Fedratinib - Mechanism of Action, Indications, Dosage, and Adverse Drug Reactions

Overview

A JAK2 (Janus kinase 2)-selective kinase inhibitor called Fedratinib has been utilized to treat adult patients with high-risk or intermediate-2 myelofibrosis (MF) (rare blood cancer). It inhibits JAK2, an enzyme essential to developing and synthesizing red blood cells. Clinical trials of Fedratinib revealed positive effects on spleen size and responses to MF symptoms.

It was placed on clinical hold from 2013 to 2017 because of concerns regarding Wernicke encephalopathy (WE) symptoms (a neurological disorder caused by thiamine deficiency, characterized by confusion, difficulty moving, and eye problems).

Fedratinib did not, as it was later discovered, directly induce WE. Fedratinib was approved by the Food and Drug Administration (FDA) on August 16th, 2019 for patients with intermediate-2 or high-risk MF or secondary myelofibrosis, including post-polycythemia vera (a myeloproliferative neoplastic disorder that changes to MF) or post-essential thrombocythemia myelofibrosis (rare hematological malignancy that changes to secondary MF), although a black box warning about the possibility of serious and fatal encephalopathy (brain disorder), including WE, was included.

Drug Group

Adults with myelofibrosis, a bone marrow malignancy in which the formation of healthy blood cells is replaced by scar tissue, are treated with Fedratinib, a kinase inhibitor. It inhibits FMS-like tyrosine kinase 3 (FLT3) and Janus-activated kinase 2 (JAK2), which stops STAT (signal transducer and activator of transcription) 3 and 5 from being phosphorylated, reducing cell division and death. Fedratinib has greater selectivity and activity against a wider range of kinases and kinase mutations than Ruxolitinib.

Indications

A kinase inhibitor called Fedratinib is prescribed for adult patients with intermediate-2 or high-risk primary or secondary myelofibrosis (MF), which includes post-polycythemia vera and post-essential thrombocythemia.

Dosage Forms and Available Strengths

A 100 mg (milligram) dosage of Fedratinib comes in capsule form.

Warnings and Precautions

The associated warnings and precautions are:

• Anemia and Thrombocytopenia: To encounter this issue, reduce the dosage, stop treatment, or get a transfusion to treat anemia (low red blood cell count) and thrombocytopenia (low platelet count).

• Gastrointestinal Toxicity: Treat gastrointestinal toxicity by reducing dosage or stopping treatment if the patient experiences severe nausea, vomiting, or diarrhea. It is advised to treat diarrhea with antidiarrhea drugs and to prevent vomiting with antiemetics.

• Hepatic Toxicity: Reduce or stop the dose to manage hepatic toxicity.

• Amylase and Lipase Elevation: Control this issue with a dose reduction or cessation.

For Patients

What Is Myelofibrosis?

A rare type of bone marrow cancer called myelofibrosis impairs the body's normal ability to produce red blood cells. It is brought on by significant bone marrow scarring that obstructs healthy blood cell formation. The symptoms include anemia-related weakness, exhaustion, or shortness of breath; an enlarged spleen causing pain or fullness below the left ribs; easy bleeding and bruising due to low platelet counts; night sweats; fever; and bone pain. Myelofibrosis is a type of persistent leukemia (cancer that affects the blood and bone marrow) that affects the body-forming tissues. It may arise on its own or from another bone marrow disorder.

How Does Fedratinib Work?

Fedratinib is a targeted inhibitor of the Janus-activated kinase 2 enzyme, which is abnormally activated in myelofibrosis, leading to overproduction of blood cells and spleen enlargement. Fedratinib's main action is to block JAK2, reducing its activity. Its effects include reducing spleen size, which can cause discomfort and complications, and improving symptoms like fatigue and pain, often caused by abnormal blood cell production.

What Are the Benefits of Fedratinib?

Several advantages of Fedratinib for the treatment of myelofibrosis (MF) include:

• Targeted Inhibition: Fedratinib inhibits the kinase JAK2 selectively. It primarily targets the enzyme JAK2, which is essential for the aberrant synthesis of blood cells in myelofibrosis.

• Reduction in Spleen Size: Fedratinib assists in shrinking the enlarged spleen that myelofibrosis patients frequently experience. This reduction in spleen size reduction can reduce pain and enhance general health.

• Symptom Relief: Fedratinib works to relieve symptoms related to myelofibrosis by blocking JAK2. Fatigue, discomfort, and other issues brought on by aberrant blood cell formation are possible symptoms.

• Clinical Evidence: Clinical trials have shown that Fedratinib suppresses cell growth, promotes apoptosis in mutant JAK2 and FLT3 cell lines, and reduces phosphorylation of signal transducer and activator of transcription (STAT3 or 5) proteins. WBC (white blood cell) counts, hematocrit (a blood test to measure the percentage of red blood cells), splenomegaly (spleen enlargement), and fibrosis (tissue thickening) are all improved by it.

How Is Fedratinib Administered?

The recommended dosage for individuals with a baseline platelet count greater than or equal to 50 x 109/L (liter) is 400 mg (milligrams) taken once daily, with or without food.

Patients with significant renal impairment or those on powerful CYP3A inhibitors ought to reduce the dosage.

What Are the Side Effects of Fedratinib?

There may be side effects from Fedratinib. If any of these symptoms of Fedratinib are severe or persistent, let the doctor know:

• Nausea.

• Vomiting.

• Having diarrhea or constipation.

• Fatigue.

• Tensed muscles.

• Bone, leg, or arm pain

• Headache.

• Gaining weight.

• Lightheadedness.

Certain adverse effects of Fedratinib may be dangerous. Call the doctor right away or seek emergency medical attention if one encounters any of the following symptoms:

• Unexpected bruising or bleeding.

• Chills, fever, coughing, painful or frequent urination, or other infection-related symptoms.

• Nausea, excessive exhaustion, unusual bleeding or bruises, lack of appetite, energy loss, upper right stomach pain, yellowing of the skin or eyes, or flu-like symptoms, such as headaches, dizziness, pale complexion, exhaustion, or confusion.

• Pain in the neck, jaw, legs, back, chest, or stomach; breaking out in cold sweat; dizziness.

• Slurred or difficult speech; abrupt facial, arm, or leg weakness or numbness; abrupt headache; abrupt visual issues; abrupt difficulty walking.

• Pain, swelling, soreness, warmth, or redness in one or both legs.

• Breathing difficulties, blood in the cough, a rapid heartbeat, rapid breathing, and difficulty inhaling deeply.

• Fedratinib may make patients more susceptible to other cancers, like lymphoma (lymphatic cancer), which starts in the immune system's cells. Discuss the possible side effects of taking Fedratinib with the doctor.

• There can be other side effects from Fedratinib. Contact the doctor if patients have any odd side effects while taking Fedratinib.

What Are the Things to Inform the Doctor Before Taking Fedratinib?

Before taking Fedratinib,

• If patients are allergic to Fedratinib, any other drug, or any ingredients in Fedratinib capsules, let the pharmacist and physician know.

• Inform the doctor and pharmacist about any additional prescription and over-the-counter drugs, vitamins, dietary supplements, and herbal remedies patients now take or intend to use. Do not forget to bring up any of the following: Metoprolol, Midazolam, Nefazodone, Nelfinavir, Omeprazole, Pantoprazole, Ribociclib, Ritonavir, Ruxolitinib, Saquinavir, Diltiazem, Erythromycin, Idelalisib, Indinavir, Itraconazole, Ketoconazole, Omeprazole, Pantoprazole, Ribociclib, Ritonavir, Ruxolitinib, and Saquinavir. The doctor may need to carefully monitor for any negative effects of Fedratinib or adjust the dosages of the medications. Fedratinib may interact with a wide range of other drugs, so inform the doctor about all the medications patients take, including those not on this list.

• Inform the doctor whether patients currently smoke or have ever smoked. Additionally, let the doctor know if patients now have or have ever had liver or kidney disease, cancer, a stroke, blood clots, heart attack, or other heart problems; pancreatitis (pancreatic swelling).

• Inform the doctor if patients intend to get pregnant or are already pregnant. Contact the doctor if patients become pregnant while taking Fedratinib.

• Do not breastfeed while using Fedratinib or for at least a month following the last dosage.

• Inform the physician or dentist that patients are taking Fedratinib if undergoing dental surgery.

Dietary Considerations

Consult the doctor about consuming grapefruit and drinking grapefruit juice while taking Fedratinib.

Missed Dose

Avoid taking a double dose of Fedratinib to compensate for a missed dose, and continue the regular Fedratinib dosing schedule.

Overdose

In the event of a Fedratinib overdose, call the poison control helpline. Make quick contact with emergency personnel if the victim passes out, experiences a seizure (an abrupt, uncontrollable spike in brain activity), has difficulty breathing, or cannot be roused.

Storage and Handling

Fedratinib should be kept at room temperature, securely closed, and out of children's reach. Use specific methods to eliminate unnecessary Fedratinib, like a medicine take-back program. For information on such programs, speak with the local recycling and waste management department or the pharmacist.

For Doctors

What Are the Pharmacological Aspects of Fedratinib?

Pharmacodynamics

Fedratinib prevents cell proliferation and triggers apoptosis (programmed cell death). Anemia, thrombocytopenia, gastrointestinal toxicity, liver toxicity, and increased lipase and amylase are possible side effects for Fedratinib patients. Reducing the dosage, halting the drug temporarily, or giving transfusions when needed are the best ways to handle these Fidratinib side effects.

Mechanism of Action

Fedratinib is an inhibitor of FMS-like tyrosine kinase 3 and Janus-activated kinase 2. Myeloproliferative neoplasms, such as myelofibrosis, are associated with high levels of JAK2 activity. The inhibition of JAK2 by Fedratinib results in STAT 3 and 5 phosphorylation, which stops cell proliferation and triggers apoptosis.

