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The following information helps you to find FDA Alerts and Pharmacist’s Applications to Practice quickly and easily. In cooperation with the Food and Drug Administration (FDA), and as a service to our members, HOPA periodically distributes information about newly approved therapies for cancer patients from FDA’s Office of Oncology Drug Products Director, Dr. Richard Pazdur to inform oncologists and professionals in oncology-related fields in a timely manner. Links to product labels will take you to relevant clinical information on the indication, contraindications, dosing, and safety. In sending this information, HOPA does not endorse any product or therapy and does not take any position on the safety or efficacy of the product or therapy described.

Along with HOPA’s Publications Committee, members also review new drug updates and provide analysis and research on the application of these new drugs or indications. Pharmacist’s Applications to Practice, or PAP, are listed after drugs that include the additional analysis.

You can also find additional information on FDA Alerts and Updates by listening to FDA Drug Safety Podcasts.

August 16, 2019, with PAP

https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212327s000lbl.pdf

On August 16, 2019, the U.S. Food and Drug Administration approved Fedratinib (Inrebic) capsules to treat adult patients with certain types of myelofibrosis.

“Prior to today, there was one FDA-approved drug to treat patients with myelofibrosis, a rare bone marrow disorder. Our approval today provides another option for patients,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “The FDA is committed to encouraging the development of treatments for patients with rare diseases and providing alternative options, as not all patients respond in the same way.”

Myelofibrosis is a chronic disorder where scar tissue forms in the bone marrow and the production of the blood cells moves from the bone marrow to the spleen and liver, causing organ enlargement. It can cause extreme fatigue, shortness of breath, pain below the ribs, fever, night sweats, itching and bone pain. When myelofibrosis occurs on its own, it is called primary myelofibrosis. Secondary myelofibrosis occurs when there is excessive red blood cell production (polycythemia vera) or excessive platelet production (essential thrombocythemia) that evolves into myelofibrosis.

Jakafi (ruxolitinib) was approved by the FDA in 2011. The approval of Inrebic for intermediate-2 or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis was based on the results of a clinical trial where 289 patients with myelofibrosis were randomized to receive two different doses (400 mg or 500 mg daily by mouth) of fedratinib or placebo. The clinical trial showed that 35 of 96 patients treated with the fedratinib 400 mg daily dose (the dose recommended in the approved label) experienced a significant therapeutic effect (measured by greater than or equal to a 35% reduction from baseline in spleen volume at the end of cycle 6 (week 24) as measured by an MRI or CT scan with a follow-up scan four weeks later). As a result of treatment with Inrebic, 36 patients experienced greater than or equal to a 50% reduction in myelofibrosis-related symptoms, such as night sweats, itching, abdominal discomfort, feeling full sooner than normal, pain under ribs on left side, and bone or muscle pain.

The prescribing information for Inrebic includes a Boxed Warning to advise health care professionals and patients about the risk of serious and fatal encephalopathy (brain damage or malfunction), including Wernicke’s, which is a neurologic emergency related to a deficiency in thiamine. Health care professionals are advised to assess thiamine levels in all patients prior to starting Inrebic, during treatment and as clinically indicated. If encephalopathy is suspected, Inrebic should be immediately discontinued.

View full prescribing information for Inrebic.

Common side effects for patients taking Inrebic are diarrhea, nausea, vomiting, fatigue and muscle spasms. Health care professionals are cautioned that patients may experience severe anemia (low iron levels) and thrombocytopenia (low level of platelets in the blood). Patients should be monitored for gastrointestinal toxicity and for hepatic toxicity (liver damage). The dose should be reduced or stopped if a patient develops severe diarrhea, nausea or vomiting. Treatment with anti-diarrhea medications may be recommended. Patients may develop high levels of amylase and lipase in their blood and should be managed by dose reduction or stopping the mediation. Inrebic must be dispensed with a patient Medication Guide that describes important information about the drug’s uses and risks.

The FDA granted this application Priority Review designation. Inrebic also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases. The FDA granted the approval of Inrebic to Impact Biomedicines, Inc., a wholly-owned subsidiary of Celgene Corporation.

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

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).


Pharmacist's Application to Practice

Fedratinib for the Treatment of Intermediate-2 or High-Risk Primary or Secondary (Post-Polycythemia Vera or Post-Essential Thrombocytopenia) Myelofibrosis

Author: Lindsay Orton, PharmD
PGY-1 Pharmacy Resident
Vanderbilt University Medical Center
Nashville, TN

What is the potential role for fedratinib in the treatment of intermediate-2 or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocytopenia) myelofibrosis (MF)?

