Welireg

Welireg (belzutifan) is a prescription targeted cancer medicine, not chemotherapy, used to treat adults with von Hippel-Lindau (VHL) disease, renal cell carcinoma (RCC), and pheochromocytoma or paraganglioma (PPGL). It is also approved for children aged 12 and older with PPGL.

Welireg is a hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor. It works by blocking a protein called HIF-2α, which promotes tumor growth under low-oxygen conditions common in certain cancers. By inhibiting this protein, belzutifan can slow or stop tumor growth without the cell-killing mechanism of traditional chemotherapy.

Welireg is taken as a tablet once daily, with or without food, for as long as it is working or until side effects become unacceptable. When used for the adjuvant treatment of clear cell renal cell carcinoma, it is taken for up to 54 weeks. It received initial FDA approval in 2021. In June 2026, it was approved for the adjuvant treatment of clear cell renal cell carcinoma in combination with pembrolizumab, and in September 2026, it was approved in combination with lenvatinib for advanced clear cell renal cell carcinoma. Welireg is manufactured by Merck Sharp and Dohme.

Welireg (belzutifan) is FDA-approved to treat certain patients with these conditions: VHL disease-associated tumors, renal cell carcinoma (RCC), and pheochromocytoma or paraganglioma (PPGL). Eligibility depends on the specific condition, prior treatments received, and other clinical factors. A new indication for advanced clear cell RCC, in combination with lenvatinib, was added in September 2026. The full indications are described below.

Von Hippel-Lindau (VHL) disease

Welireg is approved for adults with VHL disease who require treatment for associated renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas, or pancreatic neuroendocrine tumors (pNET) that do not require immediate surgery. VHL disease is a rare inherited genetic condition that causes tumors and cysts to develop in multiple parts of the body, including the kidneys, brain, spinal cord, and pancreas.

Renal cell carcinoma (RCC) with a clear cell component

Welireg has three approved uses in clear cell RCC:

• In combination with pembrolizumab, or pembrolizumab and berahyaluronidase alfa-pmph (a formulation that helps deliver pembrolizumab under the skin), for the adjuvant treatment of adults with clear cell RCC at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions. This indication was approved in June 2026.
• In combination with lenvatinib for adults with advanced clear cell RCC whose cancer has progressed following a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor. This indication was approved in September 2026.
• As monotherapy for adults with advanced clear cell RCC whose cancer has progressed following a PD-1 or PD-L1 inhibitor and a vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TKI).

Pheochromocytoma or paraganglioma (PPGL)

Welireg is approved for adults and children aged 12 and older with locally advanced, unresectable, or metastatic pheochromocytoma or paraganglioma.

Welireg (belzutifan) works by blocking a protein called hypoxia-inducible factor-2 alpha (HIF-2α). Under low-oxygen conditions, which are common in certain cancers, HIF-2α promotes the growth of new blood vessels and the proliferation of cancer cells. By inhibiting HIF-2α, Welireg cuts off the signals that allow tumors to grow and spread.

In VHL disease, a defective VHL gene causes HIF-2α to accumulate abnormally, driving tumor formation in multiple organs. Belzutifan directly targets this pathway, which is why it is effective across several VHL disease-associated tumor types.

Welireg does not kill cells directly. It is a targeted therapy that interferes with a specific molecular pathway involved in tumor growth

Welireg (belzutifan) tablets are taken once daily at the same time each day. Follow all directions on your prescription label and read the medication guide provided with your prescription.

• Take Welireg at the same time each day, with or without food
• Swallow the tablet whole. Do not crush, chew, or break it. It is not known whether crushing or breaking the tablet affects how the medicine is absorbed
• If you vomit after taking a dose, do not take an extra dose. Take your next dose at your usual scheduled time
• If you miss a dose, take it as soon as you remember on the same day. Take your next dose at the regular time the following day. Do not take two doses on the same day to make up for a missed dose
• Do not change your dose or stop taking Welireg without talking to your doctor first

Welireg can interact with other medications in two main ways: some drugs can increase the amount of belzutifan in your body, raising the risk of side effects, while Welireg itself can reduce the effectiveness of other medications you are taking. Tell your doctor and pharmacist about all prescription and over-the-counter medications, vitamins, and herbal supplements you take before starting Welireg.

