolitinib is achieved at two hours after dosing which returned to near baseline by 10 hours in patients with myelofibrosis and polycythemia vera. In clinical trials, ruxolitinib reduced splenomegaly and improved symptoms of myelofibrosis. In a mouse model of myeloproliferative neoplasms, administration of ruxolitinib was associated with prolonged survival. Ruxolitinib inhibits both mutant and wild-type JAK2; however, JAK2V617F mutation, which is often seen in approximately 50% of patients with myelofibrosis, was shown to reduce ruxolitinib sensitivity, which may also be associated with possible resistance to JAK inhibitor treatment.