  • Fedratinib is an oral inhibitor of wild-type and mutationally activated Janus Associated Kinase 2 (JAK2) and FMS-like tyrosine kinase 3 (FLT3), which reduces signal transducer phosphorylation and activation of transcription proteins (STAT3/5), inhibits cell proliferation, and induces apoptotic cell death.1
  • Based on the JAKARTA trial, the U.S. Food and Drug Administration (FDA) approved fedratinib on August 16, 2019, for adults with intermediate-2 or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocytopenia) MF. Risk stratification for primary or secondary MF is based on the International Prognostic Scoring System (IPSS) at diagnosis and the Dynamic International Prognostic Scoring System (DIPSS) or DIPSS-PLUS during treatment. Patients are then stratified into low, intermediate-1, intermediate-2, or high risk based on these scores.1,2
  • JAKARTA was a phase 3 randomized double-blind multicenter trial that compared fedratinib 400 mg (n = 96) versus fedratinib 500 mg (n = 97) versus placebo (n = 96) once daily for the treatment of intermediate-2 or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocytopenia) MF in adults. Inclusion criteria included age 18 or older, platelets >50,000/µl, palpable splenomegaly (5 cm or more below the left costal margin), Eastern Cooperative Oncology Group (ECOG) performance status 0–2, and a diagnosis of high- or intermediate-2 risk primary MF, post-polycythemia vera MF, or post-essential thrombocytopenia MF, according to the IPSS criteria. Assigned trial agents were given once daily for at least six consecutive 28-day cycles until the disease progressed or an unacceptable level of toxicity was reached. The primary endpoint was spleen response (35% or greater reduction in spleen volume by MR or CT at the end of cycle 6). The main secondary endpoint was symptom response rate based on Total Symptom Score (TSS). MF symptoms included in the score were abdominal discomfort, pain under left ribs, early satiety, night sweats, pruritis, and bone or muscle pain. An exploratory endpoint was change in JAK2 V617F allele burden. For the primary endpoint, 35 (36%) of the patients receiving 400 mg fedratinib, 39 (40%) of the patients receiving 500 mg fedratinib, and 1 (1%) of the placebo patients achieved 35% or greater reduction in spleen volume (p < .001). For the secondary endpoint of TSS, 33 (36%) of the 400 mg fedratinib patients, 31 (34%) of the 500 mg fedratinib patients, and 6 (7%) of the placebo patients achieved a 50% or greater reduction in their TSS at the end of cycle 6. No significant changes in JAK2 V617F allele burden were seen among any of the treatment groups. The most common hematologic grade 3 or 4 adverse events were anemia (43% vs. 60% vs. 25% in fedratinib 400 mg vs. fedratinib 500 mg vs. placebo), thrombocytopenia (17% vs. 27% vs. 9%), and lymphopenia (21% vs. 27% vs. 21%). The most common nonhematologic grade 3 or 4 adverse events were an increase in lipase (13% vs. 9% vs. 2%), fatigue (6% vs. 5% vs. 0%), and vomiting (3% vs. 9% vs. 0%). The most common adverse events that led to discontinuation of fedratinib included thrombocytopenia (7 patients), cardiac failure (4 patients), and gastrointestinal intolerance (4 patients).3
  • JAKARTA-2 was a phase 2 nonrandomized single-arm multicenter trial that evaluated fedratinib 400 mg (n = 97) in patients resistant or intolerant to ruxolitinib after at least 14 days of treatment for intermediate-1 or -2 or high-risk primary, post-polycythemia vera, or post-essential thrombocytopenia MF. Inclusion criteria included palpable splenomegaly (5 cm or greater below the left costal margin), platelets 50,000/µl or greater, ECOG performance status 0–2, and life expectancy of 6 months or less. Fedratinib 400 mg was given once daily for six consecutive 28-day cycles. The primary endpoint was spleen response (proportion of patients with a 35% or greater reduction in spleen volume at the end of cycle 6). For the primary endpoint, 46 of 83 assessable patients (55%) achieved a spleen response. The most common grade 3–4 adverse events were anemia (38%) and thrombocytopenia (22%), with 19% discontinuing fedratinib because of adverse events.4
  • Prior to the approval of fedratinib, another JAK inhibitor, ruxolitinib, was approved for the treatment of primary or secondary MF. Approval for ruxolitinib was based on the results of a phase 3 randomized double-blind trial comparing twice daily ruxolitinib (n = 155) to placebo (n = 154) for the treatment of intermediate-2 or high-risk MF. This trial showed similar outcomes to the JAKARTA trial, with 41.9% of ruxolitinib-treated patients achieving a 35% or greater reduction in spleen volume at 24 weeks. Similar to the fedratinib trial, the most common grade 3–4 adverse events seen in this trial were anemia (45.2%) and thrombocytopenia (12.9%).5,6
  • For the treatment of intermediate risk-2 or high-risk MF in patients with platelets 50,000/µl or greater, the National Comprehensive Cancer Network (NCCN) guidelines indicate fedratinib as a category 2B recommendation for initial treatment. In this population, ruxolitinib is indicated as a category 2A recommendation for initial treatment. Fedratinib is indicated as a category 2A recommendation for second-line therapy in patients previously treated with ruxolitinib.2

What role can the pharmacist play in the management of patients on fedratinib?

