Inrebic (Fedratinib)

What Is Inrebic and What Is It Used For?

Inrebic (fedratinib) is an oral kinase inhibitor used to treat adults with myelofibrosis who have an enlarged spleen (splenomegaly) or disease-related symptoms. It works by blocking the activity of Janus-associated kinase 2 (JAK2), an enzyme that drives the abnormal cell growth and inflammation characteristic of this rare blood cancer.

Myelofibrosis is a serious and rare myeloproliferative neoplasm in which the normal bone marrow is progressively replaced by fibrous scar tissue. This disruption of normal hematopoiesis — the process by which the body produces blood cells — leads to a cascade of clinical consequences. The bone marrow can no longer produce sufficient quantities of normal red blood cells, white blood cells, and platelets, resulting in anemia, increased infection risk, and bleeding problems. As the bone marrow fails, blood cell production shifts to other organs, particularly the spleen, which becomes significantly enlarged.

The enlarged spleen (splenomegaly) is one of the hallmark features of myelofibrosis and can cause significant discomfort, early satiety (feeling full quickly), abdominal pain, and physical limitations. In addition to splenomegaly, patients with myelofibrosis frequently experience debilitating constitutional symptoms including persistent fatigue, night sweats, unexplained fevers, bone pain, pruritus (itching), and unintentional weight loss. These symptoms substantially impair quality of life and can be difficult to manage with conventional supportive care alone.

According to the World Health Organization (WHO) classification of myeloid neoplasms, myelofibrosis can arise as a primary condition (primary myelofibrosis) or evolve from other myeloproliferative neoplasms, specifically polycythemia vera (post-polycythemia vera myelofibrosis) or essential thrombocythemia (post-essential thrombocythemia myelofibrosis). Inrebic is approved for all three subtypes. The estimated incidence of primary myelofibrosis is approximately 0.5 to 1.5 per 100,000 persons per year worldwide, making it a genuinely rare disease that often presents diagnostic and therapeutic challenges.

How Inrebic Works

The mechanism of action of fedratinib centers on the inhibition of Janus-associated kinases (JAKs), a family of intracellular enzymes that play a critical role in transmitting signals from cytokine and growth factor receptors on the cell surface to the cell nucleus. In myelofibrosis, the JAK-STAT (Signal Transducer and Activator of Transcription) signaling pathway is constitutively activated, driving the uncontrolled proliferation of abnormal blood cells and the release of inflammatory cytokines that contribute to fibrosis and systemic symptoms.

Fedratinib is a selective inhibitor of both wild-type and mutationally activated JAK2, with additional activity against FMS-like tyrosine kinase 3 (FLT3). By blocking JAK2-mediated signaling, fedratinib reduces the proliferation of malignant cells and induces apoptosis (programmed cell death) in cells that are dependent on aberrant JAK2 signaling. This therapeutic effect translates clinically into a meaningful reduction in spleen volume and improvement in myelofibrosis-associated symptoms.

The pivotal JAKARTA trial, a phase III randomized controlled study published in The Lancet Haematology, demonstrated that fedratinib achieved a statistically significant reduction in spleen volume in patients with intermediate-2 or high-risk myelofibrosis. At 24 weeks, 37% of patients receiving the 400 mg dose achieved a 35% or greater reduction in spleen volume from baseline, compared to only 1% in the placebo group. Substantial symptom improvement, as measured by the Total Symptom Score (TSS), was also observed. These results formed the basis for regulatory approval by both the European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA).

Importantly, fedratinib has demonstrated efficacy both in patients who are newly treated (JAK inhibitor-naïve) and in those who have previously received ruxolitinib, another JAK inhibitor. The JAKARTA-2 study showed meaningful clinical responses in patients with myelofibrosis who had been previously treated with ruxolitinib, establishing fedratinib as an important second-line option in the treatment algorithm for this disease.

What Should You Know Before Taking Inrebic?

Before starting Inrebic, your doctor will check your thiamine (vitamin B1) levels, blood counts, and liver and pancreatic function. You must not take Inrebic if you are allergic to fedratinib, if you are pregnant, or if you have thiamine deficiency that has not been corrected. Several medical conditions and medications require special consideration.

Inrebic is a potent kinase inhibitor that requires careful patient assessment before initiation and ongoing monitoring throughout treatment. Your hematologist will conduct a thorough evaluation to determine whether this medication is appropriate for your individual clinical situation. Understanding the contraindications, warnings, and precautions is essential for safe and effective use of this therapy.

