Atrasentan hydrochloride is an endothelin type A receptor (ETAR) antagonist.1
Primary Immunoglobulin A Nephropathy
Atrasentan is used 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.1, 2, 3 This indication is approved under accelerated approval based on a reduction of proteinuria.1 It has not been established whether atrasentan slows kidney function decline in patients with IgAN.1 Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory clinical trial.1
Safety and efficacy of atrasentan have been established in a phase 3, double-blind, randomized, controlled trial (ALIGN) in adult patients with biopsy-proven IgAN, a total urinary protein excretion of at least 1g/day, and an estimated glomerular filtration rate (eGFR) of at least 30 mL/minute per 1.73 m2 of body surface area.1, 2 Patients eligible for inclusion received treatment with a maximum tolerated dose of an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) at a stable dose for at least 12 weeks.2 Patients were excluded if they had other glomerulopathies or were recently treated with systemic immunosuppressants.1 The study included 2 cohorts of patients: 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 (SGLT2) inhibitor at baseline.1 Patients were randomly assigned to receive atrasentan 0.75 mg or placebo once daily.1, 2 The primary outcome assessed was change in the UPCR based on a 24-hour urine sample at week 36.1, 2
Among the 270 patients in the main cohort, the mean age was 45 years (range: 19-77 years); 59% were male, 36% were White, 57% were Asian, and 2% were Black or African American.1, 2 Approximately 60% of patients had a history of hypertension, 1.5% had type 2 diabetes, and 45% had hematuria.1, 2 The mean baseline eGFR was 59 mL/minute per 1.73 m2.1, 2
At the prespecified interim analysis at week 36, patients treated with atrasentan had an adjusted geometric mean percent change from baseline in UPCR of -38% compared to -3% with placebo.1, 2 The treatment effect was consistent across subgroups including age, sex, race, and baseline disease characteristics within the main cohort.1 Among the 29 patients in the SGLT2 inhibitor cohort who completed 36 weeks of the trial, the adjusted geometric mean percent change from baseline in UPCR was -40% in the atrasentan group compared to -3% in the placebo group.2
IgAN is a leading cause of chronic kidney disease and renal failure, and is the most common glomerular disease.4 In the Kidney Disease: Improving Global Outcomes (KDIGO) guideline on glomerular diseases, treatment of IgAN includes supportive care, lifestyle modifications to improve blood pressure control (exercise, weight control, smoking cessation, restriction of alcohol intake, dietary sodium restriction), and interventions to reduce cardiovascular risk.4 For patients with proteinuria >0.5 g/day, therapy with an ACE inhibitor or an ARB is recommended, regardless of hypertension.4 For patients at high risk of progressive chronic kidney disease (proteinuria >0.75-1 g/day) despite maximal supportive care, immunosuppressive therapy can be considered.4 The KDIGO guideline was published prior to the approval of atrasentan and does not address the specific place in therapy for this drug.1, 3, 4 Since its publication in 2021, 2 additional medications, budesonide (an oral corticosteroid) and sparsentan (a dual endothelin type A receptor [ETAR] and angiotensin II receptor antagonist) have been approved for use in adults with primary IgAN.3, 4
Atrasentan hydrochloride is commercially available as an oral tablet containing 0.75 mg of atrasentan.1
Swallow tablets whole.1 Do not cut, crush, or chew.1, 1
Administer the tablet with or without food.1 If a dose is missed, skip the missed dose and take the next dose at the regularly scheduled time.1
Store atrasentan tablets at 20-25°C in the original container (excursions permitted between 15-30°C).1
Dosage of atrasentan hydrochloride is expressed in terms of atrasentan.1
Immunoglobulin A Nephropathy (IgAN)
To reduce proteinuria in adults with primary IgAN at risk of rapid disease progression, the recommended adult dosage of atrasentan is 0.75 mg orally once daily.1
No dosage adjustment is required for patients with mild to moderate hepatic impairment.1
Do not initiate atrasentan in patients with severe hepatic impairment.1
No specific dosage adjustments are provided for renal impairment.3
No specific dosage adjustments are provided for geriatric patients.3
Fetal/Neonatal Morbidity and Mortality
A boxed warning regarding the risk of embryo-fetal toxicity is included in the prescribing information for atrasentan.1 Based on animal findings, atrasentan can cause fetal harm when administered during pregnancy, and is contraindicated for use in pregnant individuals.1 The available human data for endothelin receptor antagonists (ERAs) do not establish the presence or absence of major birth defects related to the use of atrasentan.1
Counsel patients who can become pregnant on the potential risk to a fetus.1 Verify that the patient is not pregnant prior to beginning atrasentan treatment.1 Advise patients to use effective contraception prior to initiating therapy, during treatment, and for 2 weeks after discontinuing the drug.1 When pregnancy is detected, discontinue atrasentan as soon as possible.1
Other Warnings and Precautions
Asymptomatic and transient transaminase elevations have been observed in patients treated with atrasentan.1
Obtain liver enzyme testing before initiating atrasentan and repeat during treatment as clinically indicated.1 In patients with elevated aminotransferases at baseline (>3 times upper limit of normal [ULN]), consider periodic liver test monitoring.1 Do not initiate atrasentan in patients with severe hepatic impairment.1
Advise patients to report symptoms suggesting hepatic injury (nausea, vomiting, right upper quadrant pain, fatigue, anorexia, jaundice, dark urine, fever or itching).1 If clinically relevant aminotransferase elevations occur, or if elevations are accompanied by an increase in bilirubin >2 times ULN, or by clinical symptoms of hepatotoxicity, discontinue atrasentan.1 Consider re-initiating atrasentan when hepatic enzyme levels normalize in patients who have not experienced clinical symptoms of hepatotoxicity or jaundice.1
ERAs may cause fluid retention, which has been observed in clinical studies in patients treated with atrasentan.1 Atrasentan has not been evaluated in IgAN patients with heart failure.1
If clinically significant fluid retention develops, consider initiating or increasing diuretic treatment and interrupting atrasentan therapy.1
Similar to other ERAs, atrasentan may have an adverse effect on spermatogenesis.1
Counsel men about the potential effects on fertility.1
There are no adequate data regarding the use of atrasentan in pregnant women.1 Animal reproductive data indicate that atrasentan can cause fetal harm, including birth defects and fetal death, when administered during pregnancy.1
In pregnant rats, oral administration of atrasentan throughout organogenesis at doses of 0.1, 0.3, 1, and 3 mg/kg per day resulted in developmental abnormalities primarily including the ear, lower jaw, or skull in all treated groups with detectable plasma exposures to atrasentan.1 In pregnant rabbits, oral administration of atrasentan throughout organogenesis at doses of 0.1, 0.3, 1, and 3 mg/kg per day resulted in visceral malformations including deformities in the cardiovascular system in all atrasentan treated groups.1
Atrasentan is contraindicated for use in pregnant individuals.1
It is not known whether atrasentan is distributed into human milk, or if the drug has any effects on the breastfed infant or on milk production.1
Advise patients to avoid breast-feeding while receiving atrasentan due to the potential for adverse reactions (e.g., fluid retention) in the breast-fed infant.1
Females and Males of Reproductive Potential
Atrasentan use is contraindicated during pