WELIREG: Uses, Dosage & Side Effects
A first-in-class HIF-2 alpha inhibitor for the treatment of advanced renal cell carcinoma and von Hippel-Lindau disease-associated tumors
WELIREG (belzutifan) is a first-in-class hypoxia-inducible factor 2 alpha (HIF-2α) inhibitor used to treat adults with advanced renal cell carcinoma (kidney cancer) with a clear cell component following prior immunotherapy and anti-angiogenic treatment, as well as adults with von Hippel-Lindau (VHL) disease who require treatment for associated tumors. Belzutifan works by blocking HIF-2α, a protein that drives tumor growth and blood vessel formation. WELIREG is taken orally as three 40 mg tablets (120 mg total) once daily and requires a prescription. It holds conditional marketing authorization in the EU and full approval from the FDA, representing a significant advance in targeted therapy for HIF-2α-driven cancers.
Quick Facts: WELIREG
Key Takeaways
- WELIREG (belzutifan) is the first approved HIF-2α inhibitor, targeting a key pathway that drives tumor growth in clear cell renal cell carcinoma and von Hippel-Lindau disease by blocking the accumulation of HIF-2α protein.
- The standard dose is 120 mg (three 40 mg tablets) taken once daily by mouth, with or without food. Tablets should be swallowed whole and taken at approximately the same time each day.
- Anemia and hypoxia are the most characteristic and clinically significant side effects, directly related to the drug’s mechanism of action on the HIF pathway; regular blood monitoring is essential throughout treatment.
- WELIREG is contraindicated in pregnancy for VHL disease patients and may reduce the effectiveness of hormonal contraceptives – non-hormonal contraception is required during treatment and for at least 1 week after the last dose.
- The drug holds conditional marketing authorization in the EU (with ongoing studies expected) and full FDA approval, representing a landmark advance in targeted therapy for HIF-2α-driven cancers.
What Is WELIREG and What Is It Used For?
WELIREG contains the active substance belzutifan, a novel anticancer medication that belongs to an entirely new class of drugs known as hypoxia-inducible factor 2 alpha (HIF-2α) inhibitors. Belzutifan represents a landmark in oncology as the first drug approved to specifically target the HIF-2α pathway, which plays a central role in the development and progression of certain types of cancer, particularly clear cell renal cell carcinoma (ccRCC) and tumors associated with von Hippel-Lindau (VHL) disease.
Under normal conditions, when oxygen levels in the body are adequate, a protein called the von Hippel-Lindau (VHL) protein continuously tags HIF-2α for destruction. This prevents HIF-2α from accumulating and activating its target genes. However, in clear cell renal cell carcinoma, the VHL gene is frequently mutated or inactivated. Without functional VHL protein, HIF-2α accumulates even when oxygen is plentiful, constitutively driving the expression of genes involved in angiogenesis (formation of new blood vessels through VEGF), cell proliferation (through cyclin D1 and other factors), and red blood cell production (through erythropoietin, EPO). This aberrant HIF-2α activity is a primary oncogenic driver in ccRCC.
Belzutifan works by binding to HIF-2α and blocking its ability to form a functional complex with its partner protein HIF-1β (also known as ARNT). By preventing this dimerization, belzutifan effectively shuts down HIF-2α-mediated gene transcription, reducing the production of VEGF, EPO, cyclin D1, and other tumor-promoting factors. This leads to reduced angiogenesis, slowed tumor growth, and in some cases tumor shrinkage. Importantly, the reduction in EPO also explains two of the drug’s most characteristic side effects: anemia (because less EPO means fewer red blood cells are produced) and, indirectly, hypoxia (because fewer red blood cells means less oxygen delivery to tissues).
WELIREG is approved for the treatment of adults in two main clinical settings:
- Advanced renal cell carcinoma with a clear cell component: WELIREG is indicated for adult patients whose cancer has spread (metastatic or locally advanced) and who have previously received both immune checkpoint inhibitor therapy (a PD-1 or PD-L1 inhibitor such as nivolumab or pembrolizumab) and anti-angiogenic therapy targeting the VEGF pathway (such as sunitinib, pazopanib, cabozantinib, or axitinib). This positions WELIREG as a later-line treatment option for patients who have exhausted the standard first- and second-line therapies.
