Belzutifan is a hypoxia-inducible factor 2 alpha (HIF-2 alpha) inhibitor approved for the treatment of renal cell cancer as well as von Hippel-Lindau (VHL) disease in patients requiring treatment of associated renal cell cancer (RCC), CNS hemangioblastomas, or pancreatic neuroendocrine tumors (pNET) that do not require immediate surgery. Belzutifan has a boxed warning for embryo-fetal toxicity; severe anemia requiring transfusion and hypoxia are also possible with belzutifan therapy.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
-Take with or without food at the same time each day.
-If a dose is missed, it can be taken as soon as possible on the same day; resume the regular schedule the next day. Do not take extra tablets to make up for a missed dose.
-If vomiting occurs, do not retake the dose. Take the next dose on the next day.
Oral Solid Formulations
-Swallow belzutifan tablets whole; do not chew, crush, or split tablets.
Anemia has been reported in patients treated with belzutifan. In 2 randomized clinical trials, a decrease in hemoglobin from baseline occurred in 88% to 93% of patients treated with belzutifan; grade 3 decreases in hemoglobin occurred in 7% of belzutifan-treated patients with von Hippel-Landau disease and in 29% of those with renal cell cancer. The median time to onset of anemia was 29 to 31 days. An interruption of therapy, dose reduction, or discontinuation of therapy is necessary for patients with a hemoglobin less than 8 g/dL; transfuse patients as clinically indicated. The safety of erythropoiesis stimulating agents for the treatment of anemia in patients with von Hippel-Landau disease receiving belzutifan has not been established. Mean plasma erythropoietin (EPO) concentrations were decreased approximately 60% from baseline after 2 weeks of consecutive belzutifan administration; reductions in EPO were dose- and exposure-dependent. The incidence of grade 3 anemia increased with higher belzutifan exposure in patients with baseline hemoglobin levels less than 12 mg/dL. Mean EPO levels gradually returned to baseline after 12 weeks of treatment.
Treatment with belzutifan can cause severe hypoxia requiring supplemental oxygen or hospitalization. Hypoxia occurred in 15% of patients with renal cell cancer treated with belzutifan compared with 1.4% of those who received everolimus in a randomized clinical trial (grade 3 or 4, 10% vs. 1.4%); 69% required treatment with supplemental oxygen. Hypoxemia occurred in 1.6% of belzutifan-treated patients with von Hippel-Landau disease in a single-arm clinical trial. Monitor oxygen saturation at baseline and periodically during treatment. Consider an interruption of therapy and possible dose reduction for patients with decreased oxygen saturation with exercise (e.g., pulse oximeter less than 88% or PaO2 55 mmHg or less). An interruption of therapy followed by dose reduction or discontinuation of therapy is necessary for patients with decreased oxygen saturation at rest. Permanently discontinue belzutifan therapy if life-threatening or recurrent symptomatic hypoxia occur. Patients should immediately report signs and symptoms of hypoxia to their health care provider.
Fatigue was reported in 43% to 64% of patients treated with belzutifan in clinical trials (grade 3 or 4, 3.2% to 5%).
Headache (12% vs. 8%; grade 3 or 4, 0.5% vs. 0.3%) and dizziness (11% vs. 1.9%) were reported more often in patients treated with belzutifan compared with everolimus in a randomized clinical trial. Headache was also reported in 39% and dizziness in 38% of belzutifan-treated patients in an open-label trial.
Nausea (17% vs. 11%; grade 3 or 4, 0.5% vs. 0.3%), constipation (15% vs. 8%), vomiting (11% vs. 8%; grade 3 or 4, 0.8% vs. 0.8%), and abdominal pain (10% vs. 8%; grade 3 or 4, 0.8% vs. 0.3%) occurred more often in patients treated with belzutifan compared with everolimus in a randomized clinical trial; diarrhea was reported in 11% of belzutifan-treated patients compared with 19% of those who received everolimus (grade 3 or 4, 1.3% vs. 1.4%). Nausea (31%), constipation (13%), and abdominal pain (13%) were also reported in patients who received belzutifan in a single-arm trial.
Blurred vision (4%), decreased visual acuity (1.1%), visual impairment (0.5%), and retinal detachment (0.3%) occurred in patients treated with belzutifan in a randomized clinical trial. Visual impairment including blurred vision, central retinal vein occlusion, and retinal detachment was reported in 21% (grade 3 or 4, 3.3%) of patients who received belzutifan in another single-arm trial; central reginal vein occlusion and retinal detachment each occurred in 1 patient.
Serious cases of pneumonia occurred in 3.5% of patients treated with belzutifan in a randomized clinical trial. Upper respiratory tract infection was reported in 21% of patients in a single-arm clinical trial; dosage interruptions also occurred due to influenza-like illness and COVID-19.
Dyspnea was reported in 16% to 20% of patients treated with belzutifan in 2 clinical trials (grade 3 or 4, 1.6%).
Musculoskeletal pain was reported in 34% of patients treated with belzutifan compared with 27% of those who received everolimus in a randomized clinical trial (grade 3 or 4, 1.1% vs. 2.2%). Arthralgia (18%), myalgia (16%), and general musculoskeletal pain were reported in patients in clinical trials.
Hypertension occurred in 6% to 13% (grade 3 or 4, 3.3% or less) of patients treated with belzutifan in clinical trials.
Edema occurred in 20% of patients treated with belzutifan compared with 23% of those who received everolimus in a randomized clinical trial (grade 3 or 4, 0.5% vs. 0.6%); weight gain occurred in 5% to 12% of belzutifan-treated patients in 2 clinical trials (grade 3 or 4, 1.6% or less).
Elevated hepatic enzymes including increased ALT (32% vs. 40%; grade 3 or 4, 2.2% vs. 1.1%) and increased AST (27% vs. 38%; grade 3 or 4, 2.2% vs. 2%) occurred less frequently in renal cell cancer patients treated with belzutifan compared with those who received everolimus in a randomized clinical 16% to 20% of belzutifan-treated patients in a single-arm trial.
Electrolyte abnormalities including hyperglycemia, hyperkalemia, hypocalcemia, hypoglycemia, hyponatremia, and hypophosphatemia have been reported in patients treated with belzutifan. In a randomized clinical trial, an increased from baseline in potassium (29% vs. 20%; grade 3 or 4, 2.5% vs. 2.8%) and a decrease from baseline in glucose (22% vs. 19%; grade 3 or 4, 1.1% vs. 1.1%) occurred more frequently in patients with renal cell cancer treated with belzutifan compared with those who received everolimus; an increase in creatinine (34% vs. 43%; grade 3 or 4, 4.7% vs. 5.1%), decrease in sodium (31% vs. 36%; grade 3 or 4, 1.6% vs. 0.8%), and decrease in calcium (21% vs. 45%; grade 3 or 4, 1.1% vs. 3.1%) were more common in the everolimus arm of this study. An increase in creatinine (64%) and glucose (34%; grade 3 or 4, 4.9%) and decreases in corrected calcium (10%) and phosphate (10%; grade 3 or 4, 1.6%) were also reported in belzutifan-treated patients in a single-arm trial.
Anaphylaxis (anaphylactoid reactions) was reported in 1 patient in a single-arm trial.
Decreased appetite/anorexia was reported in 13% of patients treated with belzutifan compared with 16% of those who received everolimus (grade 3 or 4, 1.1% vs. 0%) in a randomized clinical trial.
Bleeding occurred in 9% of patients treated with belzutifan in a randomized clinical trial, with serious cases reported in 3% of these patients; intracranial bleeding occurred in 0.8% of belzutifan-treated patients.
Pleural effusion occurred in 2.2% of patients treated with belzutifan in a randomized clinical trial.
Rash occurred in 8% of patients treated with belzutifan in a randomized clinical trial.
Lymphopenia and leukopenia have been reported in patients treated with belzutifan in clinical trials. In a randomized clinical trial, a decrease in lymphocytes from baseline occurred in 34% of patients with renal cell cancer treated with belzutifan compared with 53% of those who received everolimus (grade 3 or 4, 8% vs. 20%). Decreased leukocytes were reported in 11% of belzutifan-treated patients in a single-arm trial.
Anemia commonly occurs in patients treated with belzutifan; severe anemia requiring blood transfusion can also occur. Monitor patients for anemia at baseline and periodically during treatment. An interruption of therapy, dose reduction, or discontinuation of therapy is necessary for patients with a hemoglobin less than 8 g/dL; transfuse patients as clinically indicated. The safety of erythropoiesis stimulating agents for the treatment of anemia in patients with von Hippel-Lindau disease treated with belzutifan has not been established.
Treatment with belzutifan can cause severe hypoxemia requiring supplemental oxygen or hospitalization. Monitor oxygen saturation at baseline and periodically during treatment. Consider an interruption of therapy and possible dose reduction for patients with decreased oxygen saturation with exercise (e.g., pulse oximeter less than 88% or PaO2 55 mmHg or less). An interruption of therapy followed by dose reduction or discontinuation of therapy is necessary for patients with decreased oxygen saturation at rest. Permanently discontinue belzutifan therapy if life-threatening or recurrent symptomatic hypoxia occur. Patients should immediately report signs and symptoms of hypoxia to their health care provider.
