Jakavi® (ruxolitinib) has been listed on the PBS, making it the first JAK inhibitor to be approved by the TGA, and recommended by the PBAC, for myelofibrosis.

PBS Listing Criteria

From 1st February Jakavi has been reimbursed for intermediate-2 and high risk patients and int-1 patients with severe myelofibrosis-related symptoms intolerant, refractory or resistant to available therapies.¹

What does the data show?

Data from phase III trials (COMFORT I and II) show that more patients achieved reductions in splenomegaly with Jakavi vs placebo or best available therapy (BAT),^{5a, b, 6a, b,} improved symptoms within 4 weeks vs placebo ^{5c, d,} and impact on overall survival vs BAT in patients with myelofibrosis (p value is not significant). ¹⁴

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MINIMUM PRODUCT INFORMATION FOR JAKAVI:

Jakavi® (ruxolitinib) Indications: Treatment of disease-related splenomegaly or symptoms in patients with primary myelofibrosis (PM), post-polycythemia vera myelofibrosis or post-essential thrombocythemia myelofibrosis. Treatment of adult patients with polycythemia vera (PV) who are resistant to or intolerant of hydroxyurea. Dosage: Perform blood cell count before initiating Jakavi. Monitor complete blood counts every 2 to 4 weeks until doses are stabilised, and then as clinically indicated. In MF, orally twice daily with or without food. Recommended starting dose is based on platelet count: 5 mg twice daily (50 – 100 x 109 /L), 15 mg twice daily (100 – 200 x 109 /L) and 20 mg twice daily (> 200 x 109 /L). In PV, the recommended starting dose is 10 mg given orally twice daily with or without food. Dose titrated based on safety and efficacy. In MF and PV, dose should be reduced if the platelet count decreases below 100 x 109 /L. Interrupt treatment if platelet counts < 50 X 109 /L or ANC < 0.5 x 109 /L. In PV, dose reduction should also be considered if hemoglobin decreases below 120 g/L and is recommended if hemoglobin decreases below 100 g/L and treatment should also be interrupted when hemoglobin is below 80 g/L. Dose adjustment may be required due to thrombocytopenia or when used with strong CYP3A4 inhibitors or dual moderate inhibitors of CYP2C9 and CYP3A4 enzymes (e.g. fluconazole; avoid daily dose of fluconazole >200mg). Four weeks after initiating therapy dose may be increased in 5 mg twice daily increments at intervals of greater than 2 weeks to ensure adequate response. Max. dose is 25 mg twice daily. Limited data on initiating Jakavi in patients with platelet counts 50 – 100 x 109 /L. Only used in these patients if hepatic function is normal and renal function is normal or mildly impaired. Dose should be titrated cautiously based on response and blood cell counts. Recommend to reduce the starting dose by approx. 50% in patients with moderate to severe renal impairment (Clcr < 30 mL/min) or with hepatic impairment and monitor these patients reducing the dose as appropriate. The recommended starting dose for PV patients with severe renal impairment is 5 mg twice daily. No dosage adjustment required for elderly patients. Contraindications: Hypersensitivity to ruxolitinib or excipients. Precautions: Decrease in blood cell count: Haematological adverse reactions, including thrombocytopenia, anaemia and neutropenia. Complete blood count must be performed before initiating therapy. Dose reduction or interruption may be required in patients developing thrombocytopenia, anaemia and neutropenia. Infections: Treat active serious infections prior to initiating Jakavi therapy. Monitor patients for signs and symptoms of infections during treatment and initiate appropriate treatment for JAK0179 JANUARY 2016 infections. Risk of serious bacterial, mycobacterial, fungal and viral infection. Tuberculosis has been reported. Progressive Multifocal Leukencephalopathy (PML) reported. Physicians should be alert for neuropsychiatric symptoms suggestive of PML and if suspected must further suspend dosing until PML has been excluded. Hepatitis B viral load (HBV-DNA titre) increases reported in patients with chronic HBV infections. Patients with chronic HBV infection should be treated and monitored according to clinical guidelines. Non-Melanoma Skin Cancer (NMSC): NMSC, including basal cell, squamous cell, and Merkel cell carcinoma, reported in Jakavi treated patients. Periodic skin examination recommended. Pregnancy: not recommended during pregnancy (Category C). Breast-feeding: not to be used during breast-feeding. Paediatric: safety and efficacy not established in paediatric patients. Interactions: strong CYP3A4 inhibitors (such as ketoconazole) or dual moderate inhibitors of CYP2C9 and CYP3A4 enzymes – the total daily dose of Jakavi should be reduced by approximately 50%; avoid fluconazole daily doses >200 mg; mild or moderate CYP3A4 inhibitors (such as erythromycin); dual CYP2C9 and CYP3A4 inhibitors (such as fluconazole); CYP3A4 inducers (such as rifampicin); substances metabolised by CYP3A4 such as lovastatin, budesonide, everolimus, sirolimus, midazolam; substances transported by P-glycoprotein or other transporters such as tacrolimus, cyclosporine, diltiazem. Side effects: Very common (>10%): urinary tract infections, anaemia, thrombocytopenia, neutropenia, weight gain, hypercholesterolaemia, hypertriglycerideamia, dizziness, headache, alanine aminotransferase increased, aspartate aminotransferase increased, bruising. Common (1 to 10%): herpes zoster, flatulence, constipation, hypertension. Packs: Blister packs of 56s in 5 mg, 10mg, 15 mg and 20 mg strengths. Based on approved Jakavi Product Information dated 16 December 2015. jak161215m

