Version May 2024
Exposure to belzutifan during pregnancy can cause embryo-fetal harm. Verify pregnancy status prior to the initiation of belzutifan. Advise patients of these risks and the need for effective nonhormonal contraception. Belzutifan can render some hormonal contraceptives ineffective.
Renal cell carcinoma, advanced: Oral: 120 mg once daily; continue until disease progression or unacceptable toxicity.
von Hippel-Lindau disease: Patients with renal cell carcinoma, CNS hemangioblastoma, and pancreatic neuroendocrine tumors requiring treatment : Oral: 120 mg once daily; continue until disease progression or unacceptable toxicity (Ref).
Missed dose: If a dose is missed, administer as soon as possible on the same day and resume the regular dosing schedule the following day; do not administer additional tablets to make up for the missed dose. If vomiting occurs after administration, do not administer another dose; resume dosing the following day.
Concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Note: Kidney function estimated using the MDRD equation.
eGFR ≥30 mL/minute/1.73 m2: No dosage adjustment is necessary.
eGFR 15 to 29 mL/minute/1.73 m2: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
Mild impairment (total bilirubin ≤ ULN and AST > ULN or total bilirubin >1 to 1.5 times ULN and any AST): No dosage adjustment is necessary.
Moderate or severe impairment (total bilirubin >1.5 times ULN and any AST): There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
|
Dose level |
Belzutifan dose |
|---|---|
|
Recommended initial starting dose |
120 mg once daily |
|
First dose reduction |
80 mg once daily |
|
Second dose reduction |
40 mg once daily |
|
Third dose reduction |
Permanently discontinue belzutifan |
|
Adverse reaction |
Severity |
Dose modification |
|---|---|---|
|
a May require supplemental oxygen or hospitalization. | ||
|
Anemia |
Hemoglobin <8 g/dL or transfusion indicated |
Withhold belzutifan until hemoglobin is ≥8 g/dL. Resume at the same or at a reduced dose; or permanently discontinue belzutifan, depending on the severity. |
|
Life-threatening or urgent intervention indicated |
Withhold belzutifan until hemoglobin is ≥8 g/dL. Resume at a reduced dose or permanently discontinue belzutifan. | |
|
Hypoxiaa |
Decreased oxygen saturation with exercise (eg, pulse oximeter <88% or PaO2 ≤55 mm Hg) |
Consider withholding belzutifan until hypoxia is resolved (eg, pulse oximeter with exercise >88%). Resume at the same or reduced dose, depending on the severity. |
|
Decreased oxygen saturation at rest (eg, pulse oximeter <88% or PaO2 ≤55 mm Hg) or urgent intervention required |
Withhold belzutifan until hypoxia is resolved. Resume at a reduced dose or discontinue belzutifan, depending on the severity. | |
|
Life-threatening or recurrent symptomatic hypoxia |
Permanently discontinue belzutifan. | |
|
Other adverse reactions |
Grade 3 |
Withhold belzutifan until improved to ≤ grade 2. Consider resuming at a reduced dose (reduce by 40 mg). Permanently discontinue belzutifan if grade 3 adverse reaction recurs. |
|
Grade 4 |
Permanently discontinue belzutifan. | |
Refer to adult dosing.
Anemia has been reported in clinical trials; grade 3 anemia and severe anemia requiring blood transfusions have occurred.
Mechanism: Dose-related; inhibition of hypoxia-inducible factor 2 alpha (HIF-2α) decreases gene transcription, leading to reduced erythropoietin production and iron metabolism (Ref).
Onset: Varied; median 29 to 31 days (range: 1 day to 16.6 months).
Risk factors:
• Dual UGT2B17 and CYP2C19 poor metabolizers
Severe hypoxia has been reported, including grade 3 events; may require supplemental oxygen, discontinuation, and/or hospitalization.
Mechanism: Dose-related; inhibition of hypoxia-inducible factor 2 alpha (HIF-2α) prevents oxygen sensing regulating genes from promoting the body’s response to hypoxia.
Onset: Varied; median 30.5 days (range: 1 day to 21.1 months).
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported in adults.