Patients who are dual UGT2B17 and CYP2C19 poor metabolizers have higher belzutifan exposures, which may increase the incidence and severity of adverse reactions. Closely monitor these patients for adverse reactions.
Pregnancy should be avoided by females of reproductive potential during belzutifan treatment and for at least 1 week after the last dose. Although there are no adequately controlled studies in pregnant women, belzutifan can cause fetal harm or death when administered during pregnancy based on animal studies. Women who are pregnant or who become pregnant while receiving belzutifan should be apprised of the potential hazard to the fetus. In an animal reproduction study, oral administration of belzutifan to pregnant rats during organogenesis caused embryofetal lethality at maternal exposures approximate to the human exposure (AUC) at the recommended dose. Reduced fetal body weight, and fetal rib malformations, and reduced skeletal ossification occurred at maternal exposures of 0.2 times the human exposure at the recommended dose or higher.
Geriatric patients may be at an increased risk of experiencing adverse reactions related to belzutifan treatment. In a randomized clinical trial, dose interruptions occurred in 48% of patients 65 years of age and older compared to 34% of younger patients; dose reductions occurred in 18% and 10% of patients, respectively.
Counsel patients about the reproductive risk and contraception requirements during belzutifan treatment. Belzutifan can be teratogenic if taken by the mother during pregnancy. Females and males with female partners of reproductive potential should avoid pregnancy and use effective non-hormonal contraception during and for at least 1 week after treatment with belzutifan. Belzutifan can render some hormonal contraceptives ineffective. Females of reproductive potential should undergo pregnancy testing prior to initiation of belzutifan. Women who become pregnant while receiving belzutifan should be apprised of the potential hazard to the fetus. Although there are no data regarding the effect of belzutifan on human fertility, male and female infertility has been observed in animal studies; reversibility of the effect on fertility is unknown.
Due to the potential for serious adverse reactions in nursing infants from belzutifan, advise women to discontinue breast-feeding during treatment and for 1 week after the final dose. It is not known whether belzutifan is present in human milk, although many drugs are excreted in human milk.
For the treatment of von Hippel-Lindau disease:
-for the treatment of von Hippel-Lindau disease in patients who require therapy for associated renal cell cancer, central nervous system hemangioblastomas, or pancreatic neuroendocrine tumors (pNET), not requiring immediate surgery:
Oral dosage:
Adults: 120 mg PO once daily until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Patients with von Hippel-Lindau (VHL)-associated renal cell cancer (RCC) were treated with belzutifan in an open-label, noncomparative trial (LITESPARK-004) (n = 61); subsets of enrolled patients had other VHL-associated tumors including CNS hemangioblastomas (n = 24) and pNET (n = 12). Most patients (84%) had VHL Type 1 disease. The overall response rate (ORR) in patients with VHL-associated RCC was 49% (all partial responses), for a median duration that was not reached; 56% of patients had a median duration of response of at least 12 months. The median ORR in patients with CNS hemangioblastomas and pNET was 63% (complete response [CR], 4%) and 83% (CR, 17%), respectively. The duration of response was at least 12 months in 73% of patients with CNS hemangioblastomas and in 50% of patients with pNET. The median time to response (TTR) was 8 months (range, 2.7 to 19 months) in patients with RCC; the TTR was 3.1 months (range, 2.5 to 11 months) in patients with CNS hemangioblastomas and 8.1 months (range, 2.7 to 11 months) in patients with pNET. Deceases in size of CNS hemangioblastoma-associated peri-tumoral cysts and syringes were observed.
For the treatment of renal cell cancer:
-for the treatment of advanced renal cell cancer following treatment with a PD-1 or PD-L1 inhibitor and a VEGF-TK inhibitor:
Oral dosage:
Adults: 120 mg PO once daily until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Treatment with belzutifan significantly improved progression-free survival (PFS) compared with everolimus (5.6 months vs. 5.6 months) in patients with unresectable, locally advanced or metastatic clear cell renal cell cancer that progressed following PD-1 or PD-L1 checkpoint inhibitor therapy and VEGF inhibitor therapy either in sequence or combination in a multicenter, randomized, open-label, phase 3 clinical trial (LITESPARK-005); 22% of patients had favorable, 66% intermediate, and 12% poor IMDC risk categories. The 12-month (33.7% vs. 17.6%) and 18-month (22.5% vs. 9%) PFS rate were also improved in the belzutifan arm. The objective response rate was 22% in patients treated with belzutifan compared with 4% in those who received everolimus (complete response, 3% vs. 0%).
Therapeutic Drug Monitoring:
Dosage Adjustments for Treatment-Related Toxicities:
-First dose reduction: 80 mg PO once daily.
-Second dose reduction: 40 mg PO once daily.
-Third dose reduction: Permanently discontinue therapy.
Anemia
-Hemoglobin less than 8 g/dL or transfusion indicated: Hold belzutifan treatment. When the hemoglobin is 8 g/dL or higher, resume treatment at the same or reduced dose, or discontinue therapy depending on severity. Permanently discontinue therapy in patients who cannot tolerate a dose of 40 mg once daily.
-Life-threatening or urgent intervention indicated: Hold belzutifan treatment. When the hemoglobin is 8 g/dL or higher, resume treatment at a reduced dose or discontinue therapy. The use of erythropoiesis stimulating agents for the treatment of anemia is not recommended as the safety and efficacy in patients receiving belzutifan have not been established. Permanently discontinue therapy in patients who cannot tolerate a dose of 40 mg once daily.
Hypoxia
-Decreased oxygen saturation with exercise (e.g., pulse oximeter less than 88%): Consider withholding therapy. Upon resolution, resume treatment at the same dose or a reduced dose, depending on the severity of hypoxia. Permanently discontinue therapy in patients who cannot tolerate a dose of 40 mg once daily.
-Decreased oxygen saturation at rest (e.g., pulse oximeter less than 88% or Pa02 55 mmHg or less), or urgent intervention indicated: Hold belzutifan therapy. Upon resolution, resume treatment at a reduced dose or discontinue therapy, depending on the severity of hypoxia. Permanently discontinue therapy in patients who cannot tolerate a dose of 40 mg once daily.
-Life-threatening or recurrent symptomatic hypoxia: Permanently discontinue therapy.
Other Adverse Reactions
-Grade 3: Hold belzutifan therapy. Upon resolution to grade 2 or less, consider resuming therapy at a reduced dose. Permanently discontinue therapy if there is a recurrence of grade 3 adverse reactions, or in patients who cannot tolerate a dose of 40 mg once daily.
-Grade 4: Permanently discontinue therapy.
Maximum Dosage Limits:
-Adults
120 mg/day PO.
-Geriatric
120 mg/day PO.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
-Mild hepatic impairment (total bilirubin at the upper limit of normal [ULN] or less and AST greater than ULN; or total bilirubin 1.1 to 1.5 times ULN and any AST): No dosage adjustment necessary.
-Moderate to severe hepatic impairment (total bilirubin greater than 1.5 times ULN and any AST): Belzutifan has not been studied in this population.
Patients with Renal Impairment Dosing
-Mild to moderate renal impairment (eGFR 30 to 89 mL/min/1.73 m2 estimated by MDRD): No dosage adjustment necessary.
-Severe renal impairment (eGFR 15 to 29 mL/min/1.73 m2): Belzutifan has not been studied in this population.
*non-FDA-approved indication
Acetaminophen; Codeine: (Moderate) Monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with belzutifan is necessary; consider increasing the dose of codeine as needed. It is recommended to avoid this combination when codeine is being used for cough. If belzutifan is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Belzutifan is a weak CYP3A inducer. Concomitant use with belzutifan can increase norcodeine levels via increased CYP3A metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Acetaminophen; Hydrocodone: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with belzutifan is necessary; consider increasing the dose of hydrocodone as needed. If belzutifan is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs of respiratory depression and sedation. Hydrocodone is a CYP3A substrate and belzutifan is a weak CYP3A inducer. Concomitant use with CYP3A inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Acetaminophen; Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with belzutifan is necessary; consider increasing the dose of oxycodone as needed. If belzutifan is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A substrate and belzutifan is a weak CYP3A inducer. Concomitant use with CYP3A inducers can decrease oxycodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Alfentanil: (Moderate) Consider an increased dose of alfentanil and monitor for evidence of opioid withdrawal if coadministration with belzutifan is necessary. If belzutifan is discontinued, consider reducing the alfentanil dosage and monitor for evidence of respiratory depression. Coadministration of a weak CYP3A inducer like belzutifan with alfentanil, a CYP3A substrate, may decrease exposure to alfentanil resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to alfentanil. Alfentanil plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
Amoxicillin; Clarithromycin; Omeprazole: (Moderate) Monitor for anemia and hypoxia if concomitant use of omeprazole with belzutifan is necessary due to increased plasma exposure of belzutifan which may increase the incidence and severity of adverse reactions. Reduce the dose of belzutifan as recommended if anemia or hypoxia occur. Belzutifan is a CYP2C19 substrate and omeprazole is a CYP2C19 inhibitor.