Contraindications

You must not take Inrebic if:

• You are allergic (hypersensitive) to fedratinib or any of the other ingredients in the capsule formulation
• You are pregnant or think you may be pregnant
• You have uncorrected thiamine (vitamin B1) deficiency — this must be resolved before starting treatment

If you suspect any of these conditions apply to you, inform your doctor before beginning treatment. Thiamine deficiency is an absolute contraindication because of the risk of Wernicke encephalopathy, a potentially fatal brain condition.

Warnings and Precautions

Talk to your doctor or pharmacist before taking Inrebic and during treatment if you have any of the following:

• Fatigue, breathlessness, pale skin, or rapid heartbeat — these may be signs of a low red blood cell count (anemia), which is very common during treatment
• Unusual bleeding or bruising, prolonged bleeding after blood draws, or bleeding gums — these may indicate a low platelet count (thrombocytopenia)
• Frequent or recurrent infections — this may be a sign of a low white blood cell count (neutropenia)
• Nausea, vomiting, or diarrhea — common side effects that your doctor can help manage with supportive medications and dose adjustments
• Kidney problems — current or previous kidney disease may affect how the drug is cleared from your body
• Liver problems — liver disease can alter drug metabolism and increase the risk of toxicity
• Pancreatic problems — elevated amylase and lipase levels have been observed during treatment
• Eye problems, especially uveitis — inflammation of the eye (uveal tract) has been reported and requires ophthalmological evaluation

The following considerations apply to patients treated with JAK inhibitors as a class, based on clinical experience with similar medications:

• Age over 65 years: Older patients may have an increased risk of cardiovascular events, including heart attack, and certain types of cancer
• Heart disease: Current or previous cardiovascular problems should be discussed with your doctor
• History of cancer: Inform your doctor about any prior malignancies
• Smoking history: Current or former smokers may have elevated cardiovascular and cancer risk
• Blood clots: If you have a history of deep vein thrombosis (DVT) or pulmonary embolism (PE), or develop sudden breathlessness, chest pain, leg swelling, or limb discoloration, seek immediate medical attention
• Skin changes: Your doctor may recommend regular skin examinations during treatment, as new skin growths or changes to existing ones have been observed with JAK inhibitors

Blood Tests and Monitoring

Before and during treatment with Inrebic, your doctor will perform regular blood tests to monitor:

• Blood cell counts: Red blood cells, white blood cells, and platelets may decrease during treatment and require dose adjustments or temporary treatment interruptions
• Liver function: Liver enzyme levels (ALT, AST) will be checked to detect any hepatotoxicity
• Pancreatic enzymes: Amylase and lipase levels are monitored to detect pancreatic inflammation
• Thiamine (vitamin B1) levels: Your thiamine level will be checked before starting treatment. Your doctor will prescribe a daily dose of at least 100 mg of thiamine supplement, which you must take throughout the entire duration of your Inrebic treatment. Additional thiamine monitoring may be performed periodically
• Kidney function: Blood creatinine levels may be monitored

Based on these laboratory results, your doctor may need to adjust your dose, temporarily interrupt treatment, or discontinue Inrebic permanently.

Pregnancy and Breastfeeding

If you are pregnant, breastfeeding, think you may be pregnant, or are planning to have a baby, seek medical advice before taking Inrebic.

• Pregnancy: Inrebic must not be taken during pregnancy. Based on its mechanism of action, fedratinib may cause harm to the developing fetus. If you are of childbearing potential, you must use effective contraception during treatment and for at least one month after your last dose. If you become pregnant while taking Inrebic, contact your doctor immediately
• Breastfeeding: Do not breastfeed during treatment with Inrebic and for at least one month after your last dose. It is not known whether fedratinib passes into human breast milk, and a risk to the nursing infant cannot be excluded

Driving and Operating Machinery

Dizziness is a known side effect of Inrebic. If you experience dizziness, you should not drive vehicles or operate machinery until the symptoms have resolved. Discuss any concerns about driving safety with your healthcare provider.

Children and Adolescents

Inrebic is not approved for use in children and adolescents under 18 years of age. The safety and efficacy of fedratinib have not been studied in the pediatric population. Myelofibrosis is exceedingly rare in children, and no clinical data exist to support pediatric use.

