Jakafi by Incyte Corporation

Jakafi (ruxolitinib) is the first drug approved by the FDA for the treatment of the chronic bone marrow disease polycythemia vera.

Jakafi (ruxolitinib) tablets were originally approved in 2011 for treatment of myelofibrosis including intermediate- or high-risk myelofibrosis, primary myelofibrosis, and post-essential thrombocythemia myelofibrosis. The most recent indication for Jakafi was approved by the FDA on December 4, 2014, for treatment of the chronic bone marrow disease polycythemia vera in patients who are intolerant to treatment with oral hydroxyurea. Jakafi is the first drug approved by the FDA for treatment of polycythemia vera.¹

Mechanism of Action

Mechanistically, Jakafi is a kinase inhibitor—specifically, of the Janus-associated kinase (JAK) family, which includes JAK1 and JAK2. These kinases are mediators of cytokine and growth-factor signaling for the growth, development, and division of cytokines associated with hematopoiesis and immune function. By interrupting this signaling pathway, Jakafi may interrupt the growth of several types of myeloproliferative neoplasms, including myelofibrosis and polycythemia vera.^1,2

The active ingredient in Jakafi is metabolized primarily by CYP3A4 and to a smaller degree by CYP2C9. These metabolic processes form several metabolites that extend the 3-hour elimination half-life of the parent drug to approximately 5.8 hours if both the parent drug and metabolites are considered in pharmacokinetic calculations. Elimination is primarily renal (74%), with most of the remaining portion eliminated through the feces. Gender, age, and race did not affect pharmacokinetic parameters in healthy subjects receiving Jakafi.²

Dosage and Administration

Jakafi is available in tablets of 5, 10, 15, 20, and 25 mg. Tablets should be stored at room temperature (68°F to 77°F), with excursions to temperature as low as 59°F and as high as 86°F. Jakafi may be administered with or without food, and may be dissolved in water for nasogastric administration. If a dose is missed, patients should not take a double dose to compensate for the missed dose.²

In patients receiving Jakafi for polycythemia vera, the usual starting dose is 10 mg orally twice daily. Patients should receive a complete blood count before initiation of therapy and every 2 to 4 weeks until the patient reaches a clinically stable dose. Starting dose reductions are recommended in patients with hepatic and renal impairment, and continued dosage adjustments are required based on increases or decreases in hemoglobin and platelet levels. Specific dosage adjustment guidance is detailed in the package insert.²

Clinical Studies

Jakafi was approved for use in polycythemia vera based on a 222-patient open-label phase 3 study with an active treatment comparator. Investigators limited the study to (1) patients who had been diagnosed with polycythemia vera at least 24 weeks prior to study randomization, (2) patients who had an inadequate response to or could not tolerate hydroxyurea therapy, and (3) patients who required additional treatment with phlebotomy and had signs of splenomegaly. In addition, patients with hematocrit levels outside the 40%-to-45% range prior to randomization were excluded.²

Therapies used in the active comparator arm included hydroxyurea, interferon/pegylated interferon, anagrelide, pipobroman, lenalidomide/thalidomide, and observation. Investigators evaluated the efficacy of treatment based on the percentage of patients achieving a treatment response by week 32 of the trial, with response constituting adequate control of hematocrit levels as evidenced by no additional therapy with phlebotomy and reduced spleen volume.²

Of the 110 patients receiving Jakafi, 21% achieved therapeutic response on the primary end point by week 32 versus fewer than 1% of the 112 patients receiving an active comparator drug (P <.0001). This response was durable up to week 48 in 19% of patients receiving Jakafi.²

Warnings and Precautions

Patients receiving treatment with Jakafi should be assessed regularly for blood dyscrasias such as thrombocytopenia, anemia, and neutropenia. Adverse events (AEs) related to changes in hematologic parameters may be managed by dose adjustments contingent on clinical and laboratory parameters. Other important potential hazards of therapy may include serious infections, worsening symptoms of myelofibrosis or polycythemia vera, or an increased risk of nonmelanoma skin cancers.²

Jakafi should be avoided in patients receiving fluconazole at daily doses exceeding 200 mg, or with other strong CYP3A4 inhibitors.² Common AEs include thrombocytopenia and anemia, which occur in more than 20% of patients receiving therapy. Bruising, dizziness, and headache are the most common adverse reactions of nonhematologic origin, each of which occurred in at least 10% of patients receiving therapy.²

Although there is no evidence of teratogenicity in animal studies conducted in rats and rabbits, modest reductions in fetal weight were observed at the highest administered dose (60 mg/kg/day). Jakafi is a Pregnancy Category C drug. Use of Jakafi is not recommended in nursing mothers. For a complete discussion of potential AEs and drug interactions, please consult the product package insert.² SPT

References

• FDA approves Jakafi to treat patients with a chronic type of bone marrow disease [news release]. Silver Spring, MD: US Food and Drug Administration; December 4, 2014. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm425677.htm. Accessed July 2015.
• JAKAFI (ruxolitinib) tablets [package insert]. Wilmington, DE: Incyte Corporation; 2014.

About the Author

Michael R. Page, PharmD, RPh, earned his PharmD from the Ernest Mario School of Pharmacy at Rutgers University. He has worked as a community pharmacist at CVS Pharmacy and is currently clinical editor in clinical and scientific affairs at Pharmacy Times.