Armodafinil: (Moderate) Monitor for anemia and hypoxia if concomitant use of armodafinil with belzutifan is necessary due to increased plasma exposure of belzutifan which may increase the incidence and severity of adverse reactions. Reduce the dose of belzutifan as recommended if anemia or hypoxia occur. Belzutifan is a CYP2C19 substrate and armodafinil is a CYP2C19 inhibitor.
Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with belzutifan is necessary; consider increasing the dose of codeine as needed. It is recommended to avoid this combination when codeine is being used for cough. If belzutifan is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Belzutifan is a weak CYP3A inducer. Concomitant use with belzutifan can increase norcodeine levels via increased CYP3A metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Aspirin, ASA; Omeprazole: (Moderate) Monitor for anemia and hypoxia if concomitant use of omeprazole with belzutifan is necessary due to increased plasma exposure of belzutifan which may increase the incidence and severity of adverse reactions. Reduce the dose of belzutifan as recommended if anemia or hypoxia occur. Belzutifan is a CYP2C19 substrate and omeprazole is a CYP2C19 inhibitor.
Aspirin, ASA; Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with belzutifan is necessary; consider increasing the dose of oxycodone as needed. If belzutifan is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A substrate and belzutifan is a weak CYP3A inducer. Concomitant use with CYP3A inducers can decrease oxycodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Atogepant: (Major) Avoid use of atogepant and belzutifan when atogepant is used for chronic migraine. Use an atogepant dose of 30 or 60 mg PO once daily for episodic migraine if coadministered with belzutifan. Concurrent use may decrease atogepant exposure and reduce efficacy. Atogepant is a CYP3A substrate and belzutifan is a weak CYP3A inducer. Coadministration with a weak CYP3A inducer resulted in a 25% reduction in atogepant overall exposure and a 24% reduction in atogepant peak concentration.
Avanafil: (Major) Coadministration of avanafil with belzutifan is not recommended by the manufacturer of avanafil due to the potential for decreased avanafil efficacy. Avanafil is a CYP3A substrate and belzutifan is a CYP3A inducer. Although the potential effect of CYP inducers on the pharmacokinetics of avanafil has not been evaluated, plasma concentrations may decrease.
Benzhydrocodone; Acetaminophen: (Moderate) Monitor for reduced efficacy of benzhydrocodone and signs of opioid withdrawal if coadministration with belzutifan is necessary; consider increasing the dose of benzhydrocodone as needed. If belzutifan is discontinued, consider a dose reduction of benzhydrocodone and frequently monitor for signs of respiratory depression and sedation. Benzhydrocodone is a prodrug for hydrocodone. Hydrocodone is a CYP3A substrate and belzutifan is a weak CYP3A inducer. Concomitant use with CYP3A inducers can decrease hydrocodone concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Berotralstat: (Moderate) Monitor for anemia and hypoxia if concomitant use of berotralstat with belzutifan is necessary due to increased plasma exposure of belzutifan which may increase the incidence and severity of adverse reactions. Reduce the dose of belzutifan as recommended if anemia or hypoxia occur. Belzutifan is a CYP2C19 substrate and berotralstat is a CYP2C19 inhibitor.
Bortezomib: (Moderate) Monitor for anemia and hypoxia if concomitant use of bortezomib with belzutifan is necessary due to increased plasma exposure of belzutifan which may increase the incidence and severity of adverse reactions. Reduce the dose of belzutifan as recommended if anemia or hypoxia occur. Belzutifan is a CYP2C19 substrate and bortezomib is a CYP2C19 inhibitor.
Buprenorphine: (Moderate) Monitor for decreased efficacy of buprenorphine, and potentially the onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine, if coadministration with belzutifan is necessary; consider increasing the dose of buprenorphine until stable drug effects are achieved. If belzutifan is discontinued, consider a buprenorphine dose reduction and monitor for signs of respiratory depression. Buprenorphine is a CYP3A substrate and belzutifan is a CYP3A inducer.
Buprenorphine; Naloxone: (Moderate) Monitor for decreased efficacy of buprenorphine, and potentially the onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine, if coadministration with belzutifan is necessary; consider increasing the dose of buprenorphine until stable drug effects are achieved. If belzutifan is discontinued, consider a buprenorphine dose reduction and monitor for signs of respiratory depression. Buprenorphine is a CYP3A substrate and belzutifan is a CYP3A inducer.
Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with belzutifan is necessary; consider increasing the dose of codeine as needed. It is recommended to avoid this combination when codeine is being used for cough. If belzutifan is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Belzutifan is a weak CYP3A inducer. Concomitant use with belzutifan can increase norcodeine levels via increased CYP3A metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Butalbital; Aspirin; Caffeine; Codeine: (Moderate) Monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with belzutifan is necessary; consider increasing the dose of codeine as needed. It is recommended to avoid this combination when codeine is being used for cough. If belzutifan is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Belzutifan is a weak CYP3A inducer. Concomitant use with belzutifan can increase norcodeine levels via increased CYP3A metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Carbamazepine: (Moderate) Monitor carbamazepine concentrations closely during coadministration of belzutifan; carbamazepine dose adjustments may be needed. Concomitant use may decrease carbamazepine concentrations. Carbamazepine is a CYP3A substrate and belzutifan is a CYP3A inducer.
Cariprazine: (Major) Coadministration of cariprazine with belzutifan is not recommended as the net effect of CYP3A induction on cariprazine and its metabolites is unclear. Cariprazine is a CYP3A substrate and belzutifan is a weak CYP3A inducer. Coadministration of cariprazine with CYP3A inducers has not been evaluated.
Celecoxib; Tramadol: (Moderate) Monitor for reduced efficacy of tramadol and signs of opioid withdrawal if coadministration with belzutifan is necessary; consider increasing the dose of tramadol as needed. If belzutifan is discontinued, consider a dose reduction of tramadol and frequently monitor for seizures, serotonin syndrome, and signs of respiratory depression and sedation. Tramadol is a CYP3A substrate and belzutifan is a weak CYP3A inducer. Concomitant use with CYP3A inducers can decrease tramadol levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Cenobamate: (Moderate) Monitor for anemia and hypoxia if concomitant use of cenobamate with belzutifan is necessary due to increased plasma exposure of belzutifan which may increase the incidence and severity of adverse reactions. Reduce the dose of belzutifan as recommended if anemia or hypoxia occur. Belzutifan is a CYP2C19 substrate and cenobamate is a CYP2C19 inhibitor.
Chloramphenicol: (Moderate) Monitor for anemia and hypoxia if concomitant use of chloramphenicol with belzutifan is necessary due to increased plasma exposure of belzutifan which may increase the incidence and severity of adverse reactions. Reduce the dose of belzutifan as recommended if anemia or hypoxia occur. Belzutifan is a CYP2C19 substrate and chloramphenicol is a CYP2C19 inhibitor.
Chlorpheniramine; Codeine: (Moderate) Monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with belzutifan is necessary; consider increasing the dose of codeine as needed. It is recommended to avoid this combination when codeine is being used for cough. If belzutifan is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Belzutifan is a weak CYP3A inducer. Concomitant use with belzutifan can increase norcodeine levels via increased CYP3A metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Chlorpheniramine; Hydrocodone: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with belzutifan is necessary; consider increasing the dose of hydrocodone as needed. If belzutifan is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs of respiratory depression and sedation. Hydrocodone is a CYP3A substrate and belzutifan is a weak CYP3A inducer. Concomitant use with CYP3A inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Cimetidine: (Moderate) Monitor for anemia and hypoxia if concomitant use of cimetidine with belzutifan is necessary due to increased plasma exposure of belzutifan which may increase the incidence and severity of adverse reactions. Reduce the dose of belzutifan as recommended if anemia or hypoxia occur. Belzutifan is a CYP2C19 substrate and cimetidine is a CYP2C19 inhibitor.
Clozapine: (Moderate) Monitor for loss of clozapine effectiveness if coadministered with belzutifan. Consideration should be given to increasing the clozapine dose if necessary. When belzutifan is discontinued, reduce the clozapine dose based on clinical response. Belzutifan is a weak inducer of CYP3A, one of the isoenzymes responsible for the metabolism of clozapine.
Codeine: (Moderate) Monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with belzutifan is necessary; consider increasing the dose of codeine as needed. It is recommended to avoid this combination when codeine is being used for cough. If belzutifan is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Belzutifan is a weak CYP3A inducer. Concomitant use with belzutifan can increase norcodeine levels via increased CYP3A metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Codeine; Guaifenesin: (Moderate) Monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with belzutifan is necessary; consider increasing the dose of codeine as needed. It is recommended to avoid this combination when codeine is being used for cough. If belzutifan is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Belzutifan is a weak CYP3A inducer. Concomitant use with belzutifan can increase norcodeine levels via increased CYP3A metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with belzutifan is necessary; consider increasing the dose of codeine as needed. It is recommended to avoid this combination when codeine is being used for cough. If belzutifan is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Belzutifan is a weak CYP3A inducer. Concomitant use with belzutifan can increase norcodeine levels via increased CYP3A metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Codeine; Phenylephrine; Promethazine: (Moderate) Monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with belzutifan is necessary; consider increasing the dose of codeine as needed. It is recommended to avoid this combination when codeine is being used for cough. If belzutifan is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Belzutifan is a weak CYP3A inducer. Concomitant use with belzutifan can increase norcodeine levels via increased CYP3A metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Codeine; Promethazine: (Moderate) Monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with belzutifan is necessary; consider increasing the dose of codeine as needed. It is recommended to avoid this combination when codeine is being used for cough. If belzutifan is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Belzutifan is a weak CYP3A inducer. Concomitant use with belzutifan can increase norcodeine levels via increased CYP3A metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Conjugated Estrogens: (Major) Women taking both estrogens and belzutifan should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed belzutifan. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of belzutifan. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on belzutifan, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and belzutifan is a weak CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
Conjugated Estrogens; Bazedoxifene: (Major) Women taking both estrogens and belzutifan should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed belzutifan. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of belzutifan. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on belzutifan, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and belzutifan is a weak CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
Conjugated Estrogens; Medroxyprogesterone: (Major) Women taking both estrogens and belzutifan should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed belzutifan. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of belzutifan. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on belzutifan, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and belzutifan is a weak CYP3A4 inducer. Concurrent administration may increase estrogen elimination. (Major) Women taking both progestins and belzutifan should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed belzutifan. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of belzutifan. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and belzutifan is a weak CYP3A4 inducer.
Cyclosporine: (Moderate) Closely monitor cyclosporine concentrations and adjust the dose of cyclosporine as appropriate if coadministration with belzutifan is necessary. Concurrent use may decrease cyclosporine exposure resulting in decreased efficacy. Cyclosporine is extensively metabolized by CYP3A and has a narrow therapeutic index; belzutifan is a weak CYP3A inducer.
Desogestrel; Ethinyl Estradiol: (Major) Women taking both estrogens and belzutifan should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed belzutifan. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of belzutifan. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on belzutifan, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and belzutifan is a weak CYP3A4 inducer. Concurrent administration may increase estrogen elimination. (Major) Women taking both progestins and belzutifan should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed belzutifan. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of belzutifan. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and belzutifan is a weak CYP3A4 inducer.
Diazepam: (Moderate) Monitor patients for decreased efficacy of diazepam if coadministration with belzutifan is necessary. Concurrent use may decrease diazepam exposure. Diazepam is a CYP3A substrate and belzutifan is a CYP3A inducer.
Dienogest; Estradiol valerate: (Major) Women taking both estrogens and belzutifan should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed belzutifan. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of belzutifan. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on belzutifan, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and belzutifan is a weak CYP3A4 inducer. Concurrent administration may increase estrogen elimination. (Major) Women taking both progestins and belzutifan should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed belzutifan. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of belzutifan. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and belzutifan is a weak CYP3A4 inducer.
Doravirine: (Moderate) Concurrent administration of doravirine and belzutifan may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A substrate; belzutifan is a weak CYP3A inducer.
Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Moderate) Concurrent administration of doravirine and belzutifan may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A substrate; belzutifan is a weak CYP3A inducer.
Drospirenone: (Major) Women taking both progestins and belzutifan should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed belzutifan. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of belzutifan. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and belzutifan is a weak CYP3A4 inducer.
Drospirenone; Estetrol: (Major) Women taking both progestins and belzutifan should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed belzutifan. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of belzutifan. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and belzutifan is a weak CYP3A4 inducer.
Drospirenone; Estradiol: (Major) Women taking both estrogens and belzutifan should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed belzutifan. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of belzutifan. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on belzutifan, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and belzutifan is a weak CYP3A4 inducer. Concurrent administration may increase estrogen elimination. (Major) Women taking both progestins and belzutifan should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed belzutifan. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of belzutifan. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and belzutifan is a weak CYP3A4 inducer.
Drospirenone; Ethinyl Estradiol: (Major) Women taking both estrogens and belzutifan should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed belzutifan. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of belzutifan. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on belzutifan, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and belzutifan is a weak CYP3A4 inducer. Concurrent administration may increase estrogen elimination. (Major) Women taking both progestins and belzutifan should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed belzutifan. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of belzutifan. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and belzutifan is a weak CYP3A4 inducer.
Drospirenone; Ethinyl Estradiol; Levomefolate: (Major) Women taking both estrogens and belzutifan should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed belzutifan. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of belzutifan. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on belzutifan, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and belzutifan is a weak CYP3A4 inducer. Concurrent administration may increase estrogen elimination. (Major) Women taking both progestins and belzutifan should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed belzutifan. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of belzutifan. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and belzutifan is a weak CYP3A4 inducer.
Efavirenz: (Moderate) Monitor for anemia and hypoxia if concomitant use of efavirenz with belzutifan is necessary due to increased plasma exposure of belzutifan which may increase the incidence and severity of adverse reactions. Reduce the dose of belzutifan as recommended if anemia or hypoxia occur. Belzutifan is a CYP2C19 substrate and efavirenz is a CYP2C19 inhibitor.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Monitor for anemia and hypoxia if concomitant use of efavirenz with belzutifan is necessary due to increased plasma exposure of belzutifan which may increase the incidence and severity of adverse reactions. Reduce the dose of belzutifan as recommended if anemia or hypoxia occur. Belzutifan is a CYP2C19 substrate and efavirenz is a CYP2C19 inhibitor.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Monitor for anemia and hypoxia if concomitant use of efavirenz with belzutifan is necessary due to increased plasma exposure of belzutifan which may increase the incidence and severity of adverse reactions. Reduce the dose of belzutifan as recommended if anemia or hypoxia occur. Belzutifan is a CYP2C19 substrate and efavirenz is a CYP2C19 inhibitor.
Elagolix: (Moderate) Monitor for anemia and hypoxia if concomitant use of elagolix with belzutifan is necessary due to increased plasma exposure of belzutifan which may increase the incidence and severity of adverse reactions. Reduce the dose of belzutifan as recommended if anemia or hypoxia occur. Belzutifan is a CYP2C19 substrate and elagolix is a CYP2C19 inhibitor.
Elagolix; Estradiol; Norethindrone acetate: (Major) Women taking both estrogens and belzutifan should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed belzutifan. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of belzutifan. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on belzutifan, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and belzutifan is a weak CYP3A4 inducer. Concurrent administration may increase estrogen elimination. (Major) Women taking both progestins and belzutifan should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed belzutifan. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of belzutifan. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and belzutifan is a weak CYP3A4 inducer. (Moderate) Monitor for anemia and hypoxia if concomitant use of elagolix with belzutifan is necessary due to increased plasma exposure of belzutifan which may increase the incidence and severity of adverse reactions. Reduce the dose of belzutifan as recommended if anemia or hypoxia occur. Belzutifan is a CYP2C19 substrate and elagolix is a CYP2C19 inhibitor.
Enasidenib: (Moderate) Monitor for anemia and hypoxia if concomitant use of enasidenib with belzutifan is necessary due to increased plasma exposure of belzutifan which may increase the incidence and severity of adverse reactions. Reduce the dose of belzutifan as recommended if anemia or hypoxia occur. Belzutifan is a CYP2C19 substrate and enasidenib is a CYP2C19 inhibitor.
Eslicarbazepine: (Moderate) Monitor for anemia and hypoxia if concomitant use of eslicarbazepine with belzutifan is necessary due to increased plasma exposure of belzutifan which may increase the incidence and severity of adverse reactions. Reduce the dose of belzutifan as recommended if anemia or hypoxia occur. Belzutifan is a CYP2C19 substrate and eslicarbazepine is a CYP2C19 inhibitor.
Esomeprazole: (Moderate) Monitor for anemia and hypoxia if concomitant use of esomeprazole with belzutifan is necessary due to increased plasma exposure of belzutifan which may increase the incidence and severity of adverse reactions. Reduce the dose of belzutifan as recommended if anemia or hypoxia occur. Belzutifan is a CYP2C19 substrate and esomeprazole is a CYP2C19 inhibitor.
Esterified Estrogens: (Major) Women taking both estrogens and belzutifan should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed belzutifan. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of belzutifan. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on belzutifan, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and belzutifan is a weak CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
Esterified Estrogens; Methyltestosterone: (Major) Women taking both estrogens and belzutifan should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed belzutifan. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of belzutifan. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on belzutifan, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and belzutifan is a weak CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
Estradiol: (Major) Women taking both estrogens and belzutifan should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed belzutifan. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of belzutifan. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on belzutifan, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and belzutifan is a weak CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
Estradiol; Levonorgestrel: (Major) Women taking both estrogens and belzutifan should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed belzutifan. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of belzutifan. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on belzutifan, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and belzutifan is a weak CYP3A4 inducer. Concurrent administration may increase estrogen elimination. (Major) Women taking both progestins and belzutifan should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed belzutifan. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of belzutifan. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and belzutifan is a weak CYP3A4 inducer.
Estradiol; Norethindrone: (Major) Women taking both estrogens and belzutifan should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed belzutifan. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of belzutifan. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on belzutifan, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and belzutifan is a weak CYP3A4 inducer. Concurrent administration may increase estrogen elimination. (Major) Women taking both progestins and belzutifan should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed belzutifan. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of belzutifan. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and belzutifan is a weak CYP3A4 inducer.
