Fedratinib – Uses, Dosage, Side Effects, Interaction

Mechanism of Action

Fedratinib is an inhibitor of Janus Activated Kinase 2 (JAK2) and FMS-like tyrosine kinase 3. JAK2 is highly active in myeloproliferative neoplasms like myelofibrosis. Fedratinib’s inhibition of JAK2 inhibits phosphorylation of signal transducer and activator of transcription (STAT) 3 and 5, which prevents cell division and induces apoptosis.

Fedratinib is a kinase inhibitor that inhibits cell division and induces apoptosis. Patients taking fedratinib may experience anemia, thrombocytopenia, gastrointestinal toxicity, hepatic toxicity, or elevated amylase and lipase. These effects should be managed by reducing the dose, temporarily stopping the medication, or providing transfusions on a case-by-case basis.

Fedratinib acts as a competitive inhibitor of protein kinase JAK-2 with IC50=6 nM; related kinases FLT3 and RET are also sensitive, with IC50=25 nM and IC50=17 nM, respectively. Significantly less activity was observed against other tyrosine kinases including JAK3 (IC50=169 nM). In treated cells, the inhibitor blocks downstream cellular signaling (JAK-STAT) leading to the suppression of proliferation and induction of apoptosis.

Indications

  • Fedratinib is indicated to treat adults with primary or secondary myelofibrosis that is either intermediate-2 or high-risk.
  • Arabic is indicated for the treatment of disease-related splenomegaly or symptoms in adult patients with primary myelofibrosis, post polycythemia vera myelofibrosis, or post essential thrombocythaemia myelofibrosis who are Janus Associated Kinase (JAK) inhibitor naïve or have been treated with ruxolitinib.
  • Fedratinib is an oral selective inhibitor of Janus-associated kinase 2 (JAK-2) and FMS-like tyrosine kinase 3 (FLT3) that is used in the therapy of intermediate or high-risk, primary or secondary myelofibrosis
  • Fedratinib hydrochloride is approved for use in adults to treat: Myelofibrosis (a bone marrow disease) that is an intermediate-2 risk or high risk, including the following types: Primary myelofibrosis. Post-polycythemia vera myelofibrosis. Post-essential thrombocythemia myelofibrosis.
  • Fedratinib hydrochloride is also being studied in the treatment of other conditions.
  • For the treatment of intermediate-2 or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis (MF)
  • In the United States, fedratinib is indicated for the treatment of adults with intermediate-2 or high-risk primary or secondary (following polycythemia vera or essential thrombocythemia) myelofibrosis.
  • Primary Myelofibrosis (PMF)
  • Secondary Myelofibrosis

Use in Cancer

Toremifene is approved to treat:

Contraindications

  • A High Alanine Transaminase Level
  • A High Aspartate Transaminase Level
  • Low Amount Of Sodium In The Blood
  • Decreased Blood Platelets
  • A Type Of Brain Function Problem Called Encephalopathy
  • High Blood Pressure
  • A Low Supply Of Oxygen Rich Blood To The Heart
  • Heart Failure
  • High Blood Levels Of The Lipase Enzyme
  • High Blood Levels Of The Amylase Enzyme
  • Difficult Or Painful Urination
  • Wernicke’s Encephalopathy

Dosage

Strengths: 100 mg

Myelofibrosis

For patients with a baseline platelet count of 50 x 109/L or greater:

  • 400 mg orally once a day

Management of thiamine levels and Wernicke’s encephalopathy (WE):

  • Assess thiamine levels and nutritional status prior to starting therapy, periodically during therapy, and as indicated.
  • Do not initiate this drug in patients with thiamine deficiency; replete thiamine prior to therapy initiation and during therapy if thiamine levels are low.
  • If Wernicke’s encephalopathy is suspected, immediately discontinue therapy and initiate parenteral thiamine treatment.
  • Monitor until symptoms resolve or improve and thiamine levels normalize.

Dose Adjustments

  • Discontinue therapy in patients unable to tolerate 200 mg daily. Consider dose reductions in patients who become transfusion-dependent during therapy with this drug.

