What Is Belzutifan (Welireg)? FDA Approval, Authorization and Reimbursement Status in Turkey

• FDA Approval: Yes, Initial Approval Date: August 13, 2021
• Brand Name: Welireg
• Active Ingredient: Belzutifan
• Route of Administration: Oral (by mouth, tablet)
• Class: HIF-2α (hypoxia-inducible factor-2 alpha) inhibitor
• Category: Targeted therapy / Antineoplastic agent
• Manufacturer: Merck & Co., Inc. (MSD)
• Distribution in Turkey: Not currently authorized in Turkey.
• Cancers for Which It Is Approved: Von Hippel-Lindau (VHL) disease-associated tumors (nonmetastatic VHL-related tumors requiring surgery: renal cell carcinoma [RCC], cerebellar hemangioblastoma and pancreatic neuroendocrine tumors); advanced renal cell carcinoma (RCC); locally advanced, unresectable or metastatic pheochromocytoma or paraganglioma (PPGL) in adults and pediatric patients aged 12 and older

What Is Belzutifan (Welireg)? How Does It Work?

Belzutifan (Welireg) is an oral small-molecule HIF-2α (hypoxia-inducible factor-2 alpha) inhibitor targeting hypoxia-related tumor development. As a molecularly targeted agent, it is used particularly in malignancies associated with Von Hippel–Lindau (VHL) gene mutations. Approved by the US Food and Drug Administration (FDA) in 2021, belzutifan was the first approved HIF-2α inhibitor.

How Does It Work?

When oxygen levels fall in body tissues, cells activate proteins called HIFs (Hypoxia-Inducible Factors) to adapt. These proteins promote cell growth, new blood vessel formation (angiogenesis) and survival, particularly in the tumor environment.

This system is balanced in normal cells. In some cancers, however, particularly genetic disorders such as Von Hippel-Lindau (VHL) disease, HIF-2α becomes uncontrollably active. This creates an abnormal environment supporting tumor growth.

Belzutifan specifically targets and blocks this overactive HIF-2α protein. As a result:

• Cancer cell growth slows
• New blood vessel formation is inhibited (the tumor cannot obtain nourishment)
• Tumor survival mechanisms are suppressed
• This mechanism offers a marked treatment advantage, particularly in tumors carrying VHL mutations.

FDA (US Food and Drug Administration) Approval History

• May 14, 2025: The FDA approved Merck's Welireg (belzutifan) for adults and pediatric patients aged 12 and older with locally advanced, unresectable or metastatic pheochromocytoma or paraganglioma (PPGL).
• December 14, 2023: The FDA approved Merck's Welireg (belzutifan) for advanced renal cell carcinoma (RCC) progressing after a PD-1 or PD-L1 inhibitor and a VEGF-TKI.
• August 13, 2021: The FDA approved Welireg (belzutifan) for certain Von Hippel-Lindau (VHL) disease-associated tumors.
• March 16, 2021: Merck received FDA Priority Review for the New Drug Application for its HIF-2α inhibitor belzutifan (MK-6482).

Authorization in Turkey

Not yet officially authorized in Turkey. It may be obtained from abroad through special Ministry of Health authorization procedures. It is not on the TİCK overseas medicine list.

Resistance Mechanisms

• Mutations in the HIF-2α Gene or Protein Structure: Belzutifan binds to a specific region of HIF-2α and inactivates it. Over time, new HIF-2α gene mutations may alter the drug-binding site and reduce or completely eliminate its effect. These structural changes, known as binding-site mutations, are among the most common causes of resistance to targeted treatments.
• Activation of HIF-1α and Other Alternative Pathways: After HIF-2α inhibition, tumor cells may activate alternative pathways with similar functions, such as HIF-1α. The tumor can therefore continue growth and angiogenesis through other proteins despite HIF-2α suppression, bypassing the drug and escaping treatment.
• Further Impairment of VHL Protein Function: In patients with VHL disease or mutations, the tumor-suppressor VHL protein is already nonfunctional. However, further VHL mutations or epigenetic changes in progressing tumors may make the targeted pathways more aggressive.
• Increased Drug Metabolism or Reduced Drug Access: Some tumor cells may increase enzymes that metabolize belzutifan or expel it from the cell over time. This may prevent adequate drug concentrations within tumor cells and reduce effectiveness. Increased CYP2C19 activity, for example, may accelerate drug breakdown.
• Changes in the Tumor Microenvironment: Cells adapted to hypoxia may become more resistant through immune suppression or increased stromal support cells, creating environmental resistance to targeted therapy.

Absorption

• Belzutifan is well absorbed when taken orally.
• Bioavailability is considered high.
• Maximum plasma concentration (Cmax) is generally reached within 3–4 hours.
• Food has not been shown to significantly alter absorption, so it may be taken with or without food.