- Von Hippel-Lindau (VHL) disease: WELIREG is indicated for adult patients with VHL disease who require treatment for renal cell carcinoma, central nervous system (CNS) hemangioblastomas (tumors arising in the brain and spinal cord), or pancreatic neuroendocrine tumors (pNET), when surgery or local treatment procedures are not appropriate. VHL disease is a rare hereditary condition caused by germline mutations in the VHL gene, leading to the formation of tumors and cysts in multiple organs throughout the body. Belzutifan’s ability to directly target the HIF-2α pathway makes it a particularly rational therapeutic choice for VHL disease, where the underlying defect is precisely the loss of VHL protein function.
The approval of WELIREG for VHL disease was based on the landmark Study 004 (LITESPARK-004), an open-label trial that demonstrated an objective response rate of approximately 49% in patients with VHL-associated renal cell carcinoma and meaningful responses in CNS hemangioblastomas and pancreatic neuroendocrine tumors. The approval for advanced RCC following prior therapies was supported by the LITESPARK-005 trial, a Phase III study comparing belzutifan to everolimus in patients with advanced ccRCC after prior PD-1/PD-L1 inhibitor and VEGF-targeted therapy.
WELIREG is the first and, as of 2026, the only approved HIF-2α inhibitor worldwide. Unlike traditional anti-angiogenic drugs that block VEGF or its receptors downstream, belzutifan targets the upstream transcription factor HIF-2α itself, providing a fundamentally different mechanism of action. This approach has the potential to overcome resistance to conventional VEGF-targeted therapies and addresses the root cause of HIF-2α-driven cancers.
What Should You Know Before Taking WELIREG?
Contraindications
There are specific situations in which WELIREG must not be used. Understanding these absolute contraindications is essential before starting treatment.
- Hypersensitivity: Do not take WELIREG if you are allergic to belzutifan or any of the other ingredients in the tablet (croscarmellose sodium, hypromellose acetate succinate, magnesium stearate, mannitol, microcrystalline cellulose, colloidal anhydrous silica, and the film-coating components).
- Pregnancy in VHL disease: WELIREG must not be taken during pregnancy if you are being treated for von Hippel-Lindau disease. The drug may cause harm to an unborn child, including miscarriage. For patients with renal cell carcinoma who are pregnant, the risks and benefits must be carefully discussed with the treating physician.
Warnings and Precautions
Before and during treatment with WELIREG, discuss the following with your doctor:
WELIREG commonly causes anemia because it inhibits HIF-2α, which regulates erythropoietin (EPO) production. This is a pharmacological effect of the drug, not an idiosyncratic reaction. Symptoms include shortness of breath, fatigue, dizziness, and pale skin. Your doctor will monitor your hemoglobin levels before starting treatment and regularly throughout therapy. If severe anemia develops, your doctor may prescribe erythropoiesis-stimulating agents (ESAs), order blood transfusions, temporarily interrupt your dose, or permanently discontinue WELIREG.
WELIREG can cause hypoxia – a decrease in the oxygen saturation of your blood. This may be related to the drug-induced anemia. Seek immediate medical attention if you experience shortness of breath, rapid heartbeat, rapid breathing, bluish discoloration of the skin (especially around the mouth), inability to speak in complete sentences without catching your breath, unusual fatigue, or confusion. Your doctor will monitor your oxygen levels before and during treatment. Severe hypoxia may require supplemental oxygen therapy or dose interruption. If hypoxia recurs after dose reduction, treatment may need to be permanently discontinued.
If you have von Hippel-Lindau disease with hemangioblastomas in your brain or spinal cord, treatment with WELIREG may be associated with bleeding (hemorrhage) in the central nervous system. Contact your doctor immediately if you experience severe headache, vision problems, extreme fatigue, severe weakness on one side of the body, uncoordinated muscle movements, severe neck or back pain, or loss of sensation to pain, temperature, or touch.
