r metabolizers [see clinical pharmacology (12.3) ]. avoid coadministration of welireg with sensitive cyp3a4 substrates, for which minimal decrease in concentration may lead to therapeutic failures of the substrate. if coadministration cannot be avoided, increase the sensitive cyp3a4 substrate dosage in accordance with its prescribing information. hormonal contraceptives coadministration of welireg with hormonal contraceptives may lead to contraceptive failure or an increase in breakthrough bleeding [see clinical pharmacology (12.3) , use in specific populations (8.3) ] .

[study 001 (n=58)] in patients with advanced solid tumors who received the same dosage of welireg, anemia occurred in 76% of patients and 28% had grade 3 anemia. monitor for anemia before initiation of, and periodically throughout, treatment with welireg. closely monitor patients who are dual ugt2b17 and cyp2c19 poor metabolizers due to potential increases in exposure that may increase the incidence or severity of anemia [see clinical pharmacology (12.5) ]. transfuse patients as clinically indicated. for patients with hemoglobin <9g/dl, withhold welireg until ≥9g/dl, then resume at reduced dose or permanently discontinue welireg, depending on the severity of anemia. for life threatening anemia or when urgent intervention is indicated, withhold welireg until hemoglobin ≥9g/dl, then resume at a reduced dose or permanently discontinue welireg [see dosage and administration (2.2) ] . the use of erythropoiesis stimulating agents (esas) for treatment of anemia is not recommended in patients treated with welireg. for patients treated with welireg who develop anemia, the safety and effectiveness for use of esas have not been established. randomized controlled trials in patients with cancer receiving myelosuppressive chemotherapy with esas have shown that esas increased the risks of death and serious cardiovascular reactions, and decreased progression-free survival and/or overall survival. see the prescribing information for esas for more information. 5.2 hypoxia welireg can cause severe hypoxia that may require discontinuation, supplemental oxygen, or hospitalization [see dosage and administration (2.2) ]. in study 004, hypoxia occurred in 1.6% of patients [see adverse reactions (6.1) ] . in another clinical trial [study 001 (n=58)] in patients with advanced solid tumors who received the same dosage of welireg, hypoxia occurred in 29% of patients, including grade 3 hypoxia in 16%. monitor oxygen saturation before initiation of, and periodically throughout, treatment with welireg. for decreased oxygen saturation with exercise (e.g., pulse oximeter <88% or p a o 2 ≤55 mm hg), consider withholding welireg until pulse oximetry with exercise is greater than 88%, then resume at the same dose or at a reduced dose. for decreased oxygen saturation at rest (e.g., pulse oximeter <88% or pao2 ≤55 mm hg) or urgent intervention indicated, withhold welireg until resolved and resume at a reduced dose or discontinue. for life-threatening hypoxia or for recurrent symptomatic hypoxia, permanently discontinue welireg [see dosage and administration (2.2) ] . advise patients to report signs and symptoms of hypoxia immediately to a healthcare provider. 5.3 embryo-fetal toxicity based on findings in animals, welireg can cause fetal harm when administered to a pregnant woman. in an animal reproduction study, oral administration of belzutifan to pregnant rats during the period of organogenesis caused embryo-fetal lethality, reduced fetal body weight, and fetal skeletal malformations at maternal exposures ≥0.2 times the human exposures (auc) at the recommended dose of 120 mg daily. advise pregnant women and females of reproductive potential of the potential risk to the fetus. advise females of reproductive potential to use effective non-hormonal contraception during treatment with welireg and for 1 week after the last dose, since welireg can render some hormonal contraceptives ineffective [see drug interactions (7.1) ]. advise male patients with female partners of reproductive potential to use effective contraception during treatment with welireg and for 1 week after the last dose [see use in specific populations (8.1 , 8.3) ] .

once daily second dose reduction: welireg 40 mg orally once daily third dose reduction: permanently discontinue table 1: recommended dosage modifications for adverse reactions adverse reaction severity dosage modification anemia [see warnings and precautions (5.1) ] hemoglobin <9 g/dl or transfusion indicated withhold until hemoglobin ≥9g/dl. resume at reduced dose or discontinue depending on the severity of anemia. life-threatening or urgent intervention indicated withhold until hemoglobin ≥9g/dl. resume at a reduced dose or permanently discontinue. hypoxia [see warnings and precautions (5.2) ] decreased oxygen saturation with exercise (e.g., pulse oximeter <88%) consider withholding until resolved. resume at the same dose or at a reduced dose depending on the severity of hypoxia. decreased oxygen saturation at rest (e.g., pulse oximeter <88% or pao 2 ≤55 mm hg) or urgent intervention indicated withhold until resolved. resume at reduced dose or discontinue depending on the severity of hypoxia. life-threatening or recurrent symptomatic hypoxia permanently discontinue. other adverse reactions [see adverse reactions (6) ] grade 3 withhold dosing until resolved to ≤ grade 2. consider resuming at a reduced dose (reduce by 40 mg). permanently discontinue upon recurrence of grade 3. grade 4 permanently discontinue.

