Vanrafia Drug Information
Generic name: ATRASENTAN
Uses of Vanrafia
is indicated to reduce proteinuria in adults with primary immunoglobulin A nephropathy (IgAN) at risk of rapid disease progression, generally a urine protein-to-creatinine ratio (UPCR) ≥ 1.5 g/g. This indication is approved under accelerated approval based on a reduction of proteinuria . It has not been established whether VANRAFIA slows kidney function decline in patients with IgAN. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory clinical trial. VANRAFIA is an endothelin receptor antagonist indicated to reduce proteinuria in adults with primary immunoglobulin A nephropathy (IgAN) at risk of rapid disease progression, generally a urine protein-to-creatinine ratio (UPCR) ≥ 1.5 g/g.
This indication is approved under accelerated approval based on a reduction of proteinuria. It has not been established whether VANRAFIA slows kidney function decline in patients with IgAN. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory clinical trial.
Dosage & Administration of Vanrafia
Pregnancy Testing Exclude pregnancy before initiating
VANRAFIA .
Recommended Dosage
The recommended dose of VANRAFIA is 0.75 mg administered orally once daily with or without food . Swallow tablets whole. Do not cut, crush, or chew. If a dose or doses are missed, take the prescribed dose at the next scheduled time.
Do not double the dose to make up for a missed dose.
Side Effects of Vanrafia
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 VANRAFIA was evaluated in ALIGN (NCT04573478), a randomized, double-blind, placebo controlled clinical study in 403 adults with IgAN . The median duration of treatment was 47 weeks (range: 0 to 128 weeks). The most common adverse reactions (≥ 5%) with VANRAFIA were peripheral edema and anemia. Table 1 describes the adverse reactions that occurred in ≥ 2% of patients treated with VANRAFIA and higher than placebo in the ALIGN study.
Table 1: Adverse Reactions Reported in ≥ 2% of Adult Patients with IgAN Treated with VANRAFIA and Higher than Placebo in ALIGN * Includes related terms ** Elevations in ALT or AST > 3-fold upper limit of normal (ULN) Adverse Reaction VANRAFIA (N = 201) n (%) Placebo (N = 202) n (%) Peripheral edema* 21 (10%) 14 (7%) Anemia* 12 (6%) 2 (1%) Liver transaminase elevation** 4 (2%) 2 (1%) Laboratory Tests and Vital Signs Hemoglobin Decrease At Week 36, the mean change in hemoglobin from baseline for those patients receiving VANRAFIA in the ALIGN study was -0.7 g/dL compared to -0.2 g/dL for those receiving placebo. The incidence of a hemoglobin decrease > 2 g/dL compared to baseline and below the lower limit of normal was greater for the VANRAFIA arm (12%) compared to the placebo arm (4%). These decreases are thought to be in part due to hemodilution. There were no treatment discontinuations due to anemia or hemoglobin decrease in the ALIGN study.
Blood Pressure Decrease At Week 36, the mean change from baseline in systolic and diastolic blood pressure (BP) for patients receiving VANRAFIA in the ALIGN study was -4 mmHg and -4 mmHg, respectively, compared to +3 mmHg and +2 mmHg, respectively, in patients receiving placebo. Hypotension observed in VANRAFIA treated patients was mild or moderate in severity, rarely symptomatic, and did not necessitate treatment discontinuation.
Warnings & Cautions for Vanrafia
Embryo-Fetal Toxicity
Based on data from animal reproduction studies, VANRAFIA may cause fetal harm when administered to a pregnant patient and is contraindicated during pregnancy. The available human data for endothelin receptor antagonists do not establish the presence or absence of major birth defects related to the use of VANRAFIA. Counsel patients who can become pregnant of the potential risk to a fetus. Exclude pregnancy prior to initiation of treatment with VANRAFIA. Advise patients to use effective contraception prior to initiation of treatment, during treatment, and for two weeks after discontinuation of treatment with VANRAFIA . When pregnancy is detected, discontinue VANRAFIA as soon as possible .
Hepatotoxicity Some endothelin receptor antagonists (ERAs) have caused elevations of aminotransferases, hepatotoxicity
and liver failure. Asymptomatic and transient transaminase elevations have been observed with VANRAFIA . Obtain liver enzyme testing before initiating VANRAFIA and repeat during treatment as clinically indicated. In patients with elevated aminotransferases at baseline (>3 × upper limit of normal ), consider periodic liver test monitoring.