Pregnancy and Breastfeeding
WELIREG may cause serious harm to an unborn child and can cause miscarriage. For patients with VHL disease, WELIREG is absolutely contraindicated during pregnancy. For patients with renal cell carcinoma, the decision to use WELIREG during pregnancy must involve a careful discussion between the patient and physician regarding the potential risks to the fetus versus the benefits of treatment.
A pregnancy test is required before starting WELIREG. Women of childbearing potential must be informed that hormonal contraceptives (including pills, injections, and patches) may be less effective while taking WELIREG. Therefore, during treatment and for at least 1 week after the last dose, women should use an effective non-hormonal method of contraception (such as a copper intrauterine device or barrier methods) or ensure that their male partner uses a condom.
WELIREG may affect fertility in both men and women. If this is a concern, discuss it with your doctor before starting treatment. It is unknown whether belzutifan is excreted into breast milk. Because of the potential for harm to the breastfed infant, women should not breastfeed during treatment or for at least 1 week after the last dose.
Children and Adolescents
WELIREG is not recommended for use in children and adolescents under 18 years of age. The safety and efficacy of belzutifan have not been established in this population.
Driving and Operating Machinery
WELIREG may cause dizziness and fatigue. If you experience these symptoms, do not drive or operate machinery until the effects have subsided. Discuss any concerns about your ability to perform these activities safely with your doctor.
Important Information About Ingredients
Each WELIREG film-coated tablet contains less than 1 mmol (23 mg) sodium, meaning it is essentially sodium-free. This is relevant for patients on sodium-restricted diets.
How Does WELIREG Interact with Other Drugs?
Drug interactions with WELIREG primarily involve the enzymes responsible for its metabolism. Belzutifan is metabolized mainly by the enzyme UGT2B17, with minor contributions from CYP2C19. Medications that inhibit or induce these enzymes may therefore alter the blood levels of belzutifan, potentially affecting both its efficacy and toxicity profile. It is essential to inform your doctor about all medicines, supplements, and herbal products you are currently taking or plan to take.
One of the most clinically important interactions involves hormonal contraceptives. WELIREG may decrease the effectiveness of hormonal birth control methods. This is not a minor interaction – given the drug’s potential to cause harm to an unborn child, ensuring effective contraception is critically important. Women should use non-hormonal contraceptive methods or ensure their male partner uses condoms during treatment and for at least 1 week after the last dose.
Major Interactions
| Interacting Drug | Effect | Clinical Significance |
|---|---|---|
| Hormonal contraceptives (pills, patches, injections) | Reduced effectiveness of hormonal birth control | Use non-hormonal contraception or add barrier methods; critical due to teratogenicity risk |
| Strong CYP2C19 inhibitors (e.g., fluconazole, fluvoxamine, omeprazole) | Potential increase in belzutifan plasma levels | Monitor closely for increased side effects; dose adjustment may be needed |
| UGT2B17 inhibitors | May increase belzutifan exposure due to reduced glucuronidation | Caution when co-administering; clinical significance under investigation |
| Erythropoiesis-stimulating agents (ESAs, e.g., epoetin alfa, darbepoetin) | May be used to manage WELIREG-induced anemia; pharmacological interaction at EPO pathway level | Used as supportive care under physician supervision; monitor hemoglobin closely |
Minor Interactions
| Interacting Drug | Effect | Clinical Significance |
|---|---|---|
| CYP2C19 inducers (e.g., rifampicin, carbamazepine) | May decrease belzutifan plasma levels | Potential reduced efficacy; avoid strong inducers if possible |
| Antacids and proton pump inhibitors | No clinically significant effect on belzutifan absorption expected based on solubility profile | No dose adjustment needed |
| Other anticancer agents (prior immunotherapy, VEGF inhibitors) | WELIREG is typically used sequentially after prior therapies, not concurrently; residual effects from prior treatment possible | Ensure adequate washout period; monitor for additive toxicities especially anemia |
Belzutifan does not appear to be a significant inhibitor or inducer of the major CYP enzymes at clinically relevant concentrations. However, given that it is primarily metabolized by UGT2B17 (an enzyme with known genetic polymorphisms in the population), individual variation in drug metabolism is expected. Some patients may metabolize belzutifan faster or slower than average, which could influence both efficacy and side effect profiles. Your doctor will consider these factors when monitoring your treatment.