Distribution

• Plasma protein binding of belzutifan is approximately 45–60%.
• Volume of distribution is approximately 81 L, indicating moderate tissue distribution.

Metabolism

• Belzutifan is metabolized in the liver mainly through CYP2C19 and, to a lesser extent, CYP3A4.
• It may therefore interact with concomitant drugs affecting CYP2C19 and CYP3A4.
• No active metabolites have been identified; the drug is eliminated mainly unchanged or as inactive metabolites.

Elimination

• The elimination half-life (t½) is approximately 13 hours.
• Belzutifan is metabolized mainly in the liver, so major dose adjustment is not required in renal impairment.
• Elimination occurs largely through bile and feces, rather than urine.

Dose Range

• Adults and pediatric patients aged 12 and older weighing ≥ 40 kg: 120 mg orally once daily.
• Pediatric patients aged 12 and older weighing < 40 kg: 80 mg orally once daily.
• Taken orally 1 time daily, preferably at the same time each day: 3 tablets of 40 mg 
• May be taken with or without food, but a consistent administration time should be maintained.
• Belzutifan is continued until disease progression or intolerable side effects.
• There is no fixed number of cycles; long-term treatment may be planned.

Drug Interactions

• CYP3A4 / CYP2C19 Inhibitors (Blockers): These drugs may prolong belzutifan exposure and increase side effects. Examples include ketoconazole (an antifungal), itraconazole, clarithromycin (an antibiotic), fluconazole and ritonavir (an antiviral). Belzutifan dose adjustment may be necessary if these drugs are used.
• CYP3A4 / CYP2C19 Inducers (Accelerators): These drugs may accelerate belzutifan breakdown and reduce effectiveness. Examples include rifampin (a tuberculosis drug), carbamazepine (an epilepsy drug), phenytoin, and St. John's wort (an herbal product). These drugs should be avoided together if possible.
• Interactions With CYP3A Substrates: Belzutifan may affect the metabolism of certain drugs, particularly CYP3A substrates. Midazolam is a sedative with anesthetic effects. Its effects may increase when combined with belzutifan. Benzodiazepines, some opioids and immunosuppressants belong to this group.
• Oral Contraceptives (Hormonal): Belzutifan may reduce their effectiveness. Nonhormonal barrier methods, such as condoms or intrauterine devices, should be preferred during treatment.
• Anticoagulants (Blood Thinners): Data on interactions with drugs such as warfarin are limited; bleeding risk should be monitored.

Situations Requiring Attention

• Take the drug at the same time each day and at the dose prescribed by your physician. Usually 120 mg/day (3 tablets of 40 mg).
• May be taken with or without food.
• Take care with missed doses: if fewer than 12 hours have passed since the missed dose, take it immediately. If more than 12 hours have passed, skip it and resume at the normal time. Do not take a double dose on the same day. If you vomit after taking the drug, do not take another dose. Consult your health-care team immediately.
• Regular blood tests are required, particularly to monitor hemoglobin (anemia) and liver function. Hypoxia (low oxygen) may develop. Seek medical advice for shortness of breath, dizziness or weakness. Oxygen levels should be measured if necessary.
• Anemia is common. Monitor for dizziness, easy fatigability and pallor.
• Be alert to drug interactions, particularly with drugs affecting CYP3A4 and CYP2C19, such as midazolam, rifampin and ketoconazole. Tell your physician about all medicines you take.
• Small amounts of alcohol generally do not cause problems, but consultation with your physician is still recommended.
• Pregnancy and contraception: use effective contraception during treatment and for at least 1 week after stopping. Avoid hormonal contraception. Notify your physician immediately if pregnancy occurs. Breastfeeding is not recommended. Do not breastfeed during treatment or for 1 week after the last dose.
• Dizziness and weakness may affect driving or machinery use. Exercise caution with these activities.

Side Effects

• Low red blood cell count (anemia): 83%
• Fatigue: 32%
• Nausea: 18%
• Constipation: 17%
• Swelling of the arms or legs: 16%
• Shortness of breath: 15%
• Back pain: 15%
• Joint pain: 15%
• Muscle weakness: 15%
• Decreased appetite: 15%
• Low blood oxygen (hypoxia): 15%
• Vomiting: 13%
• Dizziness: 12%
• Elevated liver function tests: 12%
• Headache: 12%
• Diarrhea: 12%
• Increased blood creatinine: 9%
• Cough: 8%
• Itching: 8%
• Fever: 6%
• Skin rash: 5%
• Increased blood triglycerides: 4%
• Inflammation of the oral mucosa (mucositis): 4%
• High blood sugar (hyperglycemia): 3%