Estradiol; Norgestimate: (Major) Women taking both estrogens and belzutifan should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed belzutifan. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of belzutifan. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on belzutifan, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and belzutifan is a weak CYP3A4 inducer. Concurrent administration may increase estrogen elimination. (Major) Women taking both progestins and belzutifan should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed belzutifan. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of belzutifan. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and belzutifan is a weak CYP3A4 inducer.
Estradiol; Progesterone: (Major) Women taking both estrogens and belzutifan should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed belzutifan. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of belzutifan. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on belzutifan, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and belzutifan is a weak CYP3A4 inducer. Concurrent administration may increase estrogen elimination. (Major) Women taking both progestins and belzutifan should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed belzutifan. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of belzutifan. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and belzutifan is a weak CYP3A4 inducer.
Estrogens affected by CYP3A inducers: (Major) Women taking both estrogens and belzutifan should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed belzutifan. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of belzutifan. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on belzutifan, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and belzutifan is a weak CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
Estropipate: (Major) Women taking both estrogens and belzutifan should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed belzutifan. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of belzutifan. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on belzutifan, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and belzutifan is a weak CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
Ethinyl Estradiol; Norelgestromin: (Major) Women taking both estrogens and belzutifan should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed belzutifan. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of belzutifan. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on belzutifan, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and belzutifan is a weak CYP3A4 inducer. Concurrent administration may increase estrogen elimination. (Major) Women taking both progestins and belzutifan should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed belzutifan. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of belzutifan. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and belzutifan is a weak CYP3A4 inducer.
Ethinyl Estradiol; Norethindrone Acetate: (Major) Women taking both estrogens and belzutifan should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed belzutifan. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of belzutifan. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on belzutifan, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and belzutifan is a weak CYP3A4 inducer. Concurrent administration may increase estrogen elimination. (Major) Women taking both progestins and belzutifan should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed belzutifan. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of belzutifan. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and belzutifan is a weak CYP3A4 inducer.
Ethinyl Estradiol; Norgestrel: (Major) Women taking both estrogens and belzutifan should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed belzutifan. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of belzutifan. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on belzutifan, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and belzutifan is a weak CYP3A4 inducer. Concurrent administration may increase estrogen elimination. (Major) Women taking both progestins and belzutifan should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed belzutifan. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of belzutifan. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and belzutifan is a weak CYP3A4 inducer.
Ethynodiol Diacetate; Ethinyl Estradiol: (Major) Women taking both estrogens and belzutifan should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed belzutifan. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of belzutifan. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on belzutifan, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and belzutifan is a weak CYP3A4 inducer. Concurrent administration may increase estrogen elimination. (Major) Women taking both progestins and belzutifan should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed belzutifan. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of belzutifan. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and belzutifan is a weak CYP3A4 inducer.
Etonogestrel: (Major) Women taking both progestins and belzutifan should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed belzutifan. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of belzutifan. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and belzutifan is a weak CYP3A4 inducer.
Etonogestrel; Ethinyl Estradiol: (Major) Women taking both estrogens and belzutifan should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed belzutifan. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of belzutifan. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on belzutifan, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and belzutifan is a weak CYP3A4 inducer. Concurrent administration may increase estrogen elimination. (Major) Women taking both progestins and belzutifan should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed belzutifan. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of belzutifan. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and belzutifan is a weak CYP3A4 inducer.
Etravirine: (Moderate) Monitor for anemia and hypoxia if concomitant use of etravirine with belzutifan is necessary due to increased plasma exposure of belzutifan which may increase the incidence and severity of adverse reactions. Reduce the dose of belzutifan as recommended if anemia or hypoxia occur. Belzutifan is a CYP2C19 substrate and etravirine is a CYP2C19 inhibitor.
Fedratinib: (Moderate) Monitor for anemia and hypoxia if concomitant use of fedratinib with belzutifan is necessary due to increased plasma exposure of belzutifan which may increase the incidence and severity of adverse reactions. Reduce the dose of belzutifan as recommended if anemia or hypoxia occur. Belzutifan is a CYP2C19 substrate and fedratinib is a CYP2C19 inhibitor.
Felbamate: (Moderate) Monitor for anemia and hypoxia if concomitant use of felbamate with belzutifan is necessary due to increased plasma exposure of belzutifan which may increase the incidence and severity of adverse reactions. Reduce the dose of belzutifan as recommended if anemia or hypoxia occur. Belzutifan is a CYP2C19 substrate and felbamate is a CYP2C19 inhibitor.
Fentanyl: (Moderate) Consider an increased dose of fentanyl and monitor for evidence of opioid withdrawal if concurrent use of belzutifan is necessary. If belzutifan is discontinued, consider reducing the fentanyl dosage and monitor for evidence of respiratory depression. Coadministration of a CYP3A inducer like belzutifan with fentanyl, a CYP3A substrate, may decrease exposure to fentanyl resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to fentanyl. Fentanyl plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
Fexinidazole: (Moderate) Monitor for anemia and hypoxia if concomitant use of fexinidazole with belzutifan is necessary due to increased plasma exposure of belzutifan which may increase the incidence and severity of adverse reactions. Reduce the dose of belzutifan as recommended if anemia or hypoxia occur. Belzutifan is a CYP2C19 substrate and fexinidazole is a CYP2C19 inhibitor.
Fluconazole: (Moderate) Monitor for anemia and hypoxia if concomitant use of fluconazole with belzutifan is necessary due to increased plasma exposure of belzutifan which may increase the incidence and severity of adverse reactions. Reduce the dose of belzutifan as recommended if anemia or hypoxia occur. Belzutifan is a CYP2C19 substrate and fluconazole is a CYP2C19 inhibitor.
Fluoxetine: (Moderate) Monitor for anemia and hypoxia if concomitant use of fluoxetine with belzutifan is necessary due to increased plasma exposure of belzutifan which may increase the incidence and severity of adverse reactions. Reduce the dose of belzutifan as recommended if anemia or hypoxia occur. Belzutifan is a CYP2C19 substrate and fluoxetine is a CYP2C19 inhibitor.
Fluvoxamine: (Moderate) Monitor for anemia and hypoxia if concomitant use of fluvoxamine with belzutifan is necessary due to increased plasma exposure of belzutifan which may increase the incidence and severity of adverse reactions. Reduce the dose of belzutifan as recommended if anemia or hypoxia occur. Belzutifan is a CYP2C19 substrate and fluvoxamine is a CYP2C19 inhibitor.
Homatropine; Hydrocodone: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with belzutifan is necessary; consider increasing the dose of hydrocodone as needed. If belzutifan is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs of respiratory depression and sedation. Hydrocodone is a CYP3A substrate and belzutifan is a weak CYP3A inducer. Concomitant use with CYP3A inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Hydrocodone: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with belzutifan is necessary; consider increasing the dose of hydrocodone as needed. If belzutifan is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs of respiratory depression and sedation. Hydrocodone is a CYP3A substrate and belzutifan is a weak CYP3A inducer. Concomitant use with CYP3A inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Hydrocodone; Ibuprofen: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with belzutifan is necessary; consider increasing the dose of hydrocodone as needed. If belzutifan is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs of respiratory depression and sedation. Hydrocodone is a CYP3A substrate and belzutifan is a weak CYP3A inducer. Concomitant use with CYP3A inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Ibuprofen; Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with belzutifan is necessary; consider increasing the dose of oxycodone as needed. If belzutifan is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A substrate and belzutifan is a weak CYP3A inducer. Concomitant use with CYP3A inducers can decrease oxycodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Isoniazid, INH: (Moderate) Monitor for anemia and hypoxia if concomitant use of isoniazid with belzutifan is necessary due to increased plasma exposure of belzutifan which may increase the incidence and severity of adverse reactions. Reduce the dose of belzutifan as recommended if anemia or hypoxia occur. Belzutifan is a CYP2C19 substrate and isoniazid is a CYP2C19 inhibitor.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Moderate) Monitor for anemia and hypoxia if concomitant use of isoniazid with belzutifan is necessary due to increased plasma exposure of belzutifan which may increase the incidence and severity of adverse reactions. Reduce the dose of belzutifan as recommended if anemia or hypoxia occur. Belzutifan is a CYP2C19 substrate and isoniazid is a CYP2C19 inhibitor.
Isoniazid, INH; Rifampin: (Moderate) Monitor for anemia and hypoxia if concomitant use of isoniazid with belzutifan is necessary due to increased plasma exposure of belzutifan which may increase the incidence and severity of adverse reactions. Reduce the dose of belzutifan as recommended if anemia or hypoxia occur. Belzutifan is a CYP2C19 substrate and isoniazid is a CYP2C19 inhibitor.
Isradipine: (Minor) Monitor for decreased efficacy of isradipine if coadministration with belzutifan is necessary. Concomitant use may decrease isradipine exposure. Isradipine is a CYP3A substrate and belzutifan is a weak CYP3A inducer.
Leuprolide; Norethindrone: (Major) Women taking both progestins and belzutifan should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed belzutifan. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of belzutifan. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and belzutifan is a weak CYP3A4 inducer.