What Is the Correct Dosage of WELIREG?
WELIREG is taken at home as an oral medication, making it more convenient than many other cancer treatments that require hospital visits for infusion. However, it still requires careful medical supervision with regular blood tests and clinical assessments.
Adults
Standard Adult Dose
Indication: Advanced renal cell carcinoma (after prior immunotherapy and anti-angiogenic therapy) or VHL disease-associated tumors
Dose: 120 mg (three 40 mg tablets) orally once daily
Administration: Swallow tablets whole – do not split, crush, or chew. Take at approximately the same time each day.
Food: Can be taken with or without food
Duration: Continue until disease progression or unacceptable toxicity, as determined by the treating physician
Dose Adjustments
Your doctor may need to reduce your dose or temporarily stop treatment depending on side effects. The dose reduction levels are as follows:
| Dose Level | Daily Dose | Tablets per Day |
|---|---|---|
| Starting dose | 120 mg | 3 tablets (40 mg each) |
| First reduction | 80 mg | 2 tablets (40 mg each) |
| Second reduction | 40 mg | 1 tablet (40 mg) |
Dose modifications are typically guided by the severity of anemia or hypoxia. For severe anemia (hemoglobin below 8 g/dL or requiring transfusion), your doctor will interrupt WELIREG until hemoglobin recovers to an acceptable level, then restart at a reduced dose. For severe hypoxia (oxygen saturation below 88% at rest), treatment is interrupted and supplemental oxygen may be given; if hypoxia resolves, WELIREG may be restarted at a lower dose. If hypoxia recurs at the lowest dose, treatment is permanently discontinued.
Children
WELIREG is not recommended for use in children and adolescents under 18 years of age. The safety and efficacy of belzutifan in pediatric patients have not been established.
Elderly Patients
No dose adjustment is required based on age alone. However, elderly patients should be monitored carefully as they may be more susceptible to anemia and hypoxia. Overall, clinical trial data in older adults have not revealed significant differences in safety or efficacy compared with younger patients, although the sample size in the oldest age groups is limited.
Missed Dose
If you miss a dose of WELIREG, take the missed dose as soon as possible on the same day. Then take your regular dose the next day at the usual time. Do not take two doses on the same day to make up for a missed dose. If you vomit after taking WELIREG, do not take an additional dose; simply resume your regular dosing schedule the next day.
Overdose
If you take more WELIREG tablets than prescribed, contact your doctor or go to a hospital emergency department for advice immediately. There is no specific antidote for belzutifan overdose. Treatment would be supportive, focusing on managing any symptoms that arise, particularly monitoring for severe anemia and hypoxia.
WELIREG tablets must be swallowed whole. Do not split, crush, or chew the tablets. It is unknown whether the drug will work correctly if the tablets are not intact. If you have difficulty swallowing tablets, discuss alternative options with your healthcare provider.
What Are the Side Effects of WELIREG?
Like all medicines, WELIREG can cause side effects, although not everyone will experience them. The side effect profile of WELIREG is strongly linked to its mechanism of action: by inhibiting HIF-2α, the drug reduces erythropoietin (EPO) production, which leads to decreased red blood cell production (anemia) and, consequently, reduced oxygen-carrying capacity of the blood (hypoxia). These are the most clinically significant and characteristic adverse effects. Your medical team will monitor you closely with regular blood tests and oxygen level assessments.
It is important to report any new or worsening symptoms to your doctor promptly. You may need blood transfusions if your red blood cell counts become too low, supplemental oxygen if your oxygen saturation drops, or dose adjustments to manage these effects while maintaining the therapeutic benefit of treatment.