or localized to the kidney [see clinical studies (14) ] . patients received welireg 120 mg orally once daily. the median duration of exposure to welireg was 68 weeks (range: 8.4 to 104.7 weeks). serious adverse reactions occurred in 15% of patients who received welireg, including anemia, hypoxia, anaphylaxis reaction, retinal detachment, and central retinal vein occlusion (1 patient each). permanent discontinuation of welireg due to adverse reactions occurred in 3.3% of patients. adverse reactions which resulted in permanent discontinuation of welireg were dizziness and opioid overdose (1.6% each). dosage interruptions of welireg due to an adverse reaction occurred in 39% of patients. adverse reactions which required dosage interruption in >2% of patients were fatigue, decreased hemoglobin, anemia, nausea, abdominal pain, headache, and influenza-like illness. dose reductions of welireg due to an adverse reaction occurred in 13% of patients. the most frequently reported adverse reaction which required dose reduction was fatigue (7%). the most common (≥25%) adverse reactions, including laboratory abnormalities, that occurred in patients who received welireg were decreased hemoglobin, anemia, fatigue, increased creatinine, headache, dizziness, increased glucose, and nausea. table 2 summarizes the adverse reactions reported in patients treated with welireg in study 004. table 2: adverse reactions occurring in ≥10% of patients who received welireg in study 004 adverse reaction welireg n=61 all grades graded per nci ctcae v4.0 (%) grade 3-4 (%) blood and lymphatic anemia 90 7 general fatigue includes fatigue and asthenia 64 5 nervous system headache includes headache and migraine 39 0 dizziness incudes dizziness and vertigo 38 0 gastrointestinal nausea 31 0 constipation 13 0 abdominal pain includes abdominal discomfort, abdominal pain, abdominal pain upper and abdominal pain lower 13 0 eye disorders visual impairment includes visual impairment, vision blurred, central retinal vein occlusion and retinal detachment includes bronchitis, sinusitis, upper respiratory tract infection, and viral upper respiratory infection 21 3.3 infections upper respiratory tract infection Þ 21 0 respiratory, thoracic and mediastinal dyspnea 20 1.6 musculoskeletal and connective tissue arthralgia 18 0 myalgia 16 0 vascular hypertension 13 3.3 metabolism and nutrition weight increased 12 1.6 table 3 summarizes the laboratory abnormalities in study 004. table 3: select laboratory abnormalities (≥10%) that worsened from baseline in patients who received welireg in study 004 laboratory abnormality the denominator used to calculate the rate is based on all patients in the safety analysis population. welireg (n=61) grades 1-4 % grades 3-4 % chemistry increased creatinine 64 0 increased glucose 34 4.9 increased alt 20 0 increased ast 16 0 decreased calcium (corrected) 10 0 decreased phosphate 10 1.6 hematology decreased hemoglobin 93 7 decreased leukocytes 11 0 other clinical trials experience in study 001 (nct02974738), a clinical trial in patients with advanced solid tumors (n=58) treated at the recommended dose in which the median age of enrollment was 62.5 years (range 39-75) and the median number of prior therapies for cancer was 3 (range 1-9), the following additional adverse reactions have been reported following administration of welireg at the recommended dosage: edema, cough, musculoskeletal pain, vomiting, diarrhea, and dehydration.

r metabolizers [see clinical pharmacology (12.3) ]. avoid coadministration of welireg with sensitive cyp3a4 substrates, for which minimal decrease in concentration may lead to therapeutic failures of the substrate. if coadministration cannot be avoided, increase the sensitive cyp3a4 substrate dosage in accordance with its prescribing information. hormonal contraceptives coadministration of welireg with hormonal contraceptives may lead to contraceptive failure or an increase in breakthrough bleeding [see clinical pharmacology (12.3) , use in specific populations (8.3) ] .