Levonorgestrel: (Major) Women taking both progestins and belzutifan should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed belzutifan. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of belzutifan. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and belzutifan is a weak CYP3A4 inducer.
Levonorgestrel; Ethinyl Estradiol: (Major) Women taking both estrogens and belzutifan should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed belzutifan. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of belzutifan. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on belzutifan, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and belzutifan is a weak CYP3A4 inducer. Concurrent administration may increase estrogen elimination. (Major) Women taking both progestins and belzutifan should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed belzutifan. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of belzutifan. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and belzutifan is a weak CYP3A4 inducer.
Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Major) Women taking both estrogens and belzutifan should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed belzutifan. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of belzutifan. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on belzutifan, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and belzutifan is a weak CYP3A4 inducer. Concurrent administration may increase estrogen elimination. (Major) Women taking both progestins and belzutifan should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed belzutifan. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of belzutifan. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and belzutifan is a weak CYP3A4 inducer.
Levonorgestrel; Ethinyl Estradiol; Ferrous Fumarate: (Major) Women taking both estrogens and belzutifan should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed belzutifan. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of belzutifan. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on belzutifan, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and belzutifan is a weak CYP3A4 inducer. Concurrent administration may increase estrogen elimination. (Major) Women taking both progestins and belzutifan should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed belzutifan. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of belzutifan. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and belzutifan is a weak CYP3A4 inducer.
Lonafarnib: (Moderate) Monitor for anemia and hypoxia if concomitant use of lonafarnib with belzutifan is necessary due to increased plasma exposure of belzutifan which may increase the incidence and severity of adverse reactions. Reduce the dose of belzutifan as recommended if anemia or hypoxia occur. Belzutifan is a CYP2C19 substrate and lonafarnib is a CYP2C19 inhibitor.
Lopinavir; Ritonavir: (Moderate) Monitor for decreased efficacy of ritonavir if coadministered with belzutifan. Concurrent use may decrease the plasma concentrations of ritonavir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Ritonavir is a CYP3A substrate and belzutifan is a weak CYP3A inducer.
Luliconazole: (Moderate) Monitor for anemia and hypoxia if concomitant use of topical luliconazole with belzutifan is necessary due to increased plasma exposure of belzutifan which may increase the incidence and severity of adverse reactions. Reduce the dose of belzutifan as recommended if anemia or hypoxia occur. Belzutifan is a CYP2C19 substrate and topical luliconazole is a CYP2C19 inhibitor.
Lumateperone: (Major) Avoid coadministration of lumateperone and belzutifan as concurrent use may decrease lumateperone exposure which may reduce efficacy. Lumateperone is a CYP3A substrate; belzutifan is a weak CYP3A inducer.
Medroxyprogesterone: (Major) Women taking both progestins and belzutifan should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed belzutifan. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of belzutifan. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and belzutifan is a weak CYP3A4 inducer.
Mefloquine: (Moderate) Use mefloquine with caution if coadministration with belzutifan is necessary as concurrent use may decrease mefloquine exposure and efficacy. Mefloquine is a CYP3A substrate and belzutifan is a weak CYP3A inducer.
Meperidine: (Moderate) Monitor for reduced efficacy of meperidine and signs of opioid withdrawal if coadministration with belzutifan is necessary. Consider increasing the dose of meperidine as needed. If belzutifan is discontinued, consider a dose reduction of meperidine and frequently monitor for signs of respiratory depression and sedation. Meperidine is a substrate of CYP3A; belzutifan is a weak CYP3A inducer. Concomitant use can decrease meperidine exposure resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Methadone: (Moderate) Monitor for reduced efficacy of methadone and signs of opioid withdrawal if coadministration with belzutifan is necessary. Consider increasing the dose of methadone as needed. If belzutifan is discontinued, consider a dose reduction of methadone and frequently monitor for signs of respiratory depression and sedation. Methadone is a substrate of CYP3A, CYP2B6, CYP2C19, CYP2C9, and CYP2D6; belzutifan is a weak CYP3A inducer. Concomitant use can decrease methadone exposure resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Modafinil: (Moderate) Monitor for anemia and hypoxia if concomitant use of modafinil with belzutifan is necessary due to increased plasma exposure of belzutifan which may increase the incidence and severity of adverse reactions. Reduce the dose of belzutifan as recommended if anemia or hypoxia occur. Belzutifan is a CYP2C19 substrate and modafinil is a CYP2C19 inhibitor.
Nanoparticle Albumin-Bound Paclitaxel: (Moderate) Monitor for decreased efficacy of nab-paclitaxel if coadministration with belzutifan is necessary due to the risk of decreased plasma concentrations of paclitaxel. Nab-paclitaxel is a CYP3A substrate and belzutifan is a weak CYP3A inducer.
Nanoparticle Albumin-Bound Sirolimus: (Moderate) Monitor for reduced sirolimus efficacy if sirolimus is coadministered with belzutifan. Concomitant use may decrease sirolimus exposure. Sirolimus is a CYP3A substrate and belzutifan is a weak CYP3A inducer.
Naproxen; Esomeprazole: (Moderate) Monitor for anemia and hypoxia if concomitant use of esomeprazole with belzutifan is necessary due to increased plasma exposure of belzutifan which may increase the incidence and severity of adverse reactions. Reduce the dose of belzutifan as recommended if anemia or hypoxia occur. Belzutifan is a CYP2C19 substrate and esomeprazole is a CYP2C19 inhibitor.
Nicardipine: (Moderate) Monitor for anemia and hypoxia if concomitant use of nicardipine with belzutifan is necessary due to increased plasma exposure of belzutifan which may increase the incidence and severity of adverse reactions. Reduce the dose of belzutifan as recommended if anemia or hypoxia occur. Belzutifan is a CYP2C19 substrate and nicardipine is a CYP2C19 inhibitor.
Nimodipine: (Moderate) Monitor for decreased efficacy of nimodipine if coadministration with belzutifan is necessary as concomitant use may decrease plasma concentrations of nimodipine. Nimodipine is a CYP3A substrate and belzutifan is a weak CYP3A inducer.
Nirmatrelvir; Ritonavir: (Moderate) Monitor for a diminished response to nirmatrelvir if concomitant use of belzutifan is necessary. Concomitant use of nirmatrelvir and belzutifan may reduce the therapeutic effect of nirmatrelvir. Nirmatrelvir is a CYP3A substrate and belzutifan is a weak CYP3A inducer. (Moderate) Monitor for decreased efficacy of ritonavir if coadministered with belzutifan. Concurrent use may decrease the plasma concentrations of ritonavir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Ritonavir is a CYP3A substrate and belzutifan is a weak CYP3A inducer.
Nisoldipine: (Major) Avoid coadministration of nisoldipine with belzutifan as concurrent use may decrease nisoldipine exposure and efficacy. Alternative antihypertensive therapy should be considered. Nisoldipine is a CYP3A substrate and belzutifan is a CYP3A inducer. Coadministration with a strong CYP3A inducer lowered nisoldipine plasma concentrations to undetectable levels.
Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Major) Women taking both estrogens and belzutifan should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed belzutifan. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of belzutifan. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on belzutifan, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and belzutifan is a weak CYP3A4 inducer. Concurrent administration may increase estrogen elimination. (Major) Women taking both progestins and belzutifan should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed belzutifan. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of belzutifan. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and belzutifan is a weak CYP3A4 inducer.
Norethindrone: (Major) Women taking both progestins and belzutifan should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed belzutifan. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of belzutifan. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and belzutifan is a weak CYP3A4 inducer.
Norethindrone; Ethinyl Estradiol: (Major) Women taking both estrogens and belzutifan should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed belzutifan. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of belzutifan. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on belzutifan, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and belzutifan is a weak CYP3A4 inducer. Concurrent administration may increase estrogen elimination. (Major) Women taking both progestins and belzutifan should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed belzutifan. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of belzutifan. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and belzutifan is a weak CYP3A4 inducer.
Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Major) Women taking both estrogens and belzutifan should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed belzutifan. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of belzutifan. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on belzutifan, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and belzutifan is a weak CYP3A4 inducer. Concurrent administration may increase estrogen elimination. (Major) Women taking both progestins and belzutifan should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed belzutifan. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of belzutifan. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and belzutifan is a weak CYP3A4 inducer.
Norgestimate; Ethinyl Estradiol: (Major) Women taking both estrogens and belzutifan should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed belzutifan. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of belzutifan. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on belzutifan, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and belzutifan is a weak CYP3A4 inducer. Concurrent administration may increase estrogen elimination. (Major) Women taking both progestins and belzutifan should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed belzutifan. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of belzutifan. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and belzutifan is a weak CYP3A4 inducer.
Norgestrel: (Major) Women taking both progestins and belzutifan should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed belzutifan. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of belzutifan. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and belzutifan is a weak CYP3A4 inducer.
Olanzapine; Fluoxetine: (Moderate) Monitor for anemia and hypoxia if concomitant use of fluoxetine with belzutifan is necessary due to increased plasma exposure of belzutifan which may increase the incidence and severity of adverse reactions. Reduce the dose of belzutifan as recommended if anemia or hypoxia occur. Belzutifan is a CYP2C19 substrate and fluoxetine is a CYP2C19 inhibitor.
