Vafseo

 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 ].

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 ].

 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 ].

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 [see Warnings and Precautions ].

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 [see Drug Interactions ].

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

Pregnancy

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 2 to 4% and 15 to 20%, 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 [MRHD] based on AUC), which was associated with maternal toxicity defined by reduced body weight gain and food consumption.

Vadadustat was orally administered to pregnant rabbits at doses of 10, 25, or 50 mg/kg/day from gestation day 6 until gestation day 18 during the period of organogenesis. 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).

In a pre- and postnatal development study, pregnant rats were dosed orally with vadadustat 20, 40, or 80 mg/kg/day from implantation until weaning (gestation day 6 to lactation day 20) at 20, 40, or 80 mg/kg/day. 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.

Lactation

Risk Summary
There are no data on the presence of vadadustat in human milk, the effects of vadadustat on the breastfed child, or the effects on milk production. Vadadustat is present in the milk of lactating rats (see Data). When a drug is present in animal milk, it is likely that the drug will be present in human milk. Given the serious adverse reactions seen in adults treated with VAFSEO, such as thrombotic vascular events, advise patients not to breastfeed during treatment with VAFSEO, and for 2 days after the final dose.

Data
Vadadustat was detected in the milk of lactating rats after a single oral administration of radiolabeled vadadustat at 50 mg/kg. The maximum ratio of milk to plasma concentration in rats was 14.5 at 8 hours postdose and the ratio of milk to plasma AUC was 6.

Pediatric Use

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

Geriatric Use

There were 1330 patients 65 years of age and older in the pooled INNO2VATE-1 and INNO2VATE-2 clinical trials. Of the total number of VAFSEO-treated patients in these studies, 449 (23%) were 65 to 74 years of age, 194 (10%) were 75 to 84 years of age, and 24 (1%) were 85 years of age and older. No overall differences in safety or effectiveness were observed between patients 65 years of age and older and younger adult patients [see Clinical Studies ].

Hepatic Impairment

VAFSEO is not recommended in patients with cirrhosis or active, acute liver disease [see Warnings and Precautions ].

 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 ]. 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 ].

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.

 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 ].

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.

 Hypertension

VAFSEO is contraindicated in patients with uncontrolled hypertension. In the INNO2VATE-1 and INNO2VATE-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.

Seizures

Seizures have occurred in patients treated with VAFSEO. In the INNO2VATE-1 and INNO2VATE-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.

Gastrointestinal Erosion

In the INNO2VATE-1 and INNO2VATE-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.

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 ].

In large clinical trials in adults with anemia of CKD who were not on dialysis (PRO2TECT-1 and PRO2TECT-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.

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 INNO2VATE-1 and INNO2VATE-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 ].

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 INNO2VATE-1 and INNO2VATE-2 trials [see Clinical Studies ]. 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. In the pooled VAFSEO treatment arm, 71% of the participants were treated continuously for at least 6 months of VAFSEO and 44% of participants received VAFSEO for at least 1 year.

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 [see Clinical Studies ].

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 1 Adverse Reactions (≥5%) in Patients with DD-CKD During INNO2VATE-1 and INNO2VATE-2

Adjudicated fatal and non-fatal thrombotic vascular events were observed in 9.0 per 100 PY of patients in the pooled VAFSEO arm and in 8.7 per 100 PY of patients in the pooled darbepoetin alfa (see Table 2).

Table 2 Adjudicated Thrombotic Vascular Events in Patients with DD-CKD (Fatal and Non-fatal Events)*

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

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

Mechanism of Action

Vadadustat is a reversible inhibitor of HIF-prolyl-4-hydroxylases (PH)1, PH2, and PH3 (IC50 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).

Pharmacodynamics

After a single dose of vadadustat 80 to 1200 mg (0.27 to 4 times the approved recommended starting dosage) in healthy male adults, a dose-dependent increase in EPO was observed.

Cardiac Electrophysiology
At a dose of 600 mg or 1200 mg (2 or 4 times the approved recommended starting dosage), VAFSEO does not prolong the QTc interval to any clinically relevant extent.

Pharmacokinetics

Vadadustat AUC and observed peak concentration (Cmax) increased proportionally after single doses from 80 mg to 1200 mg (0.27 to 4 times the approved recommended starting dosage). Vadadustat is expected to reach steady state by day 3 following once daily dosing, with no significant accumulation.

Absorption
The time to peak plasma concentration (Tmax) of vadadustat is approximately 2 to 3 hours.

Effect of Food
No clinically significant differences in vadadustat pharmacokinetics were observed following administration of a high-fat meal.

Distribution
Protein binding of vadadustat is ≥99.5% in human plasma. Vadadustat does not distribute into red blood cells.

Elimination
The mean half-life of vadadustat in patients on chronic hemodialysis was 9.2 hours.

Metabolism
Vadadustat is primarily metabolized via glucuronidation by UDP-glucuronosyltransferase (UGT) enzymes.

Excretion
After a single radiolabeled oral dose to healthy adults, 85.9% of the total dose was recovered; 58.9% in urine (<1% of total dose unchanged); and 26.9% in feces (9% of total dose unchanged).

Specific Populations
There were no clinically significant differences in the pharmacokinetics of vadadustat based on age, sex, race/ethnicity, or moderate hepatic impairment (Child-Pugh Class B). The effect of severe hepatic impairment (Child-Pugh Class C) on the pharmacokinetics of vadadustat is unknown.

Patients with Renal Impairment
Vadadustat clearance decreased with decreasing renal function and exposures in DD-CKD were approximately 2-fold higher compared to healthy adults. In patients with Stage 5 DD-CKD, no significant differences in pharmacokinetics (Cmax, AUC or mean half-life) were observed when VAFSEO was administered 4 hours before dialysis or 2 hours after dialysis.

Drug Interaction Studies
The impact of co-administered drugs on vadadustat exposure was examined in several drug-drug interaction (DDI) studies in healthy adults. The change in vadadustat exposure with coadministration compared to VAFSEO alone is summarized in Figure 1.

Figure 1 Impact of Other Drugs on Pharmacokinetics of Vadadustat

BCRP: breast cancer resistance protein; CI: confidence interval; OAT: organic anion transporter; OATP: organic anion-transporting polypeptide. The solid vertical line represents geometric mean ratio of 1 and dotted vertical lines represent the 0.80 to 1.25 boundary.

The impact of vadadustat on the exposure of other drugs was examined in several DDI studies in healthy adults. The change in drug exposure when coadministered with VAFSEO compared to the drug alone is summarized in Figure 2.

Figure 2 Effect of Vadadustat on Pharmacokinetics of Other Drugs

BCRP: breast cancer resistance protein; CI: confidence interval; OAT: organic anion transporter; OATP: organic anion-transporting polypeptide. The solid vertical line represents geometric mean ratio of 1 and dotted vertical lines represent the 0.80 to 1.25 boundary.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Vadadustat was not carcinogenic when administered orally at doses of 2, 7, and 20 mg/kg/day in a 6-month study in transgenic mice and at doses of 5, 15, and 50 mg/kg/day in a 2-year study in rats. The highest exposure to vadadustat in rats corresponds to 0.2 times the MRHD based on AUC.

Vadadustat was negative for mutagenicity in the in vitro bacterial reverse mutation assay. Vadadustat exhibited clastogenic activity in vitro but was negative in the in vivo chromosomal aberration assay in peripheral blood lymphocytes and comet assay in rats. Based on the weight of evidence, vadadustat is not considered genotoxic.

Fertility and early embryonic development toxicity studies were conducted in rats at dose levels of 40 to 120 mg/kg/day. Vadadustat did not impact fertility or reproduction in rats up to 80 mg/kg/day (1.5 times the MRHD based on AUC).