>10%:
Cardiovascular: Edema (20%)
Endocrine & metabolic: Decreased serum calcium (21%), decreased serum glucose (22%), decreased serum sodium (31%), increased serum potassium (29%)
Gastrointestinal: Constipation (15%), decreased appetite (13%), diarrhea (11%; grades 3/4: 1%), nausea (17%; grades 3/4: <1%), vomiting (11%; grades 3/4: <1%)
Hematologic & oncologic: Lymphocytopenia (34%; grades 3/4: 8%)
Hepatic: Increased serum alanine aminotransferase (32%), increased serum aspartate aminotransferase (27%)
Nervous system: Dizziness (11%), fatigue (43%), headache (12%)
Neuromuscular & skeletal: Musculoskeletal pain (34%)
Renal: Increased serum creatinine (34%)
Respiratory: Dyspnea (16%), hypoxia (15%)
1% to 10%:
Cardiovascular: Hypertension (6%)
Dermatologic: Skin rash (8%)
Endocrine & metabolic: Weight gain (5%)
Gastrointestinal: Abdominal pain (10%)
Hematologic & oncologic: Anemia (serious: 5%), hemorrhage (9%)
Ophthalmic: Visual disturbance (including blurred vision [4%], decreased visual acuity [1%], retinal detachment [<1%], and visual impairment [<1%])
Respiratory: Pleural effusion (serious: 2%), pneumonia (serious: 4%)
<1%: Nervous system: Cerebral hemorrhage, intracranial hemorrhage
There are no contraindications listed in the manufacturer's US labeling.
Canadian labeling: Hypersensitivity to belzutifan or any component of the formulation.
Special populations:
• Older adults: Patients ≥65 years of age treated for advanced renal cell carcinoma experienced higher rates of dose interruptions and dose reductions during belzutifan therapy compared to patients <65 years of age.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Welireg: 40 mg [contains fd&c blue #2 (indigo carm) aluminum lake]
No
Tablets (Welireg Oral)
40 mg (per each): $395.48
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Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Welireg: 40 mg [contains fd&c blue #2 (indigo carm) aluminum lake]
Belzutifan is available through specialty pharmacies/distributors and various specialty institutions/accounts. Examples from the manufacturer may be found at: https://www.merckaccessprogram-welireg.com/hcp/
Oral: Administer at the same time each day, with or without food. Swallow whole; do not chew, crush, or split tablets.
This medication is not on the NIOSH (2016) list; however, it may meet the criteria for a hazardous drug. Belzutifan may cause teratogenicity or reproductive toxicity.
Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).
Note: Facilities may perform risk assessment of some hazardous drugs to determine if appropriate for alternative handling and containment strategies (USP-NF 2020). Refer to institution-specific handling policies/procedures.
An FDA-approved patient medication guide, which is available with the product and as follows, must be dispensed with this medication:
Welireg: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/215383s006lbl.pdf#page=17
Renal cell carcinoma, advanced: Treatment of advanced renal cell carcinoma in adults following a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) and a vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TKI).
von Hippel-Lindau disease: Treatment of adult patients with von Hippel-Lindau disease who require therapy for associated renal cell carcinoma, CNS hemangioblastomas, or pancreatic neuroendocrine tumors, not requiring immediate surgery.
Belzutifan may be confused with belimumab, belinostat, belumosudil, busulfan.
This medication is in a class the Institute for Safe Medication Practices (ISMP) includes among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.
Substrate of CYP2C19 (minor), CYP3A4 (minor), OATP1B1/1B3 (SLCO1B1/1B3), P-glycoprotein/ABCB1 (minor), UGT2B17; Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Induces CYP3A4 (weak)
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Atogepant: CYP3A4 Inducers (Weak) may decrease the serum concentration of Atogepant. Management: For treatment of episodic migraine, the recommended dose of atogepant is 30 mg once daily or 60 mg once daily when combined with CYP3A4 inducers. When used for treatment of chronic migraine, use of atogepant with CYP3A4 inducers should be avoided. Risk D: Consider therapy modification
CarBAMazepine: CYP3A4 Inducers (Weak) may decrease the serum concentration of CarBAMazepine. Risk C: Monitor therapy
CloZAPine: CYP3A4 Inducers (Weak) may decrease the serum concentration of CloZAPine. Risk C: Monitor therapy
CYP2C19 Inhibitors (Moderate): May increase the serum concentration of Belzutifan. Risk C: Monitor therapy
CYP2C19 Inhibitors (Strong): May increase the serum concentration of Belzutifan. Risk C: Monitor therapy
Hormonal Contraceptives: CYP3A4 Inducers (Weak) may decrease the serum concentration of Hormonal Contraceptives. Management: Advise patients to use an alternative method of contraception or a back-up method during coadministration, and to continue back-up contraception for 28 days after discontinuing a weak CYP3A4 inducer to ensure contraceptive reliability. Risk D: Consider therapy modification
NiMODipine: CYP3A4 Inducers (Weak) may decrease the serum concentration of NiMODipine. Risk C: Monitor therapy
Selpercatinib: CYP3A4 Inducers (Weak) may decrease the serum concentration of Selpercatinib. Risk C: Monitor therapy
Sirolimus (Conventional): CYP3A4 Inducers (Weak) may decrease the serum concentration of Sirolimus (Conventional). Risk C: Monitor therapy
Sirolimus (Protein Bound): CYP3A4 Inducers (Weak) may decrease the serum concentration of Sirolimus (Protein Bound). Risk C: Monitor therapy
Tacrolimus (Systemic): CYP3A4 Inducers (Weak) may decrease the serum concentration of Tacrolimus (Systemic). Risk C: Monitor therapy
Ubrogepant: CYP3A4 Inducers (Weak) may decrease the serum concentration of Ubrogepant. Management: Use an initial ubrogepant dose of 100 mg and second dose (if needed) of 100 mg when used with a weak CYP3A4 inducer. Risk D: Consider therapy modification
Verify pregnancy status prior to treatment initiation in patients who could become pregnant.
Patients who could become pregnant should use effective nonhormonal contraception during therapy and for 1 week after the last belzutifan dose. Patients with partners who could become pregnant should also use effective contraception during therapy and 1 week after the last dose of belzutifan. Belzutifan may render some hormonal contraceptives ineffective; consult drug interactions database for detailed information.
Based on animal reproduction studies, in utero exposure to belzutifan may cause fetal harm. Embryo-fetal lethality, reduced fetal body weight, and fetal skeletal malformations were observed when pregnant rats were administered belzutifan at doses resulting in maternal exposures ≥0.2 times the recommended human dose of 120 mg (based on AUC).
It is not known if belzutifan is present in breast milk.
Due to the potential for serious adverse reactions in the breastfed infant, breastfeeding is not recommended by the manufacturer during therapy and for 1 week after the last belzutifan dose.
Monitor hemoglobin (prior to therapy initiation and periodically throughout treatment); closely monitor patients who are dual UGT2B17 and CYP2C19 poor metabolizers due to the potential increased incidence or severity of anemia. Monitor oxygen saturation (prior to therapy initiation and periodically throughout treatment). Evaluate pregnancy status in patients who could become pregnant. Monitor for signs/symptoms of anemia and hypoxia. Monitor adherence.
The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.
Belzutifan is a small molecule inhibitor of hypoxia-inducible factor 2 alpha (HIF-2α), a transcription factor that regulates genes that promote adaptation to hypoxia. Inactivation of von Hippel-Lindau (VHL) gene results in abnormal stabilization and accumulation of HIF-2α, which drives tumor growth (Srinivasan 2021). Belzutifan binds to HIF-2α and prevents HIF-2α from interacting with hypoxia-inducible factor 1 beta, resulting in reduced transcription and expression of HIF-2α target genes (including genes associated with cellular proliferation, angiogenesis, and tumor growth).
Distribution: Vd: 119 L.
Protein binding: 45%.
Metabolism: Primarily hepatic via UGT2B17 and CYP2C19 and to a lesser extent by CYP3A4.
Half-life elimination: 14 hours.
Time to peak: 1 to 2 hours.
Excretion: Feces (51.7%; primarily as inactive metabolites); Urine (49.6%; primarily as inactive metabolites).
Clearance: 6 L/hour.
Pharmacogenomics: Patients who are UGT2B17, CYP2C19, or dual UGTB17 and CYP2C19 poor metabolizers are estimated to have 2.5-, 1.3-, or 3.2-fold higher belzutifan steady state AUC0-24h, respectively, compared to patients who are UGT2B17 normal (extensive) metabolizers and CYP2C19 nonpoor (ultrarapid, rapid, normal, and intermediate) metabolizers.
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