Jakafi - Drug Monograph

Introduction

Jakafi (ruxolitinib) is an oral targeted therapy belonging to the class of Janus kinase (JAK) inhibitors. It represents a significant advancement in the treatment of certain myeloproliferative neoplasms and graft-versus-host disease. Approved by the FDA in 2011, Jakafi was the first JAK inhibitor to receive approval for hematologic conditions.

Mechanism of Action

Ruxolitinib is a selective inhibitor of Janus kinase 1 (JAK1) and Janus kinase 2 (JAK2). These enzymes mediate signaling of cytokines and growth factors involved in hematopoiesis and immune function. In myeloproliferative neoplasms, abnormal JAK signaling leads to excessive production of blood cells and inflammatory cytokines. By inhibiting JAK1 and JAK2, ruxolitinib reduces:

• Constitutional symptoms (night sweats, weight loss, fever)
• Splenomegaly
• Inflammatory cytokine production
• Abnormal hematopoietic cell proliferation

Indications

FDA-approved indications: 1. Myelofibrosis: Intermediate or high-risk primary myelofibrosis, post-polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis 2. Polycythemia Vera: For patients who have had an inadequate response to or are intolerant of hydroxyurea 3. Acute Graft-Versus-Host Disease: Steroid-refractory acute GVHD in adults and pediatric patients 12 years and older 4. Chronic Graft-Versus-Host Disease: After failure of one or two lines of systemic therapy in adults and pediatric patients 12 years and older

Dosage and Administration

• Starting dose: Based on platelet count

- Platelet count >200 × 10⁹/L: 20 mg twice daily - Platelet count 100-200 × 10⁹/L: 15 mg twice daily - Platelet count 50-<100 × 10⁹/L: 5 mg twice daily

• Titrate based on efficacy and safety

• Starting dose: 10 mg twice daily
• Titrate based on efficacy and safety

• Acute GVHD: 10 mg twice daily
• Chronic GVHD: 10 mg twice daily

• Renal impairment: Dose reduction required for CrCl <60 mL/min
• Hepatic impairment: Use with caution in severe impairment
• Elderly: No specific dose adjustment required
• Pediatric: Safety established for GVHD in patients ≥12 years

Pharmacokinetics

• Absorption: Oral bioavailability approximately 95%, peak plasma concentration reached in 1-2 hours
• Distribution: Extensive tissue distribution, 97% plasma protein bound
• Metabolism: Primarily hepatic via CYP3A4
• Elimination: Half-life approximately 3 hours, primarily excreted in urine (74%) as metabolites

Contraindications

1. Hypersensitivity to ruxolitinib or any component of the formulation 2. Concomitant use with strong CYP3A4 inhibitors in patients with platelet counts <100 × 10⁹/L

Warnings and Precautions

1. Thrombocytopenia, Anemia, Neutropenia: May require dose reduction or interruption 2. Infection: Serious bacterial, mycobacterial, fungal, and viral infections may occur 3. Malignancies: Increased risk of certain cancers, including lymphoma

• Cardiovascular risk: Increased risk of major adverse cardiovascular events
• Thrombosis: Increased risk in polycythemia vera patients
• Secondary malignancies: Including non-melanoma skin cancer
• Lipid elevations: May require monitoring and treatment

Drug Interactions

• Strong CYP3A4 inhibitors (ketoconazole, clarithromycin): Reduce Jakafi dose by approximately 50%
• Fluconazole: Reduce Jakafi dose if doses >10 mg twice daily
• Strong CYP3A4 inducers (rifampin, carbamazepine): May decrease ruxolitinib exposure

Adverse Effects

• Anemia (96%)
• Thrombocytopenia (70%)
• Neutropenia (19%)
• Bruising (23%)
• Dizziness (18%)
• Headache (15%)
• Increased cholesterol (16%)

• Progressive multifocal leukoencephalopathy (PML)
• Serious infections
• Major cardiovascular events
• Thrombotic events
• Secondary malignancies
• Hepatitis B reactivation

Monitoring Parameters

• Complete blood count with differential
• Comprehensive metabolic panel
• Lipid profile
• Hepatitis B and C screening
• Pregnancy test if applicable

• CBC weekly until stable, then every 2-4 weeks
• Liver function tests monthly for first 3 months, then as clinically indicated
• Lipid panel at 8-12 weeks, then every 6 months
• Signs/symptoms of infection
• Skin examinations for new lesions
• Cardiovascular assessment

Patient Education

• Take exactly as prescribed; do not adjust dose without medical supervision
• Report signs of infection immediately (fever, chills, cough)
• Monitor for bruising, bleeding, or unusual fatigue
• Use sun protection and perform regular skin self-exams
• Inform all healthcare providers about Jakafi therapy
• Avoid grapefruit products during treatment
• Use effective contraception during treatment and for at least 1 month after discontinuation
• Do not receive live vaccines during treatment

• Store at room temperature (20-25°C/68-77°F)
• Keep in original container with desiccant
• Protect from moisture

References

1. Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366(9):799-807. 2. Vannucchi AM, Kiladjian JJ, Griesshammer M, et al. Ruxolitinib versus standard therapy for the treatment of polycythemia vera. N Engl J Med. 2015;372(5):426-435. 3. Jakafi [package insert]. Wilmington, DE: Incyte Corporation; 2023. 4. Zeiser R, von Bubnoff N, Butler J, et al. Ruxolitinib for glucocorticoid-refractory acute graft-versus-host disease. N Engl J Med. 2020;382(19):1800-1810. 5. FDA-approved labeling: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/202192s028lbl.pdf 6. NCCN Guidelines: Myeloproliferative Neoplasms (Version 2.2024) 7. European LeukemiaNet recommendations for the management of myeloproliferative neoplasms. Leukemia. 2023;37(7):1393-1410.