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U.S. Department of Health and Human Services

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Ruxolitinib

On November 16, 2011, the U. S. Food and Drug Administration approved ruxolitinib (Jakafi oral tablets, Incyte Corporation) for the treatment of intermediate and high risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential thrombocythemia myelofibrosis. Results of two randomized controlled trials in patients with intermediate or high risk myelofibrosis comparing ruxolitinib to placebo (Study 1) or to best available therapy (Study 2) were the basis of approval.

Study 1 was a double-blind, randomized, placebo-controlled study allocating 309 patients (1:1) to either ruxolitinib (15-20 mg orally twice daily) or placebo. Fifty percent of patients had primary myelofibrosis, 31% post-polycythemia vera myelofibrosis and 18% post-essential thrombocythemia myelofibrosis. Study 2 was an open-label trial allocating 219 patients (2:1) to either ruxolitinib (15-20 mg orally twice daily) or best available therapy. Fifty-three percent of patients had primary myelofibrosis, 31% post-polycythemia vera myelofibrosis, and 16% post-essential thrombocythemia myelofibrosis. The ruxolitinib starting dose in both trials was based on the entry platelet counts.

Ruxolitinib treatment in both trials continued as long as the patients continued to benefit or until unacceptable toxicity. The primary endpoint was a comparison of the proportion of patients in the two arms who achieved a ≥35% reduction in spleen volume (by CAT scan or MRI) after 24 weeks (Study 1) or after 48 weeks of treatment (Study 2)

Both randomized trials achieved their pre-specified primary endpoints. In Study 1, 42% versus 1% of patients on the ruxolitinib and placebo arms, respectively, experienced a ≥ 35% reduction of spleen volume at 24 weeks (p<0.0001, Chi-square and Fisher’s exact test). In Study 2, 29% versus 0% of patients on the ruxolitinib and best available therapy arms, respectively, experienced a ≥ 35% reduction of spleen volume at 48 weeks (p<0.0001, Cochran-Mantel-Haenszel test).

The key secondary endpoint for Study 1 was to determine the difference between the proportion of patients on ruxolitinib versus placebo who experienced ≥50% reduction of a total symptom score. This symptom score evaluated abdominal discomfort, pain under left ribs, night sweats, itching, bone/muscle pain and early satiety at 24 weeks compared to baseline. The percentage of patients who achieved a ≥50% reduction of the total symptom score at 24 weeks was 46% versus 5% on the ruxolitinib and placebo arms, respectively (p<0.0001, Chi-square test).

The key secondary endpoint on Study 2 was to determine the difference between the two arms in the proportion of patients who achieved a ≥35% reduction in spleen volume (by CAT scan or MRI) at 24 weeks of treatment. A ≥35% reduction in spleen volume occurred in 32% of the patients on the ruxolotinib arm and 0% on the best available therapy arm (p <0.0001, Chochran-Mantel-Haenszel test). At the time of approval, 75% of the patients on Study 1 and 67% on Study 2 who achieved a ≥35% reduction in spleen volume maintained this reduction in spleen volume.

The most common adverse drug reactions observed in ≥1% of the patients treated with ruxolitinib included thrombocytopenia, anemia, bruising, dizziness and headache. Adverse drug reactions (grade 3 or greater) increased on the ruxolitinib arm compared to the placebo arm in Study 1 were thrombocytopenia (13% versus 1%) and anemia (45% versus 19%). Similar results were observed in Study 2.

The recommended starting dose of ruxolitinib is 20 mg orally twice daily for patients with a platelet count >200 X 109/L and 15 mg orally twice daily for patients with a platelet count between 100 and 200 X 109/L.

Full prescribing information, including clinical trial information, safety, dosing, drug-drug interactions and contraindications is available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/202192lbl.pdf

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).