Medications that may increase Welireg levels in your body

Certain medications that inhibit enzymes called UGT2B17 or CYP2C19 can increase the amount of belzutifan in your bloodstream, which may increase the risk of Welireg side effects including anemia and hypoxia. If you take any of these medications, your doctor will monitor you for signs of anemia and low oxygen levels and may reduce your Welireg dose if needed.

Medications whose effectiveness may be reduced by Welireg

Welireg can lower the blood levels of medications that are broken down by a liver enzyme called CYP3A4, which may make those medications less effective. For some medications, even a small reduction in blood levels can cause treatment to fail. Your doctor should avoid prescribing these medications alongside Welireg where possible. If they must be taken together, the dose of the other medication may need to be increased in line with its own prescribing information.

This effect may be more pronounced in patients who are poor metabolizers of both UGT2B17 and CYP2C19, which is a genetic variation your doctor can test for.

Hormonal contraceptives

Taking Welireg alongside hormonal contraceptives such as the pill, patch, or injection may cause contraceptive failure or an increase in breakthrough bleeding. This is why a non-hormonal contraceptive method such as condoms must be used during treatment and for at least 1 week after the last dose.

Important note

This is not a complete list of interactions. Check with your healthcare provider or pharmacist before starting, stopping, or changing the dose of any medication while taking Welireg. You can also use the Drugs.com drug interaction checker to review interactions with your specific medications.

Embryo-fetal toxicity (boxed warning)

Welireg can cause serious harm to an unborn baby, including miscarriage. This is the most serious warning associated with Welireg and applies to both male and female patients.

• A pregnancy test must be performed before starting Welireg
• Women who can become pregnant must use effective non-hormonal contraception during treatment and for at least 1 week after the last dose. If you are taking Welireg in combination with another medicine, your healthcare provider will tell you how long you should use birth control. Welireg can make hormonal contraceptives such as the pill, patch, or injection less effective, so a non-hormonal method such as a condom must also be used
• Male patients with female partners who can become pregnant must use effective contraception during treatment and for at least 1 week after the last dose. If you are taking Welireg in combination with another medicine, your healthcare provider will tell you how long you should use birth control
• Tell your healthcare provider immediately if you become pregnant, or if your partner becomes pregnant, during treatment
• Welireg must not be used by pregnant women with VHL disease-associated tumors. It should only be used during pregnancy in women with advanced clear cell RCC if the doctor considers it absolutely necessary.
• If Welireg is used in combination with another medicine, do not breastfeed during treatment and for the longest time after treatment that is recommended for any of the medicines.

Anemia

Welireg commonly causes anemia (low red blood cell counts), which can be severe and may require blood transfusions. Blood tests will be done before and during treatment to monitor red blood cell levels. Tell your healthcare provider straight away if you experience tiredness, pale skin, feeling cold, shortness of breath, chest pain, or fast heartbeat. Tell your healthcare provider if you have low red blood cell counts (anemia) before taking belzutifan.

Low oxygen levels (hypoxia)

Welireg can cause hypoxia (low oxygen levels in the body), which can be severe and may require hospitalization, supplemental oxygen therapy, or discontinuation of treatment. Your oxygen levels will be monitored routinely during treatment.

Contact your healthcare provider straight away if you experience any of the following symptoms of hypoxia:

• Shortness of breath
• Chest tightness or chest pain
• Confusion
• Dizziness or lightheadedness
• Fast or irregular heartbeat
• Unusual tiredness or weakness

Do not wait for your next appointment if these symptoms develop. Severe hypoxia requires prompt medical attention.