Omeprazole: (Moderate) Monitor for anemia and hypoxia if concomitant use of omeprazole with belzutifan is necessary due to increased plasma exposure of belzutifan which may increase the incidence and severity of adverse reactions. Reduce the dose of belzutifan as recommended if anemia or hypoxia occur. Belzutifan is a CYP2C19 substrate and omeprazole is a CYP2C19 inhibitor.
Omeprazole; Amoxicillin; Rifabutin: (Moderate) Monitor for anemia and hypoxia if concomitant use of omeprazole with belzutifan is necessary due to increased plasma exposure of belzutifan which may increase the incidence and severity of adverse reactions. Reduce the dose of belzutifan as recommended if anemia or hypoxia occur. Belzutifan is a CYP2C19 substrate and omeprazole is a CYP2C19 inhibitor.
Omeprazole; Sodium Bicarbonate: (Moderate) Monitor for anemia and hypoxia if concomitant use of omeprazole with belzutifan is necessary due to increased plasma exposure of belzutifan which may increase the incidence and severity of adverse reactions. Reduce the dose of belzutifan as recommended if anemia or hypoxia occur. Belzutifan is a CYP2C19 substrate and omeprazole is a CYP2C19 inhibitor.
Oritavancin: (Moderate) Monitor for anemia and hypoxia if concomitant use of oritavancin with belzutifan is necessary due to increased plasma exposure of belzutifan which may increase the incidence and severity of adverse reactions. Reduce the dose of belzutifan as recommended if anemia or hypoxia occur. Belzutifan is a CYP2C19 substrate and oritavancin is a CYP2C19 inhibitor.
Osilodrostat: (Moderate) Monitor for anemia and hypoxia if concomitant use of osilodrostat with belzutifan is necessary due to increased plasma exposure of belzutifan which may increase the incidence and severity of adverse reactions. Reduce the dose of belzutifan as recommended if anemia or hypoxia occur. Belzutifan is a CYP2C19 substrate and osilodrostat is a CYP2C19 inhibitor.
Oxcarbazepine: (Moderate) Monitor for anemia and hypoxia if concomitant use of oxcarbazepine with belzutifan is necessary due to increased plasma exposure of belzutifan which may increase the incidence and severity of adverse reactions. Reduce the dose of belzutifan as recommended if anemia or hypoxia occur. Belzutifan is a CYP2C19 substrate and oxcarbazepine is a CYP2C19 inhibitor.
Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with belzutifan is necessary; consider increasing the dose of oxycodone as needed. If belzutifan is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A substrate and belzutifan is a weak CYP3A inducer. Concomitant use with CYP3A inducers can decrease oxycodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Paclitaxel: (Moderate) Monitor for decreased efficacy of paclitaxel if coadministration with belzutifan is necessary due to the risk of decreased plasma concentrations of paclitaxel. Paclitaxel is a CYP3A substrate and belzutifan is a weak CYP3A inducer.
Phentermine; Topiramate: (Moderate) Monitor for anemia and hypoxia if concomitant use of topiramate with belzutifan is necessary due to increased plasma exposure of belzutifan which may increase the incidence and severity of adverse reactions. Reduce the dose of belzutifan as recommended if anemia or hypoxia occur. Belzutifan is a CYP2C19 substrate and topiramate is a CYP2C19 inhibitor.
Pirtobrutinib: (Moderate) Monitor for anemia and hypoxia if concomitant use of pirtobrutinib with belzutifan is necessary due to increased plasma exposure of belzutifan which may increase the incidence and severity of adverse reactions. Reduce the dose of belzutifan as recommended if anemia or hypoxia occur. Belzutifan is a CYP2C19 substrate and pirtobrutinib is a CYP2C19 inhibitor.
Progesterone: (Major) Women taking both progestins and belzutifan should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed belzutifan. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of belzutifan. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and belzutifan is a weak CYP3A4 inducer.
Progestins: (Major) Women taking both progestins and belzutifan should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed belzutifan. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of belzutifan. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and belzutifan is a weak CYP3A4 inducer.
Relugolix; Estradiol; Norethindrone acetate: (Major) Women taking both estrogens and belzutifan should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed belzutifan. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of belzutifan. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on belzutifan, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and belzutifan is a weak CYP3A4 inducer. Concurrent administration may increase estrogen elimination. (Major) Women taking both progestins and belzutifan should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed belzutifan. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of belzutifan. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and belzutifan is a weak CYP3A4 inducer.
Ritonavir: (Moderate) Monitor for decreased efficacy of ritonavir if coadministered with belzutifan. Concurrent use may decrease the plasma concentrations of ritonavir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Ritonavir is a CYP3A substrate and belzutifan is a weak CYP3A inducer.
Rucaparib: (Moderate) Monitor for anemia and hypoxia if concomitant use of rucaparib with belzutifan is necessary due to increased plasma exposure of belzutifan which may increase the incidence and severity of adverse reactions. Reduce the dose of belzutifan as recommended if anemia or hypoxia occur. Belzutifan is a CYP2C19 substrate and rucaparib is a CYP2C19 inhibitor.
Segesterone Acetate; Ethinyl Estradiol: (Major) Women taking both estrogens and belzutifan should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed belzutifan. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of belzutifan. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on belzutifan, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and belzutifan is a weak CYP3A4 inducer. Concurrent administration may increase estrogen elimination. (Major) Women taking both progestins and belzutifan should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed belzutifan. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of belzutifan. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and belzutifan is a weak CYP3A4 inducer.
Sildenafil: (Moderate) Monitor for decreased efficacy of sildenafil if coadministration with belzutifan is necessary as concurrent use may decrease sildenafil exposure. Sildenafil is a sensitive CYP3A substrate and belzutifan is a weak CYP3A inducer. Population pharmacokinetic analysis indicates an approximately 3-fold increase in sildenafil clearance with concomitant use of weak CYP3A inducers.
Sirolimus: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of belzutifan. Concomitant use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A substrate and belzutifan is a weak CYP3A inducer.
Stiripentol: (Moderate) Monitor for anemia and hypoxia if concomitant use of stiripentol with belzutifan is necessary due to increased plasma exposure of belzutifan which may increase the incidence and severity of adverse reactions. Reduce the dose of belzutifan as recommended if anemia or hypoxia occur. Belzutifan is a CYP2C19 substrate and stiripentol is a CYP2C19 inhibitor.
Sufentanil: (Moderate) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if belzutifan must be administered. Monitor for reduced efficacy of sufentanil injection and signs of opioid withdrawal if coadministration with belzutifan is necessary; consider increasing the dose of sufentanil injection as needed. If belzutifan is discontinued, consider a dose reduction of sufentanil injection and frequently monitor for signs or respiratory depression and sedation. Sufentanil is a CYP3A substrate and belzutifan is a weak CYP3A inducer. Concomitant use with CYP3A inducers can decrease sufentanil concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Tacrolimus: (Moderate) Monitor tacrolimus serum concentrations as appropriate if coadministration with belzutifan is necessary; a tacrolimus dose adjustment may be needed. Concurrent administration may decrease tacrolimus concentrations. Tacrolimus is a sensitive CYP3A substrate with a narrow therapeutic range; belzutifan is a weak CYP3A inducer.
Tecovirimat: (Moderate) Monitor for anemia and hypoxia if concomitant use of tecovirimat with belzutifan is necessary due to increased plasma exposure of belzutifan which may increase the incidence and severity of adverse reactions. Reduce the dose of belzutifan as recommended if anemia or hypoxia occur. Belzutifan is a CYP2C19 substrate and tecovirimat is a CYP2C19 inhibitor.
Telmisartan: (Moderate) Monitor for anemia and hypoxia if concomitant use of telmisartan with belzutifan is necessary due to increased plasma exposure of belzutifan which may increase the incidence and severity of adverse reactions. Reduce the dose of belzutifan as recommended if anemia or hypoxia occur. Belzutifan is a CYP2C19 substrate and telmisartan is a CYP2C19 inhibitor.
Telmisartan; Amlodipine: (Moderate) Monitor for anemia and hypoxia if concomitant use of telmisartan with belzutifan is necessary due to increased plasma exposure of belzutifan which may increase the incidence and severity of adverse reactions. Reduce the dose of belzutifan as recommended if anemia or hypoxia occur. Belzutifan is a CYP2C19 substrate and telmisartan is a CYP2C19 inhibitor.
Telmisartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for anemia and hypoxia if concomitant use of telmisartan with belzutifan is necessary due to increased plasma exposure of belzutifan which may increase the incidence and severity of adverse reactions. Reduce the dose of belzutifan as recommended if anemia or hypoxia occur. Belzutifan is a CYP2C19 substrate and telmisartan is a CYP2C19 inhibitor.
Topiramate: (Moderate) Monitor for anemia and hypoxia if concomitant use of topiramate with belzutifan is necessary due to increased plasma exposure of belzutifan which may increase the incidence and severity of adverse reactions. Reduce the dose of belzutifan as recommended if anemia or hypoxia occur. Belzutifan is a CYP2C19 substrate and topiramate is a CYP2C19 inhibitor.