DOSE MODIFICATIONS WITH CONCOMITANT USE OF STRONG CYP450 3A4 INHIBITORS:

  • Reduce the dose of this drug when administering with strong CYP450 3A4 inhibitors to 200 mg orally once a day.
  • If the strong CYP450 3A4 inhibitor is discontinued, increase the dose of this drug to 300 mg orally once d day during the first 2 weeks after discontinuation of the CYP450 3A4 inhibitor, and then to 400 mg orally once a day thereafter as tolerated.

DOSE MODIFICATIONS FOR HEMATOLOGIC ADVERSE REACTIONS:

  • Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with active bleeding: Withhold therapy until resolved to Grade 2 or less or baseline; restart at 100 mg daily below the last given dose.
  • Grade 4 Neutropenia: Withhold therapy until resolved to Grade 2 or less or baseline, restart dose at 100 mg daily below the last given dose.

`DOSE MODIFICATIONS FOR NONHEMATOLOGIC ADVERSE REACTIONS:

  • Grade 3 or higher nausea, vomiting, or diarrhea not responding to supportive measures within 48 hours: Withhold therapy until resolved to Grade 1 or less or baseline; restart dose at 100 mg daily below the last given dose.
  • Grade 3 or higher ALT, AST, or bilirubin: Withhold therapy until resolved to Grade 1 or less or baseline; restart dose at 100 mg daily below the last given dose; monitor ALT, AST, and bilirubin (total and direct) more frequently following the dose reduction; if reoccurrence of Grade 3 or higher elevation, discontinue therapy.
  • Grade 3 or higher other nonhematologic toxicities: Withhold therapy until resolved to Grade 1 or less or baseline; restart dose at 100 mg daily below the last given dose.

Administration advice:

  • This drug may be taken with or without food.
  • Administration of a high-fat meal may reduce the incidence of nausea and vomiting.
  • If a dose is missed, the next scheduled dose should be taken the following day.
  • Patients taking ruxolitinib before initiation of this drug should taper and discontinue according to the ruxolitinib prescribing information.

Side Effects

The Most Common

  • nausea
  • vomiting
  • diarrhea
  • constipation
  • tiredness
  • muscle spasms
  • arm, leg, or bone pain
  • headache
  • weight gain
  • dizziness
  • unusual bleeding or bruising
  • fever, chills, cough, painful or frequent urination, or other signs of infection
  • nausea, extreme tiredness, unusual bruising or bleeding, lack of energy, loss of appetite, pain in the upper right part of the stomach, yellowing of the skin or eyes, or flu-like symptoms
  • shortness of breath, fast heartbeat, headache, dizziness, pale skin, confusion, or tiredness
  • pain in the chest, arms, back, neck, jaw, or stomach; breaking out in cold sweat; lightheadedness
  • slow or difficult speech; sudden weakness or numbness of the face, arm or leg; sudden headache; sudden vision problems; sudden difficulty walking
  • swelling, pain, tenderness, warmth or redness in one or both legs
  • shortness of breath, coughing up blood, fast heartbeat, fast breathing, pain when breathing deeply

More common

  • Black, tarry stools
  • bleeding gums
  • blood in the urine or stools
  • chills
  • cough
  • fever
  • lower back or side pain
  • painful or difficult urination
  • pale skin
  • pinpoint red spots on the skin
  • sore throat
  • troubled breathing with exertion
  • ulcers, sores, or white spots in the mouth
  • unusual bleeding or bruising
  • unusual tiredness or weakness
  • Bone pain
  • diarrhea
  • dizziness
  • headache
  • lack or loss of strength
  • muscle spasms
  • nausea
  • pain in the arms or legs
  • vomiting
  • weight gain

Rare

  • Bladder pain
  • cloudy urine
  • confusion
  • difficult, burning, or painful urination
  • drowsiness
  • frequent urge to urinate
  • lower back or side pain
  • shakiness and unsteady walk
  • trouble remembering
  • uncontrolled eye movements
  • unsteadiness, trembling, or other problems with muscle control or coordination

Drug Interactions

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Pregnancy and Lactation

US FDA pregnancy category: Not assigned.