How Does Inrebic Interact with Other Drugs?

Inrebic interacts with several commonly used medications. Strong CYP3A4 inhibitors such as ketoconazole and ritonavir can significantly increase fedratinib blood levels and side effect risk. Strong CYP3A4 inducers such as rifampicin and phenytoin can reduce its effectiveness. Inrebic can also affect the metabolism of other drugs including midazolam, omeprazole, metoprolol, and metformin.

Drug interactions are an important consideration with Inrebic because fedratinib is extensively metabolized by liver enzymes, particularly CYP3A4 and CYP2C19, and also acts as an inhibitor of CYP3A4, CYP2C19, and CYP2D6. Additionally, fedratinib inhibits several drug transporters including OCT1, OCT2, MATE1, and MATE2-K. These pharmacokinetic properties create the potential for clinically significant interactions with a range of other medications.

It is essential to inform your doctor about all medications you are currently taking, have recently taken, or plan to take, including prescription drugs, over-the-counter medicines, herbal products, and dietary supplements. Your doctor may need to adjust your Inrebic dose or the doses of your other medications.

Drugs That May Increase Inrebic Side Effects

Drugs That May Reduce Inrebic Effectiveness

Drugs Affected by Inrebic

If you are planning to have surgery or a medical procedure, inform your surgical team that you are taking Inrebic. Fedratinib may interact with certain sedative and anesthetic agents, and its effects on blood counts may be relevant to surgical planning.

What Is the Correct Dosage of Inrebic?

The recommended dose of Inrebic is 400 mg (four 100 mg capsules) taken by mouth once daily. Capsules should be swallowed whole, preferably with a meal to reduce nausea. Your doctor may reduce the dose to 300 mg or 200 mg once daily depending on side effects or drug interactions. Treatment continues for as long as it is clinically beneficial.

Inrebic is an oral medication designed for long-term, continuous use. Unlike some cancer treatments that are given in cycles, fedratinib is taken every day without planned breaks. The goal is to maintain steady drug levels in the body to continuously suppress the JAK2-mediated disease process. Adherence to the prescribed dosing schedule is important for optimal therapeutic benefit.

Adults

Your doctor may reduce your dose in the following situations:

• First dose reduction: 300 mg once daily (three capsules)
• Second dose reduction: 200 mg once daily (two capsules)
• If you cannot tolerate 200 mg daily, your doctor will discontinue Inrebic

Dose reductions may be necessary due to adverse effects such as anemia, thrombocytopenia, neutropenia, gastrointestinal toxicity, hepatotoxicity, or other significant side effects. Your doctor will weigh the benefits of continued treatment against the severity of side effects when making dose adjustment decisions.

How to Take Inrebic

• Swallow the capsules whole with water — do not open, break, or chew the capsules
• Inrebic can be taken with or without food, but taking it with a meal is recommended to reduce the risk of nausea and vomiting
• Take your dose at approximately the same time each day to maintain consistent blood levels
• Continue taking Inrebic for as long as your doctor instructs you to — this is a long-term treatment
• Always take your daily thiamine (vitamin B1) supplement as prescribed by your doctor

Children

Inrebic is not approved for use in children and adolescents under 18 years of age. There is no established pediatric dosing for fedratinib.

Elderly

No specific dose adjustment is required for elderly patients based solely on age. However, since myelofibrosis predominantly affects older adults, many patients receiving Inrebic are over 65. Elderly patients may have more comorbidities and be more susceptible to certain side effects, particularly gastrointestinal symptoms and cytopenias. Your doctor will consider your overall health status when determining the appropriate dose and monitoring schedule.

Missed Dose

Overdose

Stopping Treatment

Do not stop taking Inrebic unless your doctor has told you to do so. Abrupt discontinuation may lead to a return of myelofibrosis symptoms, including rapid spleen re-enlargement. If your doctor decides that treatment should be stopped, this may be done gradually. Always follow your doctor's instructions regarding discontinuation.

What Are the Side Effects of Inrebic?

The most common side effects of Inrebic include anemia, nausea, vomiting, diarrhea, and thrombocytopenia. The most serious risk is encephalopathy, including Wernicke encephalopathy, which can be fatal and requires immediate medical attention. Regular blood monitoring and mandatory thiamine supplementation are essential safety measures throughout treatment.

