vadadustat 450 MG Oral Tablet [Vafseo]

INDICATIONS AND USAGE VAFSEO is indicated for the treatment of anemia due to chronic kidney disease (CKD) in adults who have been receiving dialysis for at least three months. Limitations of Use VAFSEO has not been shown to improve quality of life, fatigue, or patient well-being. VAFSEO is not indicated for use: As a substitute for red blood cell transfusions in patients who require immediate correction of anemia In patients with anemia due to CKD not on dialysis [see Warnings and Precautions ( 5.6 )] . VAFSEO is a hypoxia-inducible factor prolyl hydroxylase (HIF PH) inhibitor indicated for the treatment of anemia due to chronic kidney disease (CKD) in adults who have been receiving dialysis for at least three months. ( 1 ) Limitations of Use Not been shown to improve quality of life, fatigue, or patient well-being. Not indicated for use: As a substitute for transfusion in patients requiring immediate correction of anemia. ( 1 ) In patients with anemia due to CKD not on dialysis. ( 1 , 5.6 )

DOSAGE AND ADMINISTRATION Recommended starting dose is 300 mg orally once daily, with or without food. ( 2.3 ) Monitor hemoglobin levels when initiating or adjusting dose and then monthly. ( 2.1 and 2.4 ) Increase the dose no more frequently than once every 4 weeks. Decreases in dose can occur more frequently. ( 2.4 ) Adjust dose in increments of 150 mg to achieve or maintain hemoglobin levels of 10 g/dL to 11 g/dL. Doses may range from 150 mg to a maximum of 600 mg. ( 2.4 ) 2.1 Pre-Treatment and On-Treatment Evaluations of Anemia, Iron Stores, and Liver Tests Evaluation of Anemia and Iron Stores Correct and exclude other causes of anemia (e.g., vitamin deficiency, metabolic or chronic inflammatory conditions, bleeding) before initiation of VAFSEO. Evaluate iron status in all patients before and during treatment. Administer supplemental iron therapy when serum ferritin is less than 100 mcg/L or when serum transferrin saturation is less than 20%. The majority of patients with CKD will require supplemental iron during the course of therapy. Measure hemoglobin (Hb) at baseline and as recommended in section 2.4 . Liver Testing Measure serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin prior to the initiation of VAFSEO and monthly after initiation for the first 6 months and then monitor as clinically indicated [see Warnings and Precautions ( 5.2 )] . Discontinue VAFSEO if there are persistent ALT or AST elevations greater than 3 times upper limit of normal (ULN) or if ALT or AST elevations greater than 3 times ULN are accompanied by a bilirubin increase greater than 2 times ULN [see Warnings and Precautions ( 5.2 )] . 2.2 Important Dosing Information Individualize dosing and use the lowest dose of VAFSEO sufficient to reduce the need for red blood cell transfusions. Do not target a hemoglobin level higher than 11 g/dL. VAFSEO can be taken with or without food. VAFSEO should be swallowed whole. Tablets should not be cut, crushed, or chewed. VAFSEO can be administered without regard to the timing or type of dialysis [see Clinical Pharmacology ( 12.3 )] . If a dose of VAFSEO is missed, it should be taken as soon as possible, unless it is the same day as the next dose. In this case, the missed dose should be skipped, and the next dose taken at the usual time. Double doses should not be taken to make-up for a missed dose. 2.3 Recommended Starting Dose of VAFSEO Adults Not Being Treated with an ESA The recommended starting dose is 300 mg orally once daily. Adults Being Switched from an ESA When converting from an ESA to VAFSEO, the recommended starting dose is 300 mg orally once daily. Taking into account the gradual rise in Hb with VAFSEO, red blood cell (RBC) transfusions or ESA treatment may be considered during the transition phase if Hb values fall below 9 g/dL or Hb response is considered not acceptable. Patients receiving RBC transfusions should continue VAFSEO treatment during the transfusion period. VAFSEO should be paused for those patients receiving temporary ESA rescue treatment and may be resumed when Hb levels are greater than or equal to 10 g/dL. Depending on the ESA used for rescue, the pause in VAFSEO treatment should be extended to: 2 days after the last dose of epoetin 7 days after the last dose of darbepoetin alfa 14 days after the last dose of methoxy polyethylene glycol-epoetin beta. Following ESA rescue, VAFSEO should be resumed at the prior dose or with a dose that is 150 mg greater than the prior dose, with subsequent titration according to the dose titration guidelines given below in this section. 2.4 Monitoring Response to Therapy and Dose Adjustment Following initiation of therapy and after each dose adjustment, monitor hemoglobin (Hb) levels, every two weeks until stable, then monitor at least monthly [see Warnings and Precautions ( 5.1 )] . Dose Titration Increase the dose no more frequently than once every 4 weeks. Decreases in dose can occur more frequently. Adjust dose in increments of 150 mg to achieve or maintain Hb levels within 10 g/dL to 11 g/dL. Doses may range from 150 mg to a maximum of 600 mg. When adjusting the dose, consider the patient’s Hb variability, Hb rate of rise and rate of decline, and VAFSEO responsiveness. A single Hb excursion may not require a dosing change. If the Hb rises rapidly (e.g., more than 1 g/dL in any 2-week period or more than 2 g/dL in 4 weeks), interrupt or reduce the dose. If the Hb level exceeds 11 g/dL, interrupt the dose of VAFSEO until Hb is less than or equal to 11 g/dL then resume with a dose that is 150 mg less than the dose prior to interruption. Treatment with VAFSEO should not be continued beyond 24 weeks of therapy if a clinically meaningful increase in Hb level is not achieved. Alternative explanations for an inadequate response should be sought and treated before re-starting therapy. 2.5 Dosage Adjustments Due to Drug Interactions Oral Iron and Phosphate Binders VAFSEO should be administered at least 1 hour before dosing oral iron supplements, products containing iron, or iron-containing phosphate binders [see Drug Interactions ( 7.1 )] . VAFSEO should be administered at least 1 hour before or 2 hours after dosing non-iron-containing phosphate binders [see Drug Interactions ( 7.1 )] .

WARNINGS AND PRECAUTIONS Hepatotoxicity: Has been reported in patients taking VAFSEO. Measure ALT, AST and bilirubin prior to the initiation of VAFSEO, monthly after initiation for the first 6 months, then as clinically indicated. Discontinue VAFSEO if ALT or AST is persistently elevated or accompanied by elevated bilirubin. ( 5.2 ) Hypertension: Worsening hypertension, including hypertensive crisis may occur. Monitor blood pressure. Adjust anti-hypertensive therapy as needed. ( 5.3 ) Seizures: Seizures have occurred in patients with CKD taking VAFSEO. Monitor for new-onset seizures, premonitory symptoms, or change in seizure frequency. ( 5.4 ) Gastrointestinal Erosion: Gastric or esophageal erosions and gastrointestinal bleeding have been reported. ( 5.5 ) Malignancy: May have unfavorable effects on cancer growth. Not recommended if active malignancy. ( 5.7 ) 5.1 Increased Risk of Death, Myocardial Infarction (MI), Stroke, Venous Thromboembolism, and Thrombosis of Vascular Access VAFSEO increases the risk of arterial and venous thrombotic events, that may be fatal, including myocardial infarction, stroke, venous thromboembolism and vascular access thrombosis [see Boxed Warning , Adverse Reactions ( 6.1 )] . Patients with cardiovascular or cerebrovascular disease are at increased risk of these events. Avoid use in patients with a history of myocardial infarction, cerebrovascular event, or acute coronary syndrome within the 3 months prior to starting VAFSEO. A rate of hemoglobin rise of greater than 1 g/dL over 2 weeks may contribute to these risks. Targeting a hemoglobin level of greater than 11 g/dL is expected to further increase the risk of death and arterial and venous thrombotic events, as occurs with ESAs, which also increase erythropoietin levels. No trial has identified a hemoglobin target level, dose of VAFSEO, or dosing strategy that does not increase these risks. Use the lowest dose of VAFSEO sufficient to reduce the need for red blood cell transfusions. Adherence to dosing and hemoglobin monitoring recommendations is important to avoid excessive erythropoiesis [see Dosage and Administration ( 2.4 )] . Advise patients to seek immediate medical attention if they develop signs or symptoms of myocardial infarction, stroke, venous thromboembolism, or thrombosis of vascular access. Evaluate and manage promptly if these occur. 5.2 Hepatotoxicity VAFSEO may cause hepatotoxicity. In clinical trials, hepatocellular injury attributed to VAFSEO was reported in less than 1% of patients, including one case of severe hepatocellular injury with jaundice. All events were asymptomatic and resolved after discontinuation of VAFSEO. The time to onset was generally within the first 3 months of treatment. Elevated serum ALT, AST, and bilirubin were seen in 1.8%, 1.8% and 0.3% of CKD patients treated with VAFSEO, respectively. Measure ALT, AST and bilirubin prior to the initiation of VAFSEO and monthly after initiation for the first 6 months and then monitor as clinically indicated [see Dosage and Administration ( 2.1 )] . Discontinue VAFSEO if there is persistent ALT or AST greater than 3 times ULN or if ALT or AST elevations greater than 3 times upper limit of normal (ULN) are accompanied by a bilirubin increase greater than 2 times ULN. VAFSEO is not recommended in patients with cirrhosis or active, acute liver disease. 5.3 Hypertension VAFSEO is contraindicated in patients with uncontrolled hypertension. In the INNO 2 VATE-1 and INNO 2 VATE-2 clinical trials, worsening of hypertension was reported in 14% (9.4 per 100 person-years [PY]) of patients receiving VAFSEO and 17% (11.8 per 100 PY) of patients receiving darbepoetin alfa. Serious worsening of hypertension was reported in 2.7% (1.7 per 100 PY) of patients receiving VAFSEO and 3% (1.8 per 100 PY) of patients receiving darbepoetin alfa. Cases of hypertensive crisis including hypertensive encephalopathy and seizures have also been reported in patients receiving VAFSEO. Periodically monitor blood pressure and adjust or initiate anti-hypertensive therapy as needed. 5.4 Seizures Seizures have occurred in patients treated with VAFSEO. In the INNO 2 VATE-1 and INNO 2 VATE-2 clinical trials, seizures occurred in 1.6% (1.0 per 100 PY) of patients who received VAFSEO and 1.6% (1.0 per 100 PY) of patients who received darbepoetin alfa. Following initiation of VAFSEO, monitor patients closely for premonitory neurologic symptoms. Advise patients to contact their healthcare practitioner for new-onset seizures, premonitory symptoms, or change in seizure frequency. 5.5 Gastrointestinal Erosion In the INNO 2 VATE-1 and INNO 2 VATE-2 clinical trials, gastric or esophageal erosions occurred in 6.4% (4.0 per 100 PY) of patients receiving VAFSEO and 5.3% (3.3 per 100 PY) of darbepoetin alfa-treated patients. Serious gastrointestinal erosions, including gastrointestinal bleeding and the need for red blood cell transfusions were reported in 3.4% (2.1 per 100 PY) and 3.3% (2.0 per 100 PY) of those receiving VAFSEO and darbepoetin alfa, respectively. Consider this risk particularly in patients at increased risk for gastrointestinal erosions, such as those with a history of gastrointestinal erosion, peptic ulcer disease, use of concomitant medications that increase the risk of gastrointestinal erosion, and current tobacco smokers and alcohol drinkers. Advise patients of the symptoms and signs of gastric and esophageal erosions and of gastrointestinal bleeding and to seek prompt medical care if these occur. 5.6 Serious Adverse Reactions in Patients with Anemia Due to Chronic Kidney Disease and Not on Dialysis The safety of VAFSEO has not been established for the treatment of anemia due to CKD in adults not on dialysis and its use is not recommended in this setting [see Indications and Usage ( 1 )] . In large clinical trials in adults with anemia of CKD who were not on dialysis (PRO 2 TECT-1 and PRO 2 TECT-2), an increased risk of mortality, stroke, myocardial infarction, serious acute kidney injury, serious hepatic injury, and serious gastrointestinal erosions was observed in patients treated with VAFSEO compared to darbepoetin alfa. 5.7 Malignancy Because increased hypoxia inducible factor (HIF)-1 levels may be associated with unfavorable effects on cancer growth, VAFSEO has not been studied and is not recommended in patients with active malignancies. In the INNO 2 VATE-1 and INNO 2 VATE-2 clinical trials, malignancies were observed in 2.2% (1.3 per 100 PY) of patients treated with VAFSEO and 3.0% (1.8 per 100 PY) of patients treated with darbepoetin alfa. No evidence of increased carcinogenicity was observed in animal studies [see Nonclinical Toxicology ( 13.1 )] .

CONTRAINDICATIONS VAFSEO is contraindicated in patients: with a known hypersensitivity to VAFSEO or any of its components [see Description ( 11 )] . with uncontrolled hypertension [see Warnings and Precautions ( 5.3 )] . Known hypersensitivity to VAFSEO or any of its components ( 4 ) Uncontrolled hypertension ( 4 )

Mechanism of Action Vadadustat is a reversible inhibitor of HIF-prolyl-4-hydroxylases (PH)1, PH2, and PH3 (IC 50 in the nM range). This activity results in the stabilization and nuclear accumulation of HIF-1α and HIF-2α transcription factors, and increased production of erythropoietin (EPO).