Pregnancy

This drug should be used during pregnancy only if the benefit outweighs the risk. Adequate methods of contraception should be encouraged. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential harm to the fetus.

Lactation

  • A decision should be made to discontinue breastfeeding or discontinue the drug, taking into account the importance of the drug to the mother.
  • Excreted into human milk: Unknown
  • Excreted into animal milk: Data not available
  • Because of the potential for serious adverse reactions in a breastfed child, advise patients not to breastfeed during therapy and for at least 1 month after.

How should this medicine be used?

Fedratinib comes as a capsule to take by mouth. It is usually taken once a day, with or without food. Taking fedratinib with a high fat meal may help to reduce nausea and vomiting. Take fedratinib at around the same time every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take fedratinib exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Your doctor will order blood tests before and during your treatment to see how you are affected by this medication. Your doctor may increase or decrease your dose of fedratinib during your treatment, or may tell you to stop taking fedratinib temporarily or permanently. This depends on how well the medication works for you, your lab test results, and if you experience side effects. Talk to your doctor about how you are feeling during your treatment.

Other uses for this medicine

This medication may be prescribed for other uses; ask your doctor or pharmacist for more information.

What special precautions should I follow?

Before taking fedratinib,

  • tell your doctor and pharmacist if you are allergic to fedratinib, any other medications, or any of the ingredients in fedratinib capsules. Ask your pharmacist or check the Medication Guide for a list of the ingredients.
  • tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention any of the following: clarithromycin (Biaxin, in PrevPac), diltiazem (Cardizem, Dilacor, Tiazac, others), erythromycin (E.E.S., E-mycin, Erythrocin), idelalisib (Zydelig), indinavir (Crixivan), itraconazole (Sporanox), ketoconazole (Nizoral), metoprolol (Lopressor, Toprol XL, in Dutoprol, others), midazolam (Versed), nefazodone, nelfinavir (Viracept), omeprazole (Prilosec, in Zegerid), pantoprazole (Protonix), ribociclib (Kisqali, Kisqali, in Femera), ritonavir (Norvir), ruxolitinib (Jakafi), and saquinavir (Invirase). Your doctor may need to change the doses of your medications or monitor you carefully for side effects. Many other medications may also interact with fedratinib, so be sure to tell your doctor about all the medications you are taking, even those that do not appear on this list.
  • tell your doctor if you if you smoke or if you have ever smoked. Also tell your doctor if you have or have ever had cancer, pancreatitis (swelling of the pancreas), blood clots, a stroke, a heart attack or other heart problems, liver or kidney disease.
  • tell your doctor if you are pregnant or plan to become pregnant. If you become pregnant while taking fedratinib, call your doctor.
  • do not breastfeed during your treatment with fedratinib and for at least 1 month after your final dose.
  • if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking fedratinib.

References

  1. https://www.cancer.gov/about-cancer/treatment/drugs/fedratinibhydrochloride
  2. https://www.drugs.com/mtm/fedratinib.html
  3. https://medlineplus.gov/druginfo/meds/a619058.html
  4. https://go.drugbank.com/drugs/DB12500
  5. https://en.wikipedia.org/wiki/Fedratinib
  6. https://www.mayoclinic.org/drugs-supplements/fedratinib-oral-route/side-effects/drg-20469997https://www.mayoclinic.org/drugs-supplements/fedratinib-oral-route/side-effects/drg-20469997
  7. https://pubchem.ncbi.nlm.nih.gov/compound/Fedratinib
  8. https://pubchem.ncbi.nlm.nih.gov/compound/Fedratinib-dihydrochloride-monohydrate
  9. https://www.webmd.com/drugs/2/drug-177751/fedratinib-oral/details/list-sideeffects
  10. ChemIDplus Chemical Information Classification
  11. CompTox Chemicals Dashboard Chemical Lists
  12. NCI Thesaurus Tree
  13. Guide to Pharmacology Target Classification
  14. PubChem
  15. Anatomical Therapeutic Chemical (ATC) classification
    Target-based classification of drugs
  16. NORMAN Suspect List Exchange Classification