Heart problems when used with lenvatinib

Serious heart problems, including heart failure, can happen when Welireg is taken in combination with lenvatinib. Your healthcare provider will check your heart function before and during treatment with Welireg. Tell your healthcare provider right away if you get symptoms of heart problems, including shortness of breath, swelling of your ankles, unusual weight gain, chest pain, or feeling faint.

Before taking Welireg, tell your healthcare provider about all your medical conditions, including if you:

• have low red blood cell counts (anemia)
• have heart problems (if you will take Welireg in combination with lenvatinib)
• Are pregnant or plan to become pregnant
• Are breastfeeding or plan to breastfeed (do not breastfeed during treatment or for at least 1 week after the last dose. If you are taking Welireg in combination with another medicine, your healthcare provider will tell you how long you should not breastfeed).

What are the most common side effects of Welireg?

The most common side effects of Welireg (belzutifan) are anemia (low red blood cell counts) and fatigue, which occur across all conditions Welireg is used to treat. Other common side effects vary depending on the condition being treated. The following side effects each occurred in 25% or more of patients in clinical trials.

Welireg side effects for VHL disease:

• Decreased hemoglobin (anemia)
• Fatigue
• Increased creatinine (a marker of kidney function)
• Headache
• Dizziness
• Increased blood glucose (blood sugar)
• Nausea

Welireg side effects for clear cell RCC in combination with pembrolizumab:

• Decreased hemoglobin (anemia)
• Increased ALT (a liver enzyme)
• Fatigue
• Increased AST (a liver enzyme)
• Decreased lymphocytes (a type of white blood cell)
• Increased alkaline phosphatase (a liver enzyme)

Welireg side effects for advanced clear cell RCC as monotherapy:

• Decreased hemoglobin (anemia)
• Fatigue
• Musculoskeletal pain (muscle and joint pain)
• Increased creatinine (a marker of kidney function)
• Decreased lymphocytes (a type of white blood cell)
• Increased ALT (a liver enzyme)
• Decreased sodium
• Increased potassium
• Increased AST (a liver enzyme)

Welireg side effects for advanced clear cell RCC in combination with lenvatinib:

• Decreased hemoglobin (anemia)
• Fatigue
• Increased AST (a liver enzyme)
• High blood pressure (hypertension)
• Increased ALT (a liver enzyme)
• Musculoskeletal pain (muscle and joint pain)
• Diarrhea
• Decreased lymphocytes (a type of white blood cell)
• Decreased sodium
• Increased creatinine (a marker of kidney function)
• Nausea
• Underactive thyroid (hypothyroidism)
• Decreased appetite
• Decreased platelets
• Increased potassium
• Increased lipase (a pancreatic enzyme)
• Protein in the urine (proteinuria)
• Decreased magnesium
• Decreased calcium
• Increased activated partial thromboplastin time (a blood clotting test)
• Rash
• Vomiting
• Weight loss
• Constipation
• Abdominal (stomach) pain
• Mouth sores (stomatitis).

Welireg side effects for PPGL:

• Anemia
• Fatigue
• Musculoskeletal pain (muscle and joint pain)
• Decreased lymphocytes (a type of white blood cell)
• Increased ALT (a liver enzyme)
• Increased AST (a liver enzyme)
• Increased calcium
• Dyspnea (shortness of breath)
• Increased potassium
• Decreased leukocytes (white blood cells)
• Headache
• Increased alkaline phosphatase (a liver enzyme)
• Dizziness
• Nausea.

Serious Welireg side effects

Get emergency medical help if you have signs of an allergic reaction: hives, difficulty breathing, swelling of your face, lips, tongue, or throat.

Call your doctor right away if you have:

• low red blood cells (anemia) - pale skin, tiredness, feeling light-headed or short of breath, cold hands and feet; or
• low oxygen levels - shortness of breath, chest pain, fast heartbeats; or
• heart problems, if you take Welireg with lenvatinib - shortness of breath, swelling of your ankles, unusual weight gain, chest pain, or feeling faint.
• vision problems, such as blurred vision, blind spots, or sudden changes in vision

Welireg may also cause the serious side effects of pneumonia, pleural effusion, sepsis, and hemorrhage.