n clinically recognized pregnancies is 2–4% and 15–20%, respectively. data animal data in a pilot embryo-fetal development study, pregnant rats received oral doses of 6, 60, or 200 mg/kg/day of belzutifan during the period of organogenesis. belzutifan caused embryo-fetal lethality at doses ≥60 mg/kg/day (approximately 1 time the human exposure at the recommended dose based on auc). reduced fetal body weights, fetal rib malformations, and reduced skeletal ossification occurred at doses of 6 and 60 mg/kg/day (approximately ≥0.2 times the human exposure at the recommended dose based on auc). 8.2 lactation risk summary there are no data on the presence of belzutifan or its metabolites in human milk or their effects on the breastfed child or on milk production. because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with welireg and for 1 week after the last dose. 8.3 females and males of reproductive potential welireg can cause fetal harm when administered to a pregnant woman [see use in specific populations (8.1) ] . pregnancy testing verify the pregnancy status of females of reproductive potential prior to initiating treatment with welireg. contraception females advise females of reproductive potential to use effective non-hormonal contraception during treatment with welireg and for 1 week after the last dose. welireg can render some hormonal contraceptives ineffective [see drug interactions (7.2) ] . males advise males with female partners of reproductive potential to use effective contraception during treatment with welireg and for 1 week after the last dose. infertility based on findings in animals, welireg may impair fertility in males and females of reproductive potential [see nonclinical toxicology (13.1) ] . the reversibility of the effect on fertility is unknown. 8.4 pediatric use safety and effectiveness of welireg have not been established in pediatric patients. 8.5 geriatric use of the patients who received welireg in study 004, 3.3% were ≥65 years old [see clinical studies (14) ] . clinical trials of welireg did not include sufficient numbers of patients aged 65 and older to determine whether they respond differently from younger patients. 8.6 renal impairment no dosage modification of welireg is recommended in patients with mild (egfr 60-89 ml/min/1.73 m 2 estimated by mdrd) and moderate (egfr 30-59 ml/min/1.73 m 2 ) renal impairment [see clinical pharmacology (12.3) ]. welireg has not been studied in patients with severe (egfr 15-29 ml/min/1.73 m 2 ) renal impairment. 8.7 hepatic impairment no dosage modification of welireg is recommended in patients with mild [total bilirubin ≤ upper limit of normal (uln) and aspartate aminotransferase (ast) > uln or total bilirubin >1 to 1.5 x uln and any ast] hepatic impairment. welireg has not been studied in patients with moderate or severe hepatic impairment (total bilirubin >1.5 x uln and any ast) [see clinical pharmacology (12.3) ] . 8.8 dual ugt2b17 and cyp2c19 poor metabolizers patients who are dual ugt2b17 and cyp2c19 poor metabolizers have higher belzutifan exposures, which may increase the incidence and severity of adverse reactions of welireg. closely monitor for adverse reactions in patients who are dual ugt2b17 and cyp2c19 poor metabolizers [see warnings and precautions (5) , adverse reactions (6) , clinical pharmacology (12.5) ] .

regnant rats received oral doses of 6, 60, or 200 mg/kg/day of belzutifan during the period of organogenesis. belzutifan caused embryo-fetal lethality at doses ≥60 mg/kg/day (approximately 1 time the human exposure at the recommended dose based on auc). reduced fetal body weights, fetal rib malformations, and reduced skeletal ossification occurred at doses of 6 and 60 mg/kg/day (approximately ≥0.2 times the human exposure at the recommended dose based on auc).