Do not initiate VANRAFIA in patients with severe hepatic impairment. Advise patients to report symptoms suggesting hepatic injury (nausea, vomiting, right upper quadrant pain, fatigue, anorexia, jaundice, dark urine, fever, or itching). If clinically relevant aminotransferase elevations occur, or if elevations are accompanied by an increase in bilirubin >2 x ULN, or by clinical symptoms of hepatotoxicity, discontinue VANRAFIA. Consider re-initiation of VANRAFIA when hepatic enzyme levels normalize in patients who have not experienced clinical symptoms of hepatotoxicity or jaundice.
Fluid Retention Fluid retention may occur with
ERAs and has been observed in clinical studies with VANRAFIA . VANRAFIA has not been evaluated in IgAN patients with heart failure. If clinically significant fluid retention develops, consider initiating or increasing diuretic treatment and interrupting VANRAFIA treatment.
Decreased Sperm Counts
VANRAFIA, similar to other ERAs, may have an adverse effect on spermatogenesis. Counsel men about potential effects on fertility .
Drug Interactions with Vanrafia
Effect of Other Drugs on
VANRAFIA Strong or Moderate CYP3A Inducers Avoid concomitant use with a strong or moderate CYP3A inducer. Atrasentan is a CYP3A substrate . Concomitant use with a strong and moderate CYP3A inducer is expected to decrease atrasentan exposure , which may reduce VANRAFIA efficacy. OATP1B1/1B3 Inhibitors Avoid concomitant use with organic anion transporting polypeptides 1B1/1B3 (OATP1B1/1B3) inhibitors.
Atrasentan is a OATP1B1/1B3 substrate . Concomitant use with a OATP1B1/1B3 inhibitor increases atrasentan exposure , which may increase the risk of VANRAFIA adverse reactions.
Pregnancy Safety for Vanrafia
Pregnancy Risk Summary Based on data from animal reproductive toxicity studies, VANRAFIA may cause fetal harm, including birth defects and fetal death, when administered to a pregnant patient and is contraindicated during pregnancy . There are no available data on VANRAFIA use in pregnancy to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Available data from published literature and post-marketing surveillance over decades of use with products in the same pharmacologic class (ERA) have not identified an increased risk of major birth defects. However, these data are limited and do not establish the presence or absence of a drug-associated risk of major birth defects.
Methodological limitations of these post marketing reports and published literature include lack of a control group; limited information regarding dose, duration, and timing of exposure; and missing data. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal endothelin receptor antagonist use. In animal reproduction studies, oral administration of atrasentan to pregnant rats and rabbits throughout organogenesis at doses that were below the maximum recommended human dose (MRHD) based on area under the curve (AUC) caused teratogenic effects in rats and rabbits (see Data). Advise pregnant patients of the potential risk to the fetus . The background risk of major birth defects and miscarriage for the indicated population is unknown.
All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data In embryo-fetal development studies in pregnant rats and rabbits, teratogenicity and/or embryo-fetal toxicity were observed.
In pregnant rats, oral administration of atrasentan throughout organogenesis at doses of 0.1, 0.3, 1.0, and 3.0 mg/kg/day resulted in developmental abnormalities primarily including the ear, lower jaw, or skull in all treated groups with detectable plasma exposures to atrasentan. The no adverse effect level of atrasentan plasma exposure was not determined. In pregnant rabbits, oral administration of atrasentan throughout organogenesis at doses of 0.1, 0.3, 1.0 and 3.0 mg/kg/day resulted in visceral malformations including deformities in the cardiovascular system in all atrasentan-treated groups.
The lowest detectable plasma exposures to atrasentan were approximately 0.2 times the AUC at the MRHD. In the pre- and postnatal development study in rats, atrasentan was orally administered to pregnant rats at doses of 1, 10, or 100 mg/kg/day during the period from gestation Day 15 through lactation Day 20. No adverse effects on pre- and postnatal development were observed at doses up to 10 mg/kg/day which resulted in maternal exposure approximately 55 times the AUC at the MRHD. Higher exposure to atrasentan (dose of 100 mg/kg/day) increased pup mortality during the pre-weaning period, and increased heart weight which correlated histologically with myocardial hypertrophy.
Pediatric Use of Vanrafia
Pediatric Use The safety and efficacy of VANRAFIA in pediatric patients have not been established.
Contraindications for Vanrafia
Pregnancy Use of
VANRAFIA is contraindicated in patients who are pregnant .
Hypersensitivity
VANRAFIA is contraindicated in patients with a history of a hypersensitivity reaction to atrasentan or any component of the product.
Overdosage Information for Vanrafia
There is no experience with overdose of VANRAFIA. Atrasentan has been given in a single dose up to 139.5 mg and multiple doses up to 40 mg/day in healthy volunteers. Overdose of VANRAFIA may result in headache or vasodilation. In the event of an overdose, standard supportive measures should be taken, as required.