For medical enquiries relating to Jakavi (ruxolitinib) please contact the Novartis Medical Information and Communication Team at 1800 671 203.

References:

1. www.pbs.gov.au

2. Scherber R et al. The Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF): International Prospective Validation and Reliability Trial in 402 patients, Blood 2011;118:401–8.

3. Cervantes et al. New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment, Blood 2009;113: 2895-2901.

4. Kroger N et al. Choosing between stem cell therapy and drugs in myelofibrosis, Leukemia 2008;22:474–86.

5. Verstovsek S et al. A Double-Blind, Placebo-Controlled Trial of Ruxolitinib for Myelofibrosis, N Engl J Med 2012;366:799–807.

6. Harrison C et al. JAK Inhibition with Ruxolitinib versus Best Available Therapy for Myelofibrosis, N Engl J Med 2012;366:787–98.

7. Cervantes F et al. Three-year efficacy, safety, and survival findings from COMFORT-II, a phase 3 study comparing ruxolitinib with best available therapy for myelofibrosis, Blood 2013;122:4047–53.

8. Emanuel RM et al. Myeloproliferative Neoplasm (MPN) Symptom Assessment Form Total Symptom Score: Prospective International Assessment of an Abbreviated Symptom Burden Scoring System Among Patients With MPNs, J Clin Oncol 2012;30:4098–103.

9. Leukaemia Foundation. National MPN Survey Results. 2014

10. Guglielmelli p, et al. Impact of mutational status on outcomes in myelofibrosis patients treated with ruxolitinib in the COMFORT-II study, Blood 2014;123:2157-60.

11. Jakavi Product Information, June 2015.

12. Verstovsek S et al. Efficacy, safety and survival with ruxolitinib in patients with myelofibrosis: results of a median 2-year follow-up of COMFORT-I, Haematologica. 2013; 98(12): 1865–1871.

13. COntrolled MyeloFibrosis Study With ORal JAK Inhibitor Treatment: The COMFORT-I Trial, Available online: https://www.clinicaltrials.gov/ct2/show/study/NCT00952289?term=COMFORT+I&rank=1§=Xg0 156 Last Accessed: 16 Sept 2015.

14. Harrison CN et al. Long-Term Efficacy and Safety in COMFORT-II, a Phase 3 Study Comparing Ruxolitinib with Best Available Therapy for the Treatment of Myelofibrosis: 5-Year Final Study Results, poster, presented at ASH Dec 5, 2015, Orlando.