i-tumor activity in mouse xenograft models of renal cell carcinoma. 12.2 pharmacodynamics reductions in plasma levels of erythropoietin (epo) were observed to be dose- and exposure-dependent at dosages up to 120 mg once daily. the maximum epo suppression occurred following 2 weeks of consecutive dosing of welireg (mean percent decrease from baseline of approximately 60%). mean epo levels gradually returned to baseline values after 12 weeks of treatment. the incidence of grade 3 anemia increased with higher belzutifan exposure in patients with baseline hemoglobin levels <12 g/dl [see warnings and precautions (5.1) ] . cardiac electrophysiology at the recommended dosage, welireg does not cause large mean increases (i.e., >20 msec) in the qt interval. 12.3 pharmacokinetics the mean steady-state (cv%) c max is 1.3 μg/ml (42%) and auc 0-24h is 16.7 μg•hr/ml (52%) in patients with vhl disease-associated rcc. steady state is reached after approximately 3 days. c max and auc increase proportionally over a dose range of 20 mg to 120 mg (0.17 to 1 times the approved recommended dose). absorption the median t max occurs at 1 to 2 hours after administration. effect of food a high-fat, high-calorie meal (total calories approximately 1000 kcal, 56 g fat, 55 g carbohydrate, and 31 g protein) delayed time to reach peak belzutifan concentration by approximately 2 hours, had no clinically meaningful effect on c max , and had no effect on auc. distribution the mean (cv%) steady-state volume of distribution is 130 l (35%). plasma protein binding of belzutifan is 45%. the blood-to-plasma concentration ratio of belzutifan is 0.88. elimination the mean (cv%) clearance is 7.3 l/hr (51%) and the mean elimination half-life is 14 hrs. metabolism belzutifan is primarily metabolized by ugt2b17 and cyp2c19 and to a lesser extent by cyp3a4 [see clinical pharmacology (12.5) ] . specific populations patients who are poor metabolizers of ugt2b17 and cyp2c19 had higher belzutifan auc [see clinical pharmacology (12.5) ] . there were no clinically significant differences in the pharmacokinetics of belzutifan based on age (19 to 84 years), sex, ethnicity (non-hispanic, hispanic), race (white, black, asian, pacific islander), body weight (42 to 166 kg), mild to moderate renal impairment (egfr 30-89 ml/min/1.73 m 2 estimated by mdrd), or mild hepatic impairment (total bilirubin ≤ uln with ast > uln or total bilirubin > uln to 1.5 x uln with any ast). the effect of severe renal impairment (egfr 15-29 ml/min/1.73 m 2 ) and moderate to severe hepatic impairment (total bilirubin > 1.5 x uln and any ast) have not been studied. drug interaction studies clinical studies and model-informed approaches effect of belzutifan on cyp3a substrates: coadministration of welireg 120 mg once daily with midazolam (a sensitive cyp3a4 substrate) decreased the midazolam auc by 40% and the c max by 34%. midazolam auc is predicted to decrease up to 70% in patients with higher belzutifan concentrations (e.g., dual poor metabolizers) [see clinical pharmacology (12.5) ] . in vitro studies cytochrome p450 (cyp) enzymes: belzutifan does not inhibit cyp1a2, cyp2b6, cyp2c8, cyp2c9, cyp2c19, cyp2d6, or cyp3a4. belzutifan does not induce cyp1a2 or cyp2b6. transporter systems: belzutifan is a substrate of p-gp, oatp1b1, and oatp1b3, but is not a substrate of bcrp. belzutifan inhibits mate2k. belzutifan does not inhibit p-gp, bcrp, oatp1b1, oatp1b3, oat1, oat3, oct2, or mate1. 12.5 pharmacogenomics patients who are ugt2b17, cyp2c19, or dual ugt2b17 and cyp2c19 poor metabolizers have 2-, 1.6-, or 3.2-fold higher belzutifan steady state auc 0-24h (respectively) compared to patients who are ugt2b17 normal (extensive) metabolizers and cyp2c19 non-poor (ultrarapid, rapid, normal, and intermediate) metabolizers [see use in specific populations (8.7) ]. ugt2b17 poor metabolizers who are homozygous for the ugt2b17*2 allele have no ugt2b17 enzyme activity. cyp2c19 poor metabolizers (such as *2/*2, *3/*3, *2/*3) have significantly reduced or absent cyp2c19 enzyme activity. approximately 15% of white, 6% of black or african american, and up to 77% of certain asian populations are ugt2b17 poor metabolizers. approximately 2% of white, 5% of black or african american, and up to 19% of certain asian populations are cyp2c19 poor metabolizers. approximately 0.4% of white, 0.3% of black or african american, and up to 15% of certain asian populations are dual ugt2b17 and cyp2c19 poor metabolizers.

belzutifan is primarily metabolized by ugt2b17 and cyp2c19 and to a lesser extent by cyp3a4 [see clinical pharmacology (12.5) ] . specific populations patients who are poor metabolizers of ugt2b17 and cyp2c19 had higher belzutifan auc [see clinical pharmacology (12.5) ] . there were no clinically significant differences in the pharmacokinetics of belzutifan based on age (19 to 84 years), sex, ethnicity (non-hispanic, hispanic), race (white, black, asian, pacific islander), body weight (42 to 166 kg), mild to moderate renal impairment (egfr 30-89 ml/min/1.73 m 2 estimated by mdrd), or mild hepatic impairment (total bilirubin ≤ uln with ast > uln or total bilirubin > uln to 1.5 x uln with any ast). the effect of severe renal impairment (egfr 15-29 ml/min/1.73 m 2 ) and moderate to severe hepatic impairment (total bilirubin > 1.5 x uln and any ast) have not been studied. drug interaction studies clinical studies and model-informed approaches effect of belzutifan on cyp3a substrates: coadministration of welireg 120 mg once daily with midazolam (a sensitive cyp3a4 substrate) decreased the midazolam auc by 40% and the c max by 34%. midazolam auc is predicted to decrease up to 70% in patients with higher belzutifan concentrations (e.g., dual poor metabolizers) [see clinical pharmacology (12.5) ] . in vitro studies cytochrome p450 (cyp) enzymes: belzutifan does not inhibit cyp1a2, cyp2b6, cyp2c8, cyp2c9, cyp2c19, cyp2d6, or cyp3a4. belzutifan does not induce cyp1a2 or cyp2b6. transporter systems: belzutifan is a substrate of p-gp, oatp1b1, and oatp1b3, but is not a substrate of bcrp. belzutifan inhibits mate2k. belzutifan does not inhibit p-gp, bcrp, oatp1b1, oatp1b3, oat1, oat3, oct2, or mate1.