Your cancer treatments may be delayed or permanently discontinued if you have certain side effects.

Some serious side effects are described in the Warnings section above, including anemia and hypoxia.

This is not a complete list of side effects, and others may occur. Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

The recommended dose of Welireg (belzutifan) is 120 mg taken orally once daily, with or without food. Welireg is available as 40 mg tablets, so the standard daily dose is three tablets taken together.

Adults

• 120 mg (three 40 mg tablets) once daily, with or without food.

When Welireg is used in combination with pembrolizumab or lenvatinib, the other medicine is given at its own recommended dose.

For adjuvant treatment of clear cell RCC, Welireg is taken until the cancer comes back, side effects become unacceptable, or for up to 54 weeks. For all other uses, it is taken until the cancer gets worse or side effects become unacceptable.

Children aged 12 and older (PPGL only)

Welireg is only approved in children for the treatment of pheochromocytoma or paraganglioma (PPGL). The dose is based on body weight:

• Weighing 40 kg or more: 120 mg once daily
• Weighing less than 40 kg: 80 mg once daily

Dose reductions

Your doctor may reduce your dose or temporarily stop treatment if you develop side effects such as severe anemia or low oxygen levels. Welireg dose reductions follow a step-down schedule from 120 mg to 80 mg to 40 mg as needed. If you take Welireg with lenvatinib and develop serious heart problems, your doctor may pause both medicines, restart them at a lower dose, or stop them permanently. Do not adjust your dose without talking to your doctor first.

Welireg (belzutifan) can cause serious harm to an unborn baby, including miscarriage and fetal harm. This risk is serious enough to carry an FDA boxed warning, the most serious warning level for prescription medicines. Welireg should not be used during pregnancy in patients with VHL disease-associated tumors, and should only be used during pregnancy in patients with advanced clear cell RCC if a doctor considers it absolutely necessary.

A pregnancy test must be done before starting treatment to confirm you are not pregnant.

Contraception during treatment

Both men and women must use effective non-hormonal contraception during treatment and for at least 1 week after the last dose. If you are taking Welireg in combination with another medicine, your healthcare provider will tell you how long you should use birth control. Hormonal contraceptives such as the pill, patch, or injection may not work as well during treatment with Welireg, which is why a non-hormonal method such as condoms must be used instead or in addition.

• Women who can become pregnant must use effective non-hormonal birth control during treatment and for at least 1 week after the last dose
• Male patients with female partners who can become pregnant must also use effective birth control during treatment and for at least 1 week after the last dose
• Tell your healthcare provider immediately if you become pregnant, or if your partner becomes pregnant, during treatment

Breastfeeding

Do not breastfeed while taking Welireg or for at least 1 week after your last dose. If you are taking Welireg in combination with another medicine, your healthcare provider will tell you how long you should not breastfeed. It is not known whether belzutifan passes into breast milk, and the potential risk to a nursing infant has not been established.

Fertility

Welireg may cause fertility problems in both men and women. Whether this effect is reversible after stopping treatment is not known. If preserving your fertility is a concern, talk to your healthcare provider before starting treatment, as fertility preservation options may be available.

Welireg should be stored at room temperature. Follow the storage instructions below to keep your medicine safe and effective

• Store at room temperature between 68°F and 77°F (20°C to 25°C)
• The bottle contains two desiccant canisters to keep the medicine dry. Do not eat or remove them
• Keep out of reach of children
• Do not use after the expiration date printed on the packaging

Active ingredient: belzutifan

Inactive ingredients: croscarmellose sodium, hypromellose acetate succinate, magnesium stearate, mannitol, microcrystalline cellulose, and silicon dioxide.

Film coating: FD&C Blue No. 2 aluminum lake, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide.