DRUG INTERACTIONS-summary

­ UGT2B17 or CYP2C19 Inhibitors: Monitor for signs and symptoms of anemia and hypoxia and reduce the dosage of WELIREG as recommended.

DRUG INTERACTIONS- details-

1. Effects of Other Drugs on WELIREG UGT2B17 or CYP2C19 Inhibitors- Coadministration of WELIREG with inhibitors of UGT2B17 or CYP2C19 increases plasma exposure of belzutifan , which may increase the incidence and severity of adverse reactions of WELIREG. Monitor for anemia and hypoxia and reduce the dosage of WELIREG as recommended

2 Effect of WELIREG on Other Drugs Sensitive CYP3A4 Substrates- Coadministration of WELIREG with CYP3A4 substrates decreases concentrations of CYP3A substrates , which may reduce the efficacy of these substrates. The magnitude of this decrease may be more pronounced in patients who are dual UGT2B17 and CYP2C19 poor metabolizers

 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.

BRIEF SUMMARY

BELZUTIFAN- (Sep 2021)

Indn-    To treat Von Hippal -Lindau(VHL) disease under certain conditions                           

Comp-  Tablets: 40 mg   The recommended dosageis 120 mg administered orally once daily with or without food.

 ADR-  Most common  adverse reactions, including laboratory abnormalities, were decreased hemoglobin, anemia, fatigue, increased creatinine, headache, dizziness, increased glucose, and nausea. 

CI-  None. 

 WARNINGS -

­ • Anemia: Monitor for anemia before initiation of and periodically throughout treatment  . Withhold  until hemoglobin =9g/dL, then resume at reduced dose or discontinue. For life threatening anemia, or for anemia requiring urgent intervention, withhold  until hemoglobin =9g/dL and resume at a reduced dose or permanently discontinue 

Pat Inform-

Anemia-                                                                                                                           Inform patients that  can cause severe anemia that may require blood transfusions and that red blood cell levels will be monitored routinely during treatment.

Contact  healthcare provider if the patient experiences any symptoms suggestive of anemia.

Hypoxia-                                                                                                                             Inform patients that  can cause severe hypoxia that may require discontinuation, supplemental oxygen, or hospitalization; and that oxygen levels will be monitored routinely during treatment.

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U.S. FDA APPROVED DRUGS SURING 2021                                          

Serial No 35

Name of the Drug-    WELIREG

Active Ingredient -   Belzutifan

Pharmacological Classification- To treat Von Hippal -Lindau(VHL) disease under certain conditions                                                                                                                                                                                                                                           

 Date of Approval-          8/13/2021

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use                                    WELIREG safely and effectively.

See full prescribing information for WELIREG. WELIREGTM (belzutifan) tablets, for oral use

Initial U.S. Approval: 2021

WARNING: EMBRYO-FETAL TOXICITY                                                                       See full prescribing information for complete boxed warning.

• Exposure to WELIREG during pregnancy can cause embryo-fetal harm.                         • Verify pregnancy status prior to the initiation of WELIREG.                                              • Advise patients of these risks and the need for effective non-hormonal contraception. WELIREG can render some hormonal contraceptives ineffective.

INDICATIONS AND USAGE-

­ WELIREG is a hypoxia-inducible factor inhibitor indicated for treatment of adult patients with von Hippel-Lindau (VHL) disease who require therapy for associated renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas, or pancreatic neuroendocrine tumors (pNET), not requiring immediate surgery

 ADVERSE REACTIONS-

 Most common (= 25%) adverse reactions, including laboratory abnormalities, were decreased hemoglobin, anemia, fatigue, increased creatinine, headache, dizziness, increased glucose, and nausea. 

CONTRAINDICATIONS-

­ None. 

 WARNINGS AND PRECAUTIONS-

­ • Anemia: Monitor for anemia before initiation of and periodically throughout treatment with WELIREG. Withhold WELIREG until hemoglobin =9g/dL, then resume at reduced dose or discontinue. For life threatening anemia, or for anemia requiring urgent intervention, withhold WELIREG until hemoglobin =9g/dL and resume at a reduced dose or permanently discontinue WELIREG.

• Hypoxia: Monitor oxygen saturation before initiation of, and periodically throughout, treatment with WELIREG. For hypoxia at rest, withhold until resolved, resume at reduced dose, or discontinue depending on severity. For life-threatening hypoxia, permanently discontinue WELIREG.

. DOSAGE AND ADMINISTRATION-

­ The recommended dosage of WELIREG is 120 mg administered orally once daily with or without food.

 DOSAGE FORMS AND STRENGTHS-

 Tablets: 40 mg

PATIENT COUNSELING INFORMATION-

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Anemia-                                                                                                                           Inform patients that WELIREG can cause severe anemia that may require blood transfusions and that red blood cell levels will be monitored routinely during treatment. Advise patients to contact their healthcare provider if the patient experiences any symptoms suggestive of anemia.

Hypoxia-                                                                                                                             Inform patients that WELIREG can cause severe hypoxia that may require discontinuation, supplemental oxygen, or hospitalization; and that oxygen levels will be monitored routinely during treatment. Advise patients to contact their healthcare provider if the patient experiences any symptoms suggestive of hypoxia

 Embryo-Fetal Toxicity-                                                                                                      • Advise pregnant women and females of reproductive potential of the risk to a fetus. Advise females to inform their healthcare provider of a known or suspected pregnancy

 • Advise females of reproductive potential to use effective non-hormonal contraception during treatment with WELIREG and for 1 week after the last dose

 • Advise male patients with female partners of reproductive potential to use effective contraception during treatment with WELIREG and for 1 week after the last dose

 Lactation-                                                                                                                      Advise females not to breastfeed during treatment with WELIREG and for 1 week after the last dose 

Infertility-                                                                                                                   Advise male and female patients that WELIREG may impair fertility

 Dosage and Administration-                                                                                  Instruct patients to take their dose of WELIREG at the same time each day (once daily). Advise patients WELIREG can be taken with or without food. Each tablet should be swallowed whole

For patent information: www.merck.com/product/patent/home.html Copyright © 2021 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved. uspi-mk6482-t-2108r000

CLINICAL PHARMACOLOGY

1. Mechanism of Action Belzutifan is an inhibitor of hypoxia-inducible factor 2 alpha (HIF-2a). HIF-2a is a transcription factor that plays a role in oxygen sensing by regulating genes that promote adaptation to hypoxia.

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.

Cardiac Electrophysiology At the recommended dosage, WELIREG does not cause large mean increases (i.e., >20 msec) in the QT interval.

3. Pharmacokinetics- The mean steady-state (CV%) Cmax is 1.3 µg/mL (42%) and AUC0-24h is 16.7 µg•hr/mL (52%) in patients with VHL disease-associated RCC. Steady state is reached after approximately 3 days. Cmax 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 Tmax 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 Cmax, 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

Specific Populations- Patients who are poor metabolizers of UGT2B17 and CYP2C19 had higher belzutifan AUC .

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 m2 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 m2) 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 Cmax 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.

 USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary-                                                                                            Based on findings in animal studies, WELIREG can cause fetal harm when administered to a pregnant woman.

There are no available data on the use of WELIREG in pregnant women to inform the drugassociated risk.

 Advise pregnant women and females of reproductive potential of the potential risk to a fetus.

The background risk of major birth defects and miscarriage for the indicated population is unknown.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.

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.

3. Females and Males of Reproductive Potential-                                                WELIREG can cause fetal harm when administered to a pregnant woman

 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

 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 . The reversibility of the effect on fertility is unknown.

4 Pediatric Use-                                                                                                                  Safety and effectiveness of WELIREG have not been established in pediatric patients.

5. Geriatric Use-                                                                                                                  Of the patients who received WELIREG in Study 004, 3.3% were =65 years old. Clinical trials of WELIREG did not include sufficient numbers of patients aged 65 and older to determine whether they respond differently from younger patients.

6. Renal Impairment-                                                                                                       No dosage modification of WELIREG is recommended in patients with mild (eGFR 60-89 mL/min/1.73 m2 estimated by MDRD) and moderate (eGFR 30-59 mL/min/1.73 m2) renal impairment . WELIREG has not been studied in patients with severe (eGFR 15-29 mL/min/1.73 m2) renal impairment.

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.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.

OVERDOSAGE-                                                                                                          There is no specific treatment for WELIREG overdose. In cases of suspected overdose, withhold WELIREG and institute supportive care. Grade 3 hypoxia occurred at dosages of 120 mg twice a day and Grade 4 thrombocytopenia occurred in some cases