Side Effects by Frequency
Very Common
May affect more than 1 in 10 patients
- Anemia (decreased red blood cells) – the most characteristic side effect, directly related to HIF-2α inhibition reducing EPO production
- Hypoxia (decreased blood oxygen levels) – related to reduced oxygen-carrying capacity from anemia
- Dyspnea (shortness of breath) – may result from anemia and/or hypoxia
- Fatigue – commonly associated with anemia and the underlying disease
- Dizziness – may be related to low hemoglobin or blood pressure changes
- Nausea
- Hemorrhage (bleeding), including CNS hemorrhage in patients with VHL-associated hemangioblastomas in the brain and spinal cord
Common
May affect up to 1 in 10 patients
- Weight gain
Serious Side Effects Requiring Immediate Medical Attention
Contact your doctor immediately or seek emergency medical care if you experience any of the following symptoms, which may indicate serious complications:
- Severe anemia symptoms: extreme tiredness, pale skin, shortness of breath at rest, chest pain, rapid heartbeat, or dizziness when standing
- Severe hypoxia symptoms: difficulty breathing, rapid or shallow breathing, bluish discoloration of the skin (particularly around the mouth and fingertips), confusion, or inability to speak in complete sentences
- CNS hemorrhage symptoms (VHL patients): sudden severe headache, vision problems, severe fatigue, weakness on one side of the body, uncoordinated movements, severe neck or back pain, or loss of sensation
Your doctor will perform regular blood tests to check your hemoglobin levels and blood oxygen saturation before and during treatment with WELIREG. Monitoring is typically performed before each cycle and as clinically indicated. Based on the results, your doctor may adjust your dose, temporarily interrupt treatment, prescribe erythropoiesis-stimulating agents (ESAs), arrange blood transfusions, or provide supplemental oxygen therapy.
Unlike many cancer drugs where anemia is an incidental side effect, WELIREG causes anemia as a direct pharmacological consequence of its mechanism of action. By blocking HIF-2α, WELIREG reduces the production of erythropoietin (EPO), the hormone that signals the bone marrow to produce red blood cells. With lower EPO levels, fewer red blood cells are made, leading to anemia. This anemia, in turn, reduces the blood’s ability to carry oxygen to tissues, which can manifest as hypoxia. Understanding this mechanism helps patients and healthcare teams anticipate and proactively manage these effects.
How Should You Store WELIREG?
Proper storage of WELIREG is important to ensure the medication remains effective and safe throughout its shelf life. Follow these guidelines:
- Temperature: No special temperature storage requirements. Store at room temperature.
- Children: Keep this medicine out of the sight and reach of children at all times.
- Expiration: Do not use WELIREG after the expiry date stated on the blister pack and outer carton after “EXP.” The expiry date refers to the last day of the stated month.
- Packaging integrity: Do not use the medicine if the packaging appears damaged or shows signs of tampering.
- Disposal: Do not dispose of WELIREG via household waste or the sewage system. Return unused medicines to your pharmacist for proper disposal. These measures help protect the environment.
WELIREG is supplied in aluminum/aluminum blister packs. Each pack contains 90 film-coated tablets (packaged in three cartons of 30 tablets each), providing a one-month supply at the standard 120 mg daily dose.
What Does WELIREG Contain?
Active Ingredient
Each film-coated tablet contains 40 mg belzutifan. Belzutifan is the active pharmaceutical ingredient responsible for the drug’s therapeutic effect as a HIF-2α inhibitor.
Inactive Ingredients (Excipients)
The tablet core contains the following excipients: croscarmellose sodium (E468), hypromellose acetate succinate, magnesium stearate (E470b), mannitol (E421), microcrystalline cellulose (E460), and colloidal anhydrous silica (E551). The film coating contains indigotine (indigo carmine aluminum lake, E132), macrogol (E1521), polyvinyl alcohol (E1203), talc (E553b), and titanium dioxide (E171).
Appearance and Packaging
WELIREG tablets are blue, oval-shaped, film-coated tablets debossed with “177” on one side and plain on the other. The tablets are supplied in aluminum/aluminum blister packs. Each package contains 90 film-coated tablets (three inner cartons of 30 tablets each), providing approximately a 30-day supply at the standard 120 mg once-daily dose.