Pharmacokinetics

• Absorption: An oral dosage of 400 mg yields an area under the curve (AUC) of 26,870 ng×hr/mL (nanograms × hour per milliliter) and a maximum concentration (Cmax) of 1804 ng/mL (nanograms per milliliter). The maximum tolerated duration (Tmax) for Fedratinib is 1.75 to 3 hours. A high-fat breakfast does not considerably impact Fedratinib absorption.

• Distribution: Fedratinib has an apparent volume of distribution of 1770 L (liters) and is greater than or equal to 92 percent protein bound in plasma.

• Metabolism: Although not much information is readily accessible, CYP3A4, CYP2C19, and flavin-containing monooxygenase are involved in the metabolism of Fedratinib.

• Excretion: Fedratinib is an oral drug having a half-life of 41 hours, a terminal half-life of 114 hours, a clearance rate of 13L/h (liters per hour), and a 77 percent elimination rate in feces, 23 percent as an unaltered drug, and five percent in urine.

Toxicity

Information on the Fedratinib overdose is not readily available. Patients who received 680 mg/day (milligrams per day) had higher rates and more severe side effects, such as increased lipase and amylase, hepatic and gastrointestinal toxicity, anemia, and thrombocytopenia. In addition to symptomatic treatment, Fedratinib dosage reductions or temporary cessation were used to address these side effects.

Drug Interactions

• Strong CYP3A4 Inhibitors: Exposure to Fedratinib is increased when Fedratinib and a potent CYP3A4 inhibitor are coadministered. The likelihood of negative reactions may rise with further exposure. Take into account alternative treatments that do not significantly impede CYP3A4 function. As an alternative, while using a potent CYP3A4 inhibitor, lower the dose of Fedratinib.

• Strong and Moderate CYP3A4 Inducers: Avoid Fedratinib when using mild and moderate CYP3A4 inducers. What happens if a strong or moderate CYP3A4 inducer and Fedratinib are administered simultaneously has not been investigated.

• Dual CYP3A4 and CYP2C19 Inhibitors: When using a combined CYP3A4 and CYP2C19 inhibitor, avoid Fedratinib. No research has been done on the impact of using Fedratinib with a dual CYP3A4 and CYP2C19 inhibitor simultaneously.

Clinical Studies

289 patients with intermediate-2 or high-risk myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocythemia myelofibrosis with splenomegaly participated in the double-blind, randomized, placebo-controlled JAKARTA trial. The patients' median age was 65, with 59 percent of participants being men and 47 percent older than 65. Primary myelofibrosis accounted for the majority of patients, with intermediate-2 risk accounting for 52 percent and high-risk disease accounting for 48 percent.

At baseline, the median platelet count was 214 x 109/L, and the median hemoglobin level was 10.2 g/dL (grams per deciliter). The patient’s baseline median spleen length, as determined by palpation, was 5.9 inches, and the baseline median spleen volume, as determined by computed tomography (CT) or magnetic resonance imaging (MRI).

The fraction of patients who achieved a spleen volume decrease of at least 35 percent from baseline at the end of cycle 6 was used to determine the effectiveness of Fedratinib in treating primary or secondary myelofibrosis.

According to Kaplan-Meier estimations, the Fedratinib 400 mg group's median spleen response length was 18.2 months. Furthermore, from baseline to the end of Cycle 6, 40 percent of patients in the Fedratinib 400 mg group and 9 percent in the placebo group had a 50 percent or greater reduction in the total symptom score. Twenty-two patients had their results eliminated, including those with a missing baseline and a baseline total symptom score of zero.

Use in Specific Populations

• Pregnancy: Fedratinib used during pregnancy has been linked to embryotoxicity in animal studies. However, there is no controlled data available on its use in humans. The US FDA has not assigned a specific pregnancy category to Fedratinib. Fedratinib should be used only if the benefit outweighs the risk. Contraception is encouraged while taking Fedratinib, and patients should be informed of potential harm to the fetus if they become pregnant while on Fedratinib.

• Breastfeeding: The study lacks data on Fedratinib's presence in human milk, its effects on breastfed children, or milk production. Due to potential adverse reactions, patients are advised not to breastfeed during Fedratinib treatment and for at least one month after the last Fedratinib dose.

• Pediatric Use: The safety and effectiveness of Fedratinib in pediatric patients have not been confirmed.

• Geriatric Use: In clinical trials, Fedratinib 400 mg was administered to 47.3 percent of myelofibrosis patients aged 65 and above and 12.3 percent of patients aged 75 and above. No discernible variations in safety or efficacy were observed between elderly patients and younger ones.

• Renal Impairment: For individuals with severe renal impairment, the dosage of Fedratinib should be lowered; however, for mild to moderate renal impairment, there should be no adjustment. Due to possible exposure increases, patients with pre-existing mild renal impairment need closer safety monitoring and dose changes based on adverse events.

• Hepatic Impairment: It is recommended to refrain from using Fedratinib as its pharmacokinetics in patients with severe hepatic impairment have not been evaluated.