Vadadustat
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alara Ece Dagsali, M.D.
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Black Box Warning
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INCREASED RISK OF DEATH, MYOCARDIAL INFARCTION, STROKE, VENOUS THROMBOEMBOLISM, AND THROMBOSIS OF VASCULAR ACCESS
See full prescribing information for complete Boxed Warning.
Condition Name: (Content)
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Overview
Vadadustat is {{{aOrAn}}} {{{drugClass}}} that is FDA approved for the treatment of 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.. There is a Black Box Warning for this drug as shown here. Common adverse reactions include *VAFSEO increases the risk of thrombotic vascular events, including major adverse cardiovascular events (MACE)
- Targeting a hemoglobin level greater than 11 g/dL is expected to further increase the risk of death and arterial and venous thrombotic events, as occurs with erythropoietin stimulating agents (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.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
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.
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.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Vadadustat in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Vadadustat in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Vadadustat FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Vadadustat in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Vadadustat in pediatric patients.
Contraindications
VAFSEO is contraindicated in patients:
- with a known hypersensitivity to VAFSEO or any of its components
- with uncontrolled hypertension
Warnings
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INCREASED RISK OF DEATH, MYOCARDIAL INFARCTION, STROKE, VENOUS THROMBOEMBOLISM, AND THROMBOSIS OF VASCULAR ACCESS
See full prescribing information for complete Boxed Warning.
Condition Name: (Content)
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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 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
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
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 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
5.4 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.
5.5 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.
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 (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.
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 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
Adverse Reactions
Clinical Trials Experience
The following clinically significant adverse reactions are discussed elsewhere in the labeling:
- Increased risk of death, myocardial infarction, stroke and venous thromboembolism, and thrombosis of vascular access
- Hepatotoxicity
- Hypertension
- Seizures
- Gastrointestinal erosion
- Serious adverse reactions in patients with anemia due to chronic kidney disease and not on dialysis
Postmarketing Experience
There is limited information regarding Vadadustat Postmarketing Experience in the drug label.
Drug Interactions
- Co-administration with oral iron supplements, products containing iron, or phosphate binders decreases the exposure of vadadustat
- Co-administration with OAT1/OAT3 (Organic Anion Transporter) inhibitors may increase the area under the concentration curve (AUC) of vadadustat.
- Vadadustat may increase the exposure of BCRP substrates
- Vadadustat increases the maximal concentration (Cmax) 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.
Use in Specific Populations
Pregnancy
Pregnancy Category (FDA): 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.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Vadadustat in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Vadadustat during labor and delivery.
Nursing Mothers
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.
Pediatric Use
The safety and effectiveness of VAFSEO in pediatric patients have not been established.
Geriatic 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
Gender
There is no FDA guidance on the use of Vadadustat with respect to specific gender populations.
Race
There is no FDA guidance on the use of Vadadustat with respect to specific racial populations.
Renal Impairment
There is no FDA guidance on the use of Vadadustat in patients with renal impairment.
Hepatic Impairment
VAFSEO is not recommended in patients with cirrhosis or active, acute liver disease
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Vadadustat in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Vadadustat in patients who are immunocompromised.
Administration and Monitoring
Administration
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.
Monitoring
Following initiation of therapy and after each dose adjustment, monitor hemoglobin (Hb) levels, every two weeks until stable, then monitor at least monthl
IV Compatibility
There is limited information regarding the compatibility of Vadadustat and IV administrations.
Overdosage
There is limited information regarding Vadadustat overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
Pharmacology
There is limited information regarding Vadadustat Pharmacology in the drug label.
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).
Structure
There is limited information regarding Vadadustat Structure in the drug label.
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.
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.
Nonclinical Toxicology
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
Clinical Studies
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.
How Supplied
150 mg,Round/white tablet shape/colour, 60 count bottle
Storage
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). Keep out of reach of children.
Images
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Patient Counseling Information
- 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.
- That hemoglobin levels will be monitored when initiating or adjusting therapy, every two weeks until stable, then at least monthly
- Of the risk of hepatotoxicity and that liver tests will be measured prior to the initiation of VAFSEO, monthly after initiation for the first 6 months, then as clinically indicated
- Of the risk of hypertension and advise patients of the importance to comply with antihypertensive therapy and monitoring of blood pressure
- Of the risk of seizures and advise patients to contact their healthcare provider for new-onset neurologic symptoms or change in seizure frequency
- Of the risk of gastrointestinal erosions and advise patients to contact their healthcare provider for signs and symptoms of gastric and esophageal erosions and of gastrointestinal bleeding
Precautions with Alcohol
Alcohol-Vadadustat interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
Brand Names
VAFSEO
Look-Alike Drug Names
There is limited information regarding Vadadustat Look-Alike Drug Names in the drug label.
Drug Shortage Status
Price
References
The contents of this FDA label are provided by the National Library of Medicine.