Vafseo Drug Information

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.

Not indicated for use: As a substitute for transfusion in patients requiring immediate correction of anemia.

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.

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.

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.

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.

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.

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. 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.

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. VAFSEO should be administered at least 1 hour before or 2 hours after dosing non-iron-containing phosphate binders.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of VAFSEO was evaluated in adults with dialysis-dependent chronic kidney disease (DD-CKD) with anemia in the INNO 2 VATE-1 and INNO 2 VATE-2 trials. Both trials randomized patients to VAFSEO or darbepoetin alfa.

Results in this section are based on the pooled VAFSEO treatment arms and pooled darbepoetin alfa arms from these trials. There were 1947 patients treated with VAFSEO and 1955 patients treated with darbepoetin alfa. VAFSEO was non-inferior to darbepoetin alfa on the time to first occurrence of major adverse cardiovascular events (MACE) in adults with anemia due to CKD who were on dialysis.

Permanent treatment discontinuation due to an adverse reaction was reported in 4.9% of patients treated with VAFSEO and 1.1% of patients treated with darbepoetin alfa. Gastrointestinal symptoms (nausea, vomiting and diarrhea) resulted in permanent treatment discontinuation in 1.8% of patients treated with VAFSEO. The most common adverse reactions (>10% of VAFSEO-treated patients) were hypertension and diarrhea.

Table 1 lists the adverse reactions that occurred in at least 5% or greater of patients with DD-CKD treated with VAFSEO. Table 2 Adjudicated Thrombotic Vascular Events in Patients with DD-CKD Fatal and Non-fatal

Effect of Other Drugs on VAFSEO Table 3 describes clinically significant drug interactions where concomitant use of another drug affects VAFSEO. Table 3 Drug Interactions with VAFSEO that Affect Vadadustat Exposure Iron supplements and phosphate binders Clinical Effect Co-administration with oral iron supplements, products containing iron, or phosphate binders decreases the exposure of vadadustat, which may reduce the effectiveness of VAFSEO. Prevention or Management Stagger administration when VAFSEO is used with oral iron supplements, products containing iron, iron-containing phosphate binders, or non-iron-containing phosphate binders.

Examples Iron supplements: ferric citrate, ferrous sulfate, sodium ferrous citrate Iron-containing phosphate binders: ferric citrate, sucroferric oxyhydroxide Non-iron-containing phosphate binders: calcium acetate, sevelamer carbonate Organic anion transporter (OAT) OAT1/OAT3 inhibitors Clinical Effect Co-administration with OAT1/OAT3 (Organic Anion Transporter) inhibitors may increase the area under the concentration curve (AUC) of vadadustat, which may increase the risk of VAFSEO adverse reactions. Prevention or Management Closely monitor for too large or too rapid an increase in Hb response and for adverse reactions. Examples OAT1 inhibitors: probenecid, rifampicin OAT3 inhibitors: gemfibrozil, probenecid, teriflunomide These examples are not a comprehensive list of all possible drugs that may fit this category.

Effect of VAFSEO on Other Drugs Table 4 describes clinically significant drug interactions where VAFSEO affects the co-administered drug. Table 4 Drug Interactions with VAFSEO that affect co-administered drugs BCRP substrates Clinical Effect Vadadustat may increase the exposure of BCRP substrates, which may increase the risk of adverse reactions related to the BCRP substrate. Vadadustat increases the maximal concentration (C max ) and AUC of some statins when co-administered.

Vadadustat may increase the exposure of co-administered OAT3 substrates, which may increase the risk of adverse reactions related to these substrates.

Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to VAFSEO during pregnancy. Health care providers and patients are encouraged to report pregnancies by calling 1-844-445-3799. Risk Summary Available data with VAFSEO use in pregnant women are insufficient to establish a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.

There are risks to the mother and fetus associated with CKD (see Clinical Considerations). Vadadustat administration orally to pregnant rats and rabbits during the period of organogenesis was associated with reduced fetal weight at doses that caused maternal toxicity. In rat and rabbit studies, vadadustat was not teratogenic (see Data).

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is respectively.

VAFSEO should only be used during pregnancy if the benefit justifies the potential risk to the fetus. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk: CKD in pregnancy increases the risk for maternal hypertension, preeclampsia, miscarriage, stillbirth, preterm delivery, low birth weight infants, and polyhydramnios. Data Animal Data Vadadustat decreased fetal weight and reduced fetal skeletal ossification in rats at a dose of 160 mg/kg/day (1.7 times the maximum recommended human dose based on AUC), which was associated with maternal toxicity defined by reduced body weight gain and food consumption.

Vadadustat administration at 50 mg/kg/day resulted in maternal toxicity of reduced body weight gain, but no adverse effects on embryofetal development were observed at doses less than or equal to 50 mg/kg/day (1.5 times the MRHD based on AUC). There were decreased body weights of offspring at the dose of 80 mg/kg/day but no adverse effects were observed at doses less than or equal to 80 mg/kg/day (0.3 times the MRHD based on AUC) in dams.

Pediatric Use The safety and effectiveness of VAFSEO in pediatric patients have not been established.

VAFSEO is contraindicated in patients: with a known hypersensitivity to VAFSEO or any of its components. with uncontrolled hypertension.

VAFSEO overdose may result in exaggeration of the pharmacologic effects such as increased Hb. VAFSEO overdose should be managed as clinically appropriate (e.g., reduction of VAFSEO dose or discontinuation). Approximately 16% of the vadadustat dose is removed by dialysis.

There is no specific antidote.