Brand Name
Welireg
Generic Name
Belzutifan
View Brand Information FDA approval date: August 13, 2021
Classification: Hypoxia-inducible Factor Inhibitor
Form: Tablet
What is Welireg (Belzutifan)?
WELIREG is indicated for treatment of adult patients with von Hippel-Lindau disease who require therapy for associated renal cell carcinoma , central nervous system hemangioblastomas, or pancreatic neuroendocrine tumors , not requiring immediate surgery. WELIREG is a hypoxia-inducible factor inhibitor indicated for treatment of adult patients with von Hippel-Lindau disease who require therapy for associated renal cell carcinoma , central nervous system hemangioblastomas, or pancreatic neuroendocrine tumors , not requiring immediate surgery.
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Related Clinical Trials
A Phase 2 Study to Evaluate the Efficacy and Safety of Belzutifan (MK-6482, Formerly PT2977) Monotherapy in Participants With Advanced Pheochromocytoma/Paraganglioma (PPGL), Pancreatic Neuroendocrine Tumor (pNET), Von Hippel-Lindau (VHL) Disease-Associated Tumors, Advanced Gastrointestinal Stromal Tumor (wt GIST), or Advanced Solid Tumors With HIF-2α Related Genetic Alterations
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Brand Information
WELIREG (belzutifan)
WARNING: EMBRYO-FETAL TOXICITY
- Exposure to WELIREG during pregnancy can cause embryo-fetal harm.
- Verify pregnancy status prior to the initiation of WELIREG.
- Advise patients of these risks and the need for effective non-hormonal contraception. WELIREG can render some hormonal contraceptives ineffective
1DOSAGE FORMS AND STRENGTHS
Tablets: 40 mg, blue, oval shaped, film-coated, debossed with “177” on one side and plain on the other side.
2CONTRAINDICATIONS
None.
3ADVERSE REACTIONS
The following clinically significant adverse reactions are discussed elsewhere in the labeling:
- Anemia
- Hypoxia
3.1Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
von Hippel-Lindau (VHL) disease
LITESPARK-004
The safety of WELIREG was evaluated in an open-label clinical trial (LITESPARK-004) in 61 patients with VHL disease who had at least one measurable solid tumor localized to the kidney
Serious adverse reactions occurred in 15% of patients who received WELIREG, including anemia, hypoxia, anaphylaxis reaction, retinal detachment, and central retinal vein occlusion (1 patient each).
Permanent discontinuation of WELIREG due to adverse reactions occurred in 3.3% of patients. Adverse reactions which resulted in permanent discontinuation of WELIREG were dizziness and opioid overdose (1.6% each).
Dosage interruptions of WELIREG due to an adverse reaction occurred in 39% of patients. Adverse reactions which required dosage interruption in >2% of patients were fatigue, decreased hemoglobin, anemia, nausea, abdominal pain, headache, and influenza-like illness.
Dose reductions of WELIREG due to an adverse reaction occurred in 13% of patients. The most frequently reported adverse reaction which required dose reduction was fatigue (7%).
The most common (≥25%) adverse reactions, including laboratory abnormalities, that occurred in patients who received WELIREG were decreased hemoglobin, fatigue, increased creatinine, headache, dizziness, increased glucose, and nausea.
Table 2 summarizes the adverse reactions reported in patients treated with WELIREG in LITESPARK-004.
Table 3 summarizes the laboratory abnormalities in LITESPARK-004.
Advanced Renal Cell Carcinoma (RCC)
LITESPARK-005
The safety of WELIREG was evaluated in a randomized, active-controlled study (LITESPARK- 005) in 732 patients with advanced RCC with a clear cell component that has progressed after prior PD-1 or PD-L1 checkpoint inhibitor and VEGF receptor targeted therapies
Serious adverse reactions occurred in 38% of patients who received WELIREG. Serious adverse reactions in ≥2% of patients treated with WELIREG were hypoxia (7%), anemia (5%), pneumonia (3.5%), hemorrhage (3%), and pleural effusion (2.2%). Fatal adverse reactions occurred in 3.2% of patients who received WELIREG, including sepsis (0.5%) and hemorrhage (0.5%).
Permanent discontinuation of WELIREG due to adverse reactions occurred in 6% of patients. Adverse reactions which resulted in permanent discontinuation (≥0.5%) of WELIREG were hypoxia (1.1%), anemia (0.5%), and hemorrhage (0.5%).
Dosage interruptions of WELIREG due to an adverse reaction occurred in 39% of patients. Adverse reactions which required dosage interruption in ≥2% of patients were anemia (8%), hypoxia (5%), COVID-19 (4.3%), fatigue (3.2%), and hemorrhage (2.2%).
Dose reductions of WELIREG due to an adverse reaction occurred in 13% of patients. Adverse reactions which required dose reduction in ≥1% of patients were hypoxia (5%) and anemia (3.2%).
The most common (≥25%) adverse reactions, including laboratory abnormalities, that occurred in patients who received WELIREG were decreased hemoglobin, fatigue, musculoskeletal pain, increased creatinine, decreased lymphocytes, increased alanine aminotransferase, decreased sodium, increased potassium, and increased aspartate aminotransferase.
Table 4 summarizes the adverse reactions in LITESPARK-005.
Clinically relevant adverse reactions in <10% of patients who received WELIREG in LITESPARK-005 included hemorrhage (9%) [including intracranial/cerebral hemorrhage (0.8%)], rash (8%), hypertension (6%), visual impairment [including vision blurred (4%), visual acuity decreased (1.1%), visual impairment (0.5%), and retinal detachment (0.3%)] (6%) and increased weight (5%).
Table 5 summarizes the laboratory abnormalities in LITESPARK-005.
Pheochromocytoma or Paraganglioma
LITESPARK-015
The safety of WELIREG was evaluated in an open-label clinical trial (LITESPARK-015) in 72 patients with locally advanced, unresectable, or metastatic pheochromocytoma or paraganglioma (PPGL)
The median duration of exposure to WELIREG was 20 months (range: 0.3 to 32.5 months).
Serious adverse reactions occurred in 36% of patients who received WELIREG. Serious adverse reactions occurring in ≥2% of patients treated with WELIREG were anemia and hypertension (4.2% each) and pyelonephritis, pneumonia, hypoxia, dyspnea and hemorrhage (2.8% each).
Permanent discontinuation of WELIREG due to adverse reactions occurred in 2 patients (2.8%). Adverse reactions which resulted in permanent discontinuation of WELIREG were increased alanine aminotransferase and paraparesis (1.4% each).
Dosage interruptions of WELIREG due to an adverse reaction occurred in 40% of patients. Adverse reactions which required dosage interruption in >3% of patients were hypoxia, nausea and fatigue (4.2% each).
Dose reductions of WELIREG due to an adverse reaction occurred in 14% of patients. The most frequently reported adverse reaction which required dose reduction was hypoxia (4.2%).
The most common (≥25%) adverse reactions, including laboratory abnormalities, that occurred in patients who received WELIREG were anemia, fatigue, musculoskeletal pain, decreased lymphocytes, increased alanine aminotransferase, increased aspartate aminotransferase, increased calcium, dyspnea, increased potassium, decreased leukocytes, headache, increased alkaline phosphatase, dizziness, and nausea.
Table 6 summarizes the adverse reactions reported in patients treated with WELIREG in LITESPARK-015.
Table 7 summarizes the laboratory abnormalities in LITESPARK-015.
4OVERDOSAGE
There is no specific treatment for WELIREG overdose. In cases of suspected overdose, withhold WELIREG and institute supportive care. Grade 3 hypoxia occurred at dosages of 120 mg twice a day and Grade 4 thrombocytopenia occurred at dosages of 240 mg once daily (approximately 2 times the recommended dosage).
5DESCRIPTION
Belzutifan is an inhibitor of hypoxia-inducible factor-2α (HIF-2α). The chemical name of belzutifan is 3-[[(1S,2S,3R)-2,3-Difluoro-2,3-dihydro-1-hydroxy-7-(methylsulfonyl)-1H-inden-4-yl]oxy]-5-fluorobenzonitrile. The molecular formula is C
Belzutifan is a white to light brown powder that is soluble in acetonitrile, dimethoxyethane, and acetone, sparingly soluble in ethyl acetate, very slightly soluble in isopropanol and toluene, and insoluble in water.
WELIREG is supplied as blue, film-coated tablets for oral use containing 40 mg of belzutifan together with croscarmellose sodium, hypromellose acetate succinate, magnesium stearate, mannitol, microcrystalline cellulose, and silicon dioxide, as inactive ingredients. In addition, the film-coating contains FD&C Blue #2 aluminum lake, polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide.
6HOW SUPPLIED/STORAGE AND HANDLING
How Supplied
WELIREG tablets are supplied as 40 mg blue, oval shaped, film-coated, debossed with “177” on one side and plain on the other side, available in:
- bottles of 90 tablets with child-resistant closure: NDC 0006-5331-01.
The bottle also contains two desiccant canisters. Do not eat.
Storage and Handling
Store at 20°C to 25°C (68°F to 77°F), excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature].
7PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (
Anemia
Inform patients that WELIREG can cause severe anemia that may require blood transfusions and that red blood cell levels will be monitored routinely during treatment. Advise patients to contact their healthcare provider if the patient experiences any symptoms suggestive of anemia
Hypoxia
Inform patients that WELIREG can cause severe hypoxia that may require discontinuation, supplemental oxygen, or hospitalization; and that oxygen levels will be monitored routinely during treatment. Advise patients to contact their healthcare provider if the patient experiences any symptoms suggestive of hypoxia
Embryo-Fetal Toxicity
- Advise pregnant women and females of reproductive potential of the risk to a fetus. Advise females to inform their healthcare provider of a known or suspected pregnancy
- Advise females of reproductive potential to use effective non-hormonal contraception during treatment with WELIREG and for 1 week after the last dose
- Advise male patients with female partners of reproductive potential to use effective contraception during treatment with WELIREG and for 1 week after the last dose
Lactation
Advise females not to breastfeed during treatment with WELIREG and for 1 week after the last dose
Infertility
Advise male and female patients that WELIREG may impair fertility
Dosage and Administration
Instruct patients to take their dose of WELIREG at the same time each day (once daily). Advise patients WELIREG can be taken with or without food. Each tablet should be swallowed whole
8PRINCIPAL DISPLAY PANEL - 40 mg Bottle Label
NDC 0006-5331-01
Welireg
40 mg
Dispense the accompanying Medication
Each tablet contains 40 mg of belzutifan.
Rx only
90 Tablets