Treatment of Anemia Due to Chronic Kidney Disease in Adults on Dialysis

The efficacy and safety of VAFSEO given once daily for the treatment of anemia in adults with CKD on dialysis were demonstrated in two global, multi-center, randomized, active-controlled, non-inferiority, open-label trials in a total of 3923 patients with DD-CKD (INNO2VATE-1 and INNO2VATE-2). Patients in each trial were randomized 1:1 to receive VAFSEO with a starting dose of 300 mg once daily or darbepoetin alfa administered subcutaneously or intravenously as per the prescribing information for 52 weeks to assess the efficacy endpoints. VAFSEO was titrated in increments of 150 mg up to 600 mg to achieve the Hb target. After 52 weeks, patients continued study medication to assess long-term safety until the event-driven major adverse cardiovascular event (MACE) endpoints were reached. Efficacy in each study was based on the difference in mean change of Hb from baseline to the primary evaluation period (Weeks 24 to 36). An additional efficacy endpoint was the difference in mean change of Hb from baseline to the secondary evaluation period (Weeks 40 to 52). MACE was defined as all-cause mortality, non-fatal MI and non-fatal stroke and was evaluated in both trials.

The baseline Hb values were between 8 to 11 g/dL in the United States (US) and 9 to 12 g/dL outside the US. INNO2VATE-1 (NCT02865850) included patients with incident DD-CKD who initiated dialysis within 16 weeks prior to the beginning their trial participation and who were ESA-naive, had limited prior ESA use or were maintained on ESAs. INNO2VATE-2 (NCT02892149) included patients on chronic maintenance dialysis for more than 12 weeks who had converted from prior ESA therapy. In INNO2VATE-1, INNO2VATE-2, and the pooled INNO2VATE program the median and range of time from initiating dialysis to starting vadadustat was 0.1 (0.01 to 0.4), 2.7 (0.2 to 31.3) and 2.3 (0.01 to 31.3) years, respectively. The pooled population from the two trials had a range of 19 to 93 years of age, 55.9% were male, and the percentage of Caucasian, Hispanic, Black (including African Americans) and Asian patients was 64.5%, 38.5%, 24.1% and 4.5%, respectively. In both trials, VAFSEO was non-inferior to darbepoetin alfa in correcting and maintaining Hb levels across geographic-specific target Hb ranges [10 to 11 g/dL in the US and 10 to 12 g/dL outside the US] in adults with DD-CKD at weeks 24 to 36 and weeks 40 to 52.

Efficacy results are provided in Table 5. There were no apparent differences in response to VAFSEO across subgroups of age, gender, race and region.

Table 5 VAFSEO EFFICACY RESULTS: INNO2VATE TRIALS

Cardiovascular Outcomes - Patients with Dialysis-Dependent CKD
MACE was assessed in a combined analysis of INNO2VATE-1 and INNO2VATE-2. VAFSEO was non-inferior to darbepoetin alfa in time to first occurrence of MACE (Hazard Ratio 0.96; 95% CI 0.83, 1.11). Non-inferiority of VAFSEO was established because the upper bound of the 95% CI for the MACE hazard ratio was less than the pre-specified non-inferiority margin of 1.25. The results were consistent for the individual components of the MACE endpoint (see Table 6).

Table 6 Major Adverse Cardiovascular Events in the INNO2VATE Trials (ITT Analysesa)

An analysis of the US region (N=2361 of 3902 total patients globally) for MACE and the individual MACE components, where patients were treated to a Hb target of 10 to 11 g/dL, showed a similar risk of MACE compared to darbepoetin alfa. The results were consistent for the individual components of the MACE endpoint (see Table 7).

Table 7 INNO2VATE Analyses of the MACE endpoint and the individual components for the US region where the patients were treated to a Hb target of 10 to 11 g/dL

Storage and Handling

• Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP controlled room temperature]. Keep out of reach of children.