  • Fedratinib has a black-box warning for serious and fatal encephalopathy, including Wernicke’s encephalopathy. Serious cases were reported in 1.3% (8/608) of patients treated with fedratinib in clinical trials, with 0.16% (1/608) of the cases being fatal.
    • Thiamine levels should be assessed prior to starting fedratinib and periodically during treatment. Fedratinib should not be started in patients with a thiamine deficiency.
    • If encephalopathy is suspected (with signs and symptoms such as altered mental status, seizures, or tremors), immediately discontinue fedratinib and initiate parenteral thiamine.1,3
  • Creatinine, blood urea nitrogen (BUN), hepatic panel, amylase and lipase, and complete blood count with platelets should also be obtained prior to starting treatment with fedratinib and periodically during treatment.1
  • Coadministration of fedratinib with a strong CYP3A4 inhibitor increases fedratinib exposure, which may increase the risk of adverse events. Coadministration of fedratinib with CYP3A4, CYP2C19, or CYP2D6 substrates increases the concentrations of these drugs, which may increase the risk of adverse events of these drugs.1
  • The recommended dose of fedratinib is 400 mg by mouth once daily for patients with a platelet count 50,000/µl or greater. The dose should be reduced to 200 mg by mouth once daily when it is being administered with strong CYP3A4 inhibitors or in patients with severe renal impairment (creatinine clearance 15–29 ml/min).1
  • When transitioning from ruxolitinib to fedratinib, patients should be gradually tapered off ruxolitinib, for example, by 5 mg twice daily each week, prior to initiating fedratinib.1,5
  • Fedratinib pharmacokinetics have not been evaluated in patients with severe hepatic impairment (total bilirubin >3 times the upper limit of normal and any aspartate aminotransferase). Avoid use of fedratinib in patients with severe hepatic impairment.1
  • For grade 3 thrombocytopenia with active bleeding, grade 4 thrombocytopenia, or grade 4 neutropenia, interrupt the dose until the thrombocytopenia has resolved to grade 2 or lower. For nonhematologic grade 3 or 4 adverse events, interrupt the dose until the adverse events have resolved to grade 1 or lower. Restart the dose at 100 mg daily below the last given dose. If patients are unable to tolerate a dose of 200 mg daily, discontinue fedratinib. Dose reductions should also be considered in patients who become transfusion-dependent during treatment with fedratinib.1

Clinical Pearls

  • Fedratinib is supplied in 100-mg capsules.1
  • Fedratinib may be taken with or without food. Administration with a high-fat meal may reduce the incidence of nausea and vomiting. A high-fat, high-calorie meal can increase the bioavailability of fedratinib by up to 24%.1
  • Fedratinib should be stored at room temperature below 86°F (30°C).1
  • Instruct patients that if they miss a dose of fedratinib, they should skip the dose and take it the next day and return to their normal schedule. Warn patients not to take two doses to make up for the missed dose.1
  • The Celgene commercial co-pay program can assist patients with commercial or private insurance that does not cover the full cost of fedratinib. It can help reduce co-pay responsibilities to $25 for fedratinib.7
  • The Celgene patient assistance program can assist with medication costs for patients who are uninsured or underinsured.7
  • The mechanistic difference between fedratinib and ruxolitinib is that fedratinib is a JAK2 selective inhibitor with activity against FLT3, whereas ruxolitinib is a JAK1 and JAK2 selective inhibitor. Because fedratinib also inhibits FLT3, it causes more gastrointestinal toxicities than ruxolitinib.1,5

References

  1. Inrebic (fedratinib) [package insert]. Summit, NJ: Impact Biomedicines, Inc., 2019.
  2. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Myeloproliferative Neoplasms. Version 3.2019. (September 4, 2019). Available at https://www.nccn.org/professionals/physician_gls/pdf/mpn.pdf
  3. Pardanani A, Harrison C, Cortes J, et al. Safety and efficacy of fedratinib in patients with primary or secondary myelofibrosis. JAMA Oncol. 2015;1(5):643-651.
  4. Harrison C, Schaap N, Vannucchi A, et al. Janus kinase-2 inhibitor fedratinib in patients with myelofibrosis previously treated with ruxolitinib (JAKARTA-2): a single-arm, open-label, non-randomised, phase 2, multicenter study. Lancet Haematol. 2017;4(7):PE317-324.
  5. Jakafi (ruxolitinib) [package insert]. Wilmington, DE: Incyte Corp., 2011.
  6. Verstovsek S, Mesa R, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitnib for myelofibrosis. N Engl J Med. 2012;366:799-807.
  7. Inrebric (fedratinib). Celgene Patient Support. 2019. Available at https://www.inrebicpro.com/access-support
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