ry period. belzutifan had no adverse effects on female reproductive organs in repeat-dose toxicity studies up to 3-month duration; however, belzutifan caused embryo-fetal lethality (post-implantation loss) in pregnant rats given oral doses ≥60 mg/kg/day (approximately 1 time the human exposure at the recommended dose based on auc) during the period of organogenesis [see use in specific population (8.1) ].

no adverse effects on female reproductive organs in repeat-dose toxicity studies up to 3-month duration; however, belzutifan caused embryo-fetal lethality (post-implantation loss) in pregnant rats given oral doses ≥60 mg/kg/day (approximately 1 time the human exposure at the recommended dose based on auc) during the period of organogenesis [see use in specific population (8.1) ].

e native hawaiian or other pacific islander; 82% had an ecog ps of 0, 16% had an ecog ps of 1, and 1.6% had an ecog ps of 2; and 84% had vhl type i disease. the median diameter of rcc target lesions per central independent review committee (irc) was 2.2 cm (range 1-6.1). median time from initial radiographic diagnosis of vhl-associated rcc tumors that led to enrollment on study 004 to the time of treatment with welireg was 17.9 months (range 2.8-96.7). seventy-seven percent of patients had prior surgical procedures for rcc. the major efficacy endpoint for the treatment of vhl-associated rcc was overall response rate (orr) measured by radiology assessment using recist v1.1 as assessed by irc. additional efficacy endpoints included duration of response (dor), and time to response (ttr). table 4 summarizes the efficacy results for vhl-associated rcc in study 004. table 4: efficacy results (irc assessment) for welireg for vhl-associated rcc efficacy outcome measure welireg n=61 + denotes ongoing response. overall response rate, % (n) (95% ci) 49% (30) all patients with a response were followed for a minimum of 18 months from the start of treatment. (36, 62) complete response 0% partial response 49% duration of response median in months (range) not reached (2.8+, 22+) % (n) with dor ≥ 12 months 56% (17/30) for vhl-associated rcc, median ttr was 8 months (range 2.7, 19). table 5 summarizes the efficacy results for vhl-associated pnet or cns hemangioblastomas in study 004. table 5. efficacy results (irc assessment) for welireg for vhl-associated subgroups with cns hemangioblastomas or pnet endpoint patients with cns hemangioblastomas n=24 number of patients with measurable solid lesions, based on irc assessment. patients with pnet n=12 + denotes ongoing response. overall response rate, % (n) (95% ci) 63%, (15) (41, 81) 83% (10) (52, 98) complete response 4% (1) 17% (2) partial response 58% (14) 67% (8) duration of response median in months (range) not reached (3.7+, 22+) not reached (11+, 19+) % (n) with dor ≥12 months 73% (11/15) 50% (5/10) for vhl-associated cns hemangioblastomas, ttr was 3.1 months (range 2.5, 11). for vhl-associated pnet, median ttr was 8.1 months (range 2.7, 11). decreases in size of cns hemangioblastoma-associated peri-tumoral cysts and syringes were observed.

warnings and precautions (5.3) and use in specific population (8.1) ] . advise females of reproductive potential to use effective non-hormonal contraception during treatment with welireg and for 1 week after the last dose [see use in specific populations (8.3) ] . advise male patients with female partners of reproductive potential to use effective contraception during treatment with welireg and for 1 week after the last dose [see use in specific populations (8.3) ] . lactation advise females not to breastfeed during treatment with welireg and for 1 week after the last dose [see use in specific populations (8.2) ] . infertility advise male and female patients that welireg may impair fertility [see use in specific populations (8.3) ] . dosage and administration instruct patients to take their dose of welireg at the same time each day (once daily). advise patients welireg can be taken with or without food. each tablet should be swallowed whole [see dosage and administration (2.1) ].