Tramadol: (Moderate) Monitor for reduced efficacy of tramadol and signs of opioid withdrawal if coadministration with belzutifan is necessary; consider increasing the dose of tramadol as needed. If belzutifan is discontinued, consider a dose reduction of tramadol and frequently monitor for seizures, serotonin syndrome, and signs of respiratory depression and sedation. Tramadol is a CYP3A substrate and belzutifan is a weak CYP3A inducer. Concomitant use with CYP3A inducers can decrease tramadol levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Tramadol; Acetaminophen: (Moderate) Monitor for reduced efficacy of tramadol and signs of opioid withdrawal if coadministration with belzutifan is necessary; consider increasing the dose of tramadol as needed. If belzutifan is discontinued, consider a dose reduction of tramadol and frequently monitor for seizures, serotonin syndrome, and signs of respiratory depression and sedation. Tramadol is a CYP3A substrate and belzutifan is a weak CYP3A inducer. Concomitant use with CYP3A inducers can decrease tramadol levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Triclabendazole: (Moderate) Monitor for anemia and hypoxia if concomitant use of triclabendazole with belzutifan is necessary due to increased plasma exposure of belzutifan which may increase the incidence and severity of adverse reactions. Reduce the dose of belzutifan as recommended if anemia or hypoxia occur. Belzutifan is a CYP2C19 substrate and triclabendazole is a CYP2C19 inhibitor.
Ubrogepant: (Major) Increase the initial and second dose of ubrogepant to 100 mg if coadministered with belzutifan as concurrent use may decrease ubrogepant exposure and reduce its efficacy. Ubrogepant is a CYP3A substrate; belzutifan is a weak CYP3A inducer.
Valproic Acid, Divalproex Sodium: (Moderate) Monitor for anemia and hypoxia if concomitant use of valproic acid with belzutifan is necessary due to increased plasma exposure of belzutifan which may increase the incidence and severity of adverse reactions. Reduce the dose of belzutifan as recommended if anemia or hypoxia occur. Belzutifan is a CYP2C19 substrate and valproic acid is a CYP2C19 inhibitor.
Vonoprazan: (Moderate) Monitor for anemia and hypoxia if concomitant use of vonoprazan with belzutifan is necessary due to increased plasma exposure of belzutifan which may increase the incidence and severity of adverse reactions. Reduce the dose of belzutifan as recommended if anemia or hypoxia occur. Belzutifan is a CYP2C19 substrate and vonoprazan is a CYP2C19 inhibitor.
Vonoprazan; Amoxicillin: (Moderate) Monitor for anemia and hypoxia if concomitant use of vonoprazan with belzutifan is necessary due to increased plasma exposure of belzutifan which may increase the incidence and severity of adverse reactions. Reduce the dose of belzutifan as recommended if anemia or hypoxia occur. Belzutifan is a CYP2C19 substrate and vonoprazan is a CYP2C19 inhibitor.
Vonoprazan; Amoxicillin; Clarithromycin: (Moderate) Monitor for anemia and hypoxia if concomitant use of vonoprazan with belzutifan is necessary due to increased plasma exposure of belzutifan which may increase the incidence and severity of adverse reactions. Reduce the dose of belzutifan as recommended if anemia or hypoxia occur. Belzutifan is a CYP2C19 substrate and vonoprazan is a CYP2C19 inhibitor.
Voriconazole: (Moderate) Monitor for anemia and hypoxia if concomitant use of voriconazole with belzutifan is necessary due to increased plasma exposure of belzutifan which may increase the incidence and severity of adverse reactions. Reduce the dose of belzutifan as recommended if anemia or hypoxia occur. Belzutifan is a CYP2C19 substrate and voriconazole is a CYP2C19 inhibitor.
Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with belzutifan is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. The R-enantiomer of warfarin is a CYP3A substrate and belzutifan is a CYP3A inducer. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
The Von Hippel-Lindau (VHL) gene is a tumor suppressor gene that encodes for a tumor suppressor protein (pVHL) that is involved in cellular signaling pathways via regulation of the transcription factor hypoxia-inducible factor (HIF), which regulates genes that promote adaptation to hypoxia. Under normal oxygen levels, pVHL targets HIF-2 alpha for ubiquitin-proteasomal degradation. Hypoxic conditions or lack of functional VHL protein results in the stabilization and accumulation of HIF-2 alpha, leading to sustained expression of molecules including VEGF, PDGF, and TGF-alpha, leading to tumor cell proliferation, tumorigenesis, and angiogenesis. Upon stabilization, HIF-2 alpha translocates into the nucleus, resulting in a transcriptional complex with HIF-1 beta that induces expression of downstream genes including those associated with cellular proliferation, angiogenesis, and tumor growth. Belzutifan binds to HIF-2 alpha, blocking the HIF-2 alpha / HIF-1 beta interaction in conditions of hypoxia or pVHL impairment, leading to reduced transcription and expression of HIF-2 alpha target genes. In vivo, belzutifan demonstrated anti-tumor activity in mouse xenograft models of renal cell cancer.
Belzutifan is administered orally. It is approximately 45% bound to plasma proteins. The estimated mean volume of distribution is 119 L (CV, 28%). The blood-to-plasma ratio of belzutifan is 0.88. The mean clearance is 6 L/hour and the mean elimination half-life is 14 hours. Steady-state is reached after approximately 3 days. After oral administration, approximately 49.6% of a radiolabeled dose of belzutifan was recovered in the urine and 51.7% in the feces, primarily as inactive metabolites.
Affected cytochrome P450 isoenzymes and drug transporters: UGT2B17, CYP2C19, and CYP3A4
Belzutifan is primarily metabolized by UGT2B17 and CYP2C19; it is metabolized to a lesser extent by CYP3A4; it is also a weak inducer of CYP3A4. Additionally, belzutifan is a substrate of P-glycoprotein (P-gp), OATP1B1, and OATP1B3 in vitro; it inhibits MATE2K.
-Route-Specific Pharmacokinetics
Oral Route
The estimated geometric mean steady-state Cmax and AUC of belzutifan are 1.5 mcg/mL (CV, 45%) and 20.4 mcg x hour/mL (CV, 62%), respectively, in patients treated with belzutifan. The Cmax and AUC increased proportionally over a dose range of 20 mg to 120 mg. The median Tmax occurred 1 to 2 hours after administration. A high-fat, high-calorie meal (1,000 calories, 56 g fat, 55 g carbohydrate, and 31 g protein) delayed the Tmax by approximately 2 hours. Food did not have a clinically meaningful effect on the Cmax, and had no effect on the AUC.
-Special Populations
Hepatic Impairment
Mild hepatic impairment (total bilirubin at the upper limit of normal [ULN] or less with AST greater than ULN; or total bilirubin 1.1 to 1.5 times ULN with any AST) does not have a clinically significant effect on the pharmacokinetics of belzutifan. The effect of moderate to severe hepatic impairment (total bilirubin greater than 1.5 times ULN and any AST) on the pharmacokinetics of belzutifan has not been studied.
Renal Impairment
Mild to moderate renal impairment (eGFR 30 to 89 mL/min/1.73 m2 by MDRD) does not have a clinically significant effect on the pharmacokinetics of belzutifan. The effect of severe renal impairment (eGFR 15 to 29 mL/min/1.73 m2) on the pharmacokinetics of belzutifan has not been studied.
Geriatric
Age (19 to 90 years) does not have a clinically significant effect on the pharmacokinetics of belzutifan.
Gender Differences
Sex does not have a clinically significant effect on the pharmacokinetics of belzutifan.
Ethnic Differences
Ethnicity (non-Hispanic, Hispanic) and race (White, Black, Asian, Native American, Pacific Islander) do not have a clinically significant effect on the pharmacokinetics of belzutifan.
Obesity
Body weight (42 to 166 kg) does not have a clinically significant effect on the pharmacokinetics of belzutifan.
Other
Poor metabolizers of UGT2B17 and CYP2C19
Patients who are UGT2B17, CYP2C19, or dual UGT2B17 and CYP2C19 poor metabolizers have a 2.5-fold, 1.3-fold, or 3.2-fold higher steady-state belzutifan AUC, respectively, compared to patients who are UGT2B17 normal (extensive) metabolizers and CYP2C19 non-poor (ultrarapid, rapid, normal, and intermediate) metabolizers. The AUC of midazolam is predicted to decrease up to 70% in patients with higher belzutifan concentrations (e.g., dual poor metabolizers), with belzutifan functioning as a moderate rather than weak CYP3A4 inducer. Poor metabolizers of UGT2B17 who are homozygous for the UGT2B17*2 allele have no UGT2B17 enzyme activity; approximately 15% of White, 6% of Black, and up to 77% of certain Asian populations are UGT2B17 poor metabolizers. Poor metabolizers of CYP2C19 (e.g., *2/*2, *3/*3, *2/*3) have significantly reduced or absent CYP2C19 enzyme activity; approximately 2% of White, 5% of Black, and up to 19% of certain Asian populations are CYP2C19 poor metabolizers. Dual UGT2B17 and CYP2C19 poor metabolizers comprise approximately 0.4% of White, 0.3% of Black, and up to 15% of certain Asian populations.