Like all medicines, Inrebic can cause side effects, although not every patient will experience them. Some side effects are very common and often manageable with supportive care and dose adjustments, while others are rare but serious and require immediate medical attention. Understanding the possible side effects, their frequency, and their warning signs will help you and your healthcare team manage your treatment safely.

Managing Gastrointestinal Side Effects

Nausea, vomiting, and diarrhea are among the most common side effects of Inrebic and typically occur during the first two weeks of treatment. These symptoms often improve over time as your body adjusts to the medication. Your doctor may prescribe anti-nausea medications (antiemetics) and recommend taking Inrebic with a meal. In some cases, temporary dose reduction may be necessary. Maintaining adequate hydration is important if you experience diarrhea or vomiting.

Blood Count Changes

Decreases in red blood cells (anemia), platelets (thrombocytopenia), and white blood cells (neutropenia) are expected effects of Inrebic and reflect its activity on the bone marrow. Your doctor will monitor your blood counts regularly and may adjust your dose, temporarily interrupt treatment, or prescribe supportive therapies such as blood transfusions if needed. It is important to report any symptoms of low blood counts, such as unusual fatigue, bleeding, bruising, or recurrent infections, to your healthcare team promptly.

Reporting Side Effects

It is important to report any suspected side effects to your healthcare team and to your national pharmacovigilance authority. Reporting helps regulatory agencies continuously monitor the benefit-risk balance of medicines. In Europe, adverse drug reactions can be reported through national agencies listed on the EMA website. In the United States, reports can be submitted to the FDA MedWatch program.

How Should You Store Inrebic?

Store Inrebic in the original container with the lid tightly closed to protect from moisture. No special temperature requirements apply. Keep out of the sight and reach of children. Do not use after the expiration date printed on the carton and bottle.

Proper storage of Inrebic helps ensure that the capsules maintain their potency and safety throughout the treatment period. The following storage guidelines should be observed:

• Keep the bottle tightly closed at all times when not removing capsules, as the product is sensitive to moisture
• No special temperature storage conditions are required — store at normal room temperature
• Keep the capsules in the original high-density polyethylene (HDPE) bottle with the child-resistant polypropylene cap
• Do not use Inrebic after the expiration date (EXP) shown on the carton and bottle. The expiration date refers to the last day of the stated month
• Keep this medicine out of the sight and reach of children at all times

Do not dispose of unused or expired medications in household waste or by flushing them down the drain. Ask your pharmacist about proper disposal methods for medications that are no longer needed. These measures help protect the environment.

What Does Inrebic Contain?

Each Inrebic hard capsule contains 100 mg of fedratinib (as fedratinib dihydrochloride monohydrate). The capsules are reddish-brown, imprinted with “FEDR” on the cap and “100 mg” on the body in white ink. They are supplied in bottles of 120 capsules.

Active Ingredient

The active substance is fedratinib. Each hard capsule contains fedratinib dihydrochloride monohydrate, equivalent to 100 mg of fedratinib. Fedratinib is a small-molecule kinase inhibitor with the molecular formula C₂₇H₃₁ClN₆O₃S (free base) and a molecular weight of approximately 524 g/mol for the dihydrochloride monohydrate salt.

Excipients (Inactive Ingredients)

The capsule formulation contains the following inactive ingredients:

• Capsule contents: Silicified microcrystalline cellulose (containing microcrystalline cellulose [E460] and colloidal anhydrous silicon dioxide [E551]), and sodium stearyl fumarate
• Capsule shell: Gelatin (E441), titanium dioxide (E171), and red iron oxide (E172)
• Printing ink (white): Shellac (E904), titanium dioxide (E171), and propylene glycol (E1520)

Appearance and Packaging

Inrebic capsules are hard gelatin capsules measuring 21.4 to 22.0 mm in length. They are reddish-brown in color and imprinted with “FEDR” on the cap and “100 mg” on the body in white ink. The capsules are packaged in a high-density polyethylene (HDPE) bottle with a child-resistant polypropylene cap and heat-sealed closure. Each bottle contains 120 capsules and is packaged in a cardboard carton.

Manufacturer Information

Inrebic is marketed by Bristol-Myers Squibb. The marketing authorization holder in the European Union is Bristol-Myers Squibb Pharma EEIG, Dublin, Ireland. The manufacturing site is Celgene Distribution B.V., Utrecht, Netherlands. Inrebic was first approved by the U.S. FDA in August 2019 and subsequently received EMA approval for the European market.