Dialysis is unlikely to be effective because atrasentan is highly protein-bound.
Clinical Studies of Vanrafia
IgA Nephropathy
The effect of VANRAFIA on proteinuria was assessed in a randomized, double-blind, placebo-controlled, multicenter, global study (ALIGN, NCT04573478) in adults with biopsy-proven primary IgAN, an eGFR ≥ 30 mL/min/1.73 m 2, and urine protein ≥ 1 g/day on a stable dose of maximally tolerated renin angiotensin system inhibitor. The study included two cohorts: a main cohort of 340 patients and an exploratory cohort of 64 patients who were also on a stable dose of sodium glucose co-transporter 2 inhibitor (SGLT2i) at baseline. Patients with chronic kidney disease due to another condition in addition to IgAN or those who had been recently treated with systemic immunosuppressants were excluded.
Patients were randomized (1:1) to receive either VANRAFIA 0.75 mg or placebo once daily. RAS inhibitor therapy was continued throughout the study. Rescue immunosuppressive treatment could be initiated per investigator discretion during the trial.
The efficacy analysis included the first 270 patients in the main cohort who reached the Week 36 visit. At baseline, the mean age was 45 years (range: 19 to 77 years); 59% were male, 36% White, 57% Asian, 2% Black or African American and 5% other or not specified. At baseline, 60% had a history of hypertension, 1.5% had a history of type 2 diabetes, and 45% had hematuria based on urine dipstick.
The mean baseline eGFR was 59 mL/min/1.73 m 2. The geometric mean baseline UPCR was 1.5 g/g sampled from a 24-hour urine and 15% of patients had proteinuria > 3.5 g/day. The primary endpoint was the percent reduction in UPCR at Week 36 relative to baseline (see Table 2). Table 2: Percent Reduction in UPCR at Week 36 Relative to Baseline in ALIGN a Supportive care: primarily a stable dose of maximally-tolerated RAS inhibitor therapy. b Least squares geometric mean ratio in UPCR (sampled from a 24-hr urine collection) to baseline was reported as a percent reduction along with the respective 95% confidence interval. c The estimate of the ratio of least squares geometric mean ratio in UPCR (sampled from a 24-hr urine collection) to baseline comparing VANRAFIA with placebo was reported as a relative percent reduction along with the respective 95% confidence interval and 2-sided p-value. d Mixed model repeated measures analysis included all observed UPCR data except for subjects with intercurrent events (i.e., restricted medication use, chronic dialysis, kidney transplant). These subjects had UPCR data excluded beginning at the start date of the earliest event. The only intercurrent events observed were restricted medication use, which occurred in 3.0% and 5.2% of VANRAFIA and placebo treated subjects, respectively. e Two-sided p-value statistically significant at the 0.01 level.
Abbreviations: CI, confidence interval; N, number of randomized subjects in each group in the main cohort; UPCR, urine protein-to-creatinine ratio; RAS, renin-angiotensin system. VANRAFIA on top of supportive care a (N = 135) Placebo on top of supportive care a (N = 135) % Reduction in UPCR (95% CI) at Week 36 relative to baseline b,d 38% (32%, 44%) 3% (-7%, 12%) VANRAFIA versus placebo: % reduction in UPCR (95% CI) at Week 36 relative to baseline compared on a relative scale c,d 36% (26%, 45%) p-value e < 0.0001 The adjusted geometric mean percent change from baseline in UPCR over time is displayed in Figure 1. Figure 1: Geometric Mean Percent Change from Baseline in UPCR by Visit in ALIGN Adjusted % change relative to baseline in UPCR (sampled from a 24-hr urine collection) was estimated based on the MMRM analysis in Table 2. N represents the number of evaluable subjects included in the analysis (i.e., with non-missing UPCR values and baseline covariates, and did not initiate restricted medication use, chronic dialysis, or kidney transplant) for each visit and treatment group. Values reported in the figure were expressed as percent change from baseline and 95% CI, estimated from the regression model in Table 2. Abbreviations: CI, confidence interval; MMRM, mixed model repeated measures; UPCR, urine protein-to-creatinine ratio.
The treatment effect on UPCR at Week 36 was consistent across subgroups including age, sex, race, baseline disease characteristics (such as baseline eGFR and proteinuria levels) within the main cohort. The treatment effect on UPCR at Week 36 was also consistent in the exploratory SGLT2i cohort. Figure 1: Geometric Mean Percent Change from Baseline in UPCR by Visit in ALIGN
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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