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belzutifan
Βelzսtifаո is an inhibitor of hypoxia-inducible factor 2 alpha (HIF-2α), a transcription factor that promotes cell adaptation to hypoxia. Impairment of the von Hippel-Lindau (VHL) protein function prevents HIF-2α degradation, leading to accumulation of HIF-2α. Inhibition of HIF-2α results in reduced expression of downstream genes involved in cellular proliferation, angiogenesis, and tumor growth.
| Effects with food |
No significant effect on drug exposure when given with a high-fat, high-calorie meal, although a delayed Tmax was observed. |
| Time to reach steady state |
3 days |
| PPB |
45% |
Belzutifan is primarily metabolized by UGT2B17 and CYP2C19.
| Active metabolites |
Unknown |
| Inactive metabolites |
Yes |
| Half-life |
14 hours |
| Feces |
51.7%, mostly as inactive metabolites |
| Urine |
49.6% (6% unchanged) |
- Von Hippel-Lindau (VHL) disease
- Renal Cell Carcinoma (RCC)
Refer to the product monograph for a full list and details of approved indications.
Emetogenic Potential:
The following table lists adverse effects that occurred in ≥ 5% of patients with advanced RCC treated with belzutifan versus everolimus in a randomized Phase 3 study. This table also includes severe or life-threatening adverse effects from other studies.
| ORGAN SITE | SIDE EFFECT* (%) | ONSET** | |||
|---|---|---|---|---|---|
| Cardiovascular | Hypertension (6%) | E | |||
| Thromboembolism (3%) | E | ||||
| Dermatological | Rash (8%) | E | |||
| Gastrointestinal | Abdominal pain (11%) | E | |||
| Anorexia (15%) | E | ||||
| Constipation (17%) | E | ||||
| Diarrhea (12%) | E | ||||
| Nausea, vomiting (18%) | E | ||||
| Weight gain (6%) | E | ||||
| General | Edema (20%) | E | |||
| Fatigue (46%) (3% severe) | E | ||||
| Hematological | Anemia (83%) (33% severe) | E D | |||
| Hemorrhage (10%) (3% severe, including CNS) | E | ||||
| Hepatobiliary | ↑ LFTs (12%) | E | |||
| Metabolic / Endocrine | Hyperglycemia (3%) | E | |||
| Musculoskeletal | Musculoskeletal pain (38%) | E | |||
| Nervous System | Dizziness (14%) | E | |||
| Headache (12%) | E | ||||
| Ophthalmic | Visual disorders (8%) (may be severe, including retinal vein occlusion, retinal detachment) | E | |||
| Renal | Creatinine increased (9%) | E | |||
| Respiratory | Cough, dyspnea (17%) | E | |||
| Hypoxia (15%) (11% severe) | E D | ||||
* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare"
may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal
reports.
** I = immediate (onset in hours to days)
E = early (days to weeks)
D = delayed (weeks to months)
L = late (months to years)
The most common side effects for belzutifan include anemia, fatigue, musculoskeletal pain, edema, nausea, vomiting, constipation, cough, dyspnea, anorexia, hypoxia, and dizziness.
Severe anemia may require blood transfusion and erythropoiesis stimulating agents (ESAs). The safety of ESAs in patients with VHL disease treated with belzutifan has not been established. Of the renal cell cancer patients with anemia, 22% received transfusions only, 20% received ESAs only and 14% received both transfusion and ESAs. Baseline hemoglobin (≤ 120g/L) may increase the risk of developing ≥ Grade 3 anemia. Median time to onset of all Grade anemia events was ~1 month in clinical trials.
Hypoxia may be asymptomatic. Healthcare providers may instruct patients to monitor oxygen saturation at home at their discretion. Severe hypoxia may require discontinuation, supplemental oxygen, or hospitalization. Of the patients with hypoxia, 70% were treated with oxygen therapy. The median onset of hypoxia was reported to be 1 month in clinical trials.
Refer to protocol by which the patient is being treated.
Screen for hepatitis B virus in all cancer patients starting systemic treatment. Refer to the hepatitis B virus screening and management guideline.
| Dose Level | Belzutifan (mg daily) |
| 0 | 120 |
| -1 | 80 |
| -2 | 40 |
| -3 | Discontinue |
| Toxicity | Severity/Grade | Action |
| Anemia | Grade 3 or transfusion indicated |
Hold* Resume at same dose or at 1 dose level ↓ OR consider discontinuing depending on severity and/or persistence of toxicity. |
| Grade 4 |
Hold* Resume at 1 dose level ↓ OR discontinue. |
|
| Hypoxia | Grade 2 |
Consider continuing or holding until resolved. If held, consider resuming at reduced dose depending on severity and/or persistence of toxicity. |
| Grade 3 |
Hold until resolved. Resume at 1 dose level ↓ OR discontinue depending on severity and/or persistence of toxicity. |
|
| Grade 4 or recurrent symptomatic hypoxia | Discontinue. | |
| Other Adverse Reactions | Grade 3 |
Hold* Consider resuming at 1 dose level ↓. Discontinue if recurrence of Grade 3. |
| Grade 4 | Discontinue. |
*Do not restart until toxicity resolved to ≤ Grade 2.
| Bilirubin | AST | Belzutifan Dose | |
| ≤ ULN | and | > ULN | No dose adjustment recommended |
| >1 to 1.5 x ULN | and | Any | |
| > 1.5 x ULN | and | Any | No data |
| Creatinine Clearance* | Belzutifan Dose |
| ≥ 30 | No dose adjustment recommended |
| < 30 | No data |
*Reported as eGFR in mL/min/1.73m2
No dose adjustment is needed in patients ≥ 65 years of age. No overall difference in safety or efficacy was reported between patients ≥ 65 years of age and over and younger patients. Differences in belzutifan tolerability profile were observed in patients ≥ 65 years of age compared to younger patients.
No dose adjustment required. Population pharmacokinetics analysis showed a 1.6-fold higher belzutifan exposure in female patients compared to male patients.
No dose adjustment required. Population pharmacokinetics analysis showed a 2.3-fold higher belzutifan exposure in Asian patients compared to Caucasian patients. This difference can be due to higher frequencies of UGT2B17 poor metabolizers and combined UGT2B17 and CYP2C19 poor metabolizers in Asian patients, compared to Caucasian and African American patients (also refer to Drug Interactions section).
The safety and efficacy of belzutifan in pediatric patients under 18 years of age have not been established.
-
Administer belzutifan with or without food.
-
Tablets should be swallowed whole. Do not chew, crush, or split the tablets.
-
If a dose is missed, it can be given as soon as possible on the same day. Then administer the scheduled dose on the next day. Do not give extra tablets to make up for the missed dose.
-
If a patient vomits after taking belzutifan, do not give another dose. The next dose should be given at the scheduled time on the following day.
-
Store at room temperature (15°C to 30°C).
- Patients who have a hypersensitivity to this drug or any of its components
- Caution with driving or using machinery as dizziness may occur with treatment.
Other Drug Properties:
-
Carcinogenicity:
Unknown
-
Genotoxicity:
No
-
Mutagenicity:
No
-
Embryotoxicity:
Documented in animals
-
Fetotoxicity:
Documented in animals
-
Pregnancy:
Belzutifan is not recommended for use in pregnancy. Adequate contraception should be used by patients and their partners during treatment, and for at least 1 week after the last dose.
Use non-hormonal (e.g., barrier) methods of contraception since belzutifan may reduce the effectiveness of hormonal contraceptives (See Interactions section).
-
Breastfeeding:
Breastfeeding is not recommended during treatment and for at least 1 week after the last dose.
-
Fertility effects:
Probable
Documented in animal studies. Discuss fertility preservation with patients prior to starting treatment.
Belzutifan is primarily metabolized by UGT2B17 and CYP2C19 and to a lesser extent by CYP3A4.
Belzutifan is a moderate CYP3A4 inducer.
Belzutifan is a weak P-gp, OATP1B1 and OATP1B3 substrate, and inhibits MATE2K; the clinical significance is unknown.
Individuals who are UGT2B17 poor metabolizers or combined UGT2B17 and CYP2C19 poor metabolizers have higher belzutifan exposures (2.7-fold or 3.3 -fold respectively). No dose adjustment is recommended. Monitor closely for adverse reactions.
| AGENT | EFFECT | MECHANISM | MANAGEMENT |
|---|---|---|---|
| Sensitive CYP3A4 substrates (i.e. midazolam) | ↓ CYP3A4 substrates concentration and/or efficacy. (May be more pronounced in patients who are combined UGT2B17 and CYP2C19 poor metabolizers.) | Belzutifan is a moderate CYP 3A4 inducer | Avoid concomitant use with CYP3A4 sensitive substrates for which minimal concentration ↓ may lead to substrates' therapeutic failures. If must co-administer, ↑ dosage of CYP3A4 substrate as per substrate's product monograph. |
| Hormonal contraceptives | Coadministration may lead to contraceptive failure or an increase in breakthrough bleeding | Belzutifan is a moderate CYP 3A4 inducer | Avoid concomitant use with hormonal contraceptives. Advise patients of the need for highly effective non-hormonal contraception methods. |
| UGT2B17 or CYP2C19 inhibitors | ↑ belzutifan exposure and/or toxicity | Belzutifan is metabolized by UGT2B17 and CYP2C19 | Caution; monitor for increased adverse reactions. |
Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.
Refer to the hepatitis B virus screening and management guideline for monitoring during and after treatment.
| Monitor Type | Monitor Frequency |
|---|---|
CBC |
Baseline, at each visit, and as clinically indicated |
Oxygen saturation |
Baseline and at each visit, and as clinically indicated (May consider monitoring at home when starting treatment and as clinically indicated) |
Liver function tests |
Baseline, at each visit, and as clinically indicated |
Renal function tests |
Baseline, at each visit, and as clinically indicated |
Clinical toxicity assessment for fatigue, musculoskeletal pain, edema, ophthalmic or GI effects, dyspnea, bleeding |
At each visit |
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
Exceptional Access Program (EAP Website)
- Belzutifan – For the treatment of adult patients with von Hippel-Lindau (VHL) disease, based on criteria
Belzutifan [Drug information]. UpToDate Inc. (2025). Accessed January 21, 2025.
Choueiri TK, Powles T, Peltola K, et al Belzutifan versus Everolimus for Advanced Renal-Cell Carcinoma. N Engl J Med. 2024 Aug 22;391(8):710-721. doi: 10.1056/NEJMoa2313906.
Jonasch E, Donskov F, Iliopoulos O, et al. Belzutifan for Renal Cell Carcinoma in von Hippel-Lindau Disease. N Engl J Med. 2021 Nov 25;385(22):2036-2046. doi: 10.1056/NEJMoa2103425.
Prescribing Information: Welireg® (belzutifan). Merck & Co., Inc. (US). December 2023.
Product Monograph: WELIREG® (belzutifan). Merck Canada Inc. December 17, 2024.
June 2025 New drug monograph
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
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