WELIREG is manufactured and distributed by Merck Sharp & Dohme B.V. (Haarlem, Netherlands), part of the MSD (Merck & Co., Inc.) group of companies. The drug holds marketing authorization in numerous countries worldwide, including conditional approval in the European Union and full approval from the U.S. Food and Drug Administration.
Frequently Asked Questions About WELIREG
WELIREG (belzutifan) is used to treat two main conditions: (1) advanced renal cell carcinoma (kidney cancer) with a clear cell component in adults whose cancer has progressed after prior immunotherapy and VEGF-targeted therapy, and (2) von Hippel-Lindau (VHL) disease in adults who need treatment for associated renal cell carcinoma, central nervous system hemangioblastomas, or pancreatic neuroendocrine tumors when surgery is not appropriate.
WELIREG is the first and only approved HIF-2α inhibitor, making it a first-in-class medication. Unlike traditional anti-angiogenic drugs (such as sunitinib or pazopanib) that block VEGF receptors downstream, or immune checkpoint inhibitors (such as nivolumab or pembrolizumab) that activate the immune system, WELIREG works by directly targeting the HIF-2α transcription factor upstream. This means it blocks the root cause of tumor-promoting gene expression in HIF-2α-driven cancers, offering a fundamentally different mechanism of action.
WELIREG causes anemia as a direct consequence of its mechanism of action. By inhibiting HIF-2α, the drug reduces the production of erythropoietin (EPO), a hormone produced mainly by the kidneys that stimulates the bone marrow to make red blood cells. Lower EPO levels mean fewer red blood cells are produced, resulting in anemia. This is an expected pharmacological effect rather than an unexpected side effect, and your doctor will monitor your hemoglobin levels closely throughout treatment.
Yes, WELIREG can be taken with or without food. The absorption of belzutifan is not significantly affected by food intake. The important thing is to take the three 40 mg tablets (120 mg total dose) at approximately the same time each day and to swallow the tablets whole without splitting, crushing, or chewing them.
Yes, WELIREG may reduce the effectiveness of hormonal contraceptives, including birth control pills, injections, and patches. Because WELIREG can harm an unborn child, effective contraception is critically important during treatment. Women should use non-hormonal contraceptive methods (such as a copper IUD or barrier methods) or ensure their male partner uses a condom during treatment and for at least 1 week after the last dose. Discuss suitable contraceptive options with your doctor.
If you miss a dose, take it as soon as possible on the same day. Then take your regular dose the next day at the usual time. Do not take two doses on the same day. If you vomit after taking WELIREG, do not take an additional dose – simply resume your regular schedule the next day. If you have any questions about missed doses, contact your healthcare provider for guidance.
References
- European Medicines Agency (EMA). WELIREG – Summary of Product Characteristics. Last updated 2025. Available at: EMA EPAR: WELIREG.
- U.S. Food and Drug Administration (FDA). WELIREG (belzutifan) – Prescribing Information. Merck Sharp & Dohme LLC. Last revised 2024.
- Choueiri TK, Bauer TM, Papadopoulos KP, et al. Inhibition of hypoxia-inducible factor-2α in renal cell carcinoma with belzutifan: a phase 1/2 trial and biomarker analysis. Nat Med. 2021;27(5):802–805.
- Jonasch E, Donskov F, Iliopoulos O, et al. Belzutifan for renal cell carcinoma in von Hippel-Lindau disease. N Engl J Med. 2021;385(22):2036–2046.
- Choueiri TK, Porta C, Ikeda M, et al. Phase III study of belzutifan versus everolimus in advanced renal cell carcinoma (LITESPARK-005). J Clin Oncol. 2023;41(suppl):LBA4502.
- National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology: Kidney Cancer. Version 2.2025.
- European Society for Medical Oncology (ESMO). Clinical Practice Guidelines: Renal Cell Carcinoma. Updated 2024.
- World Health Organization (WHO). Model List of Essential Medicines. 23rd List, 2023.
Editorial Team
This article was written and reviewed by the iMedic Medical Editorial Team, comprising licensed specialist physicians with expertise in oncology, urology, clinical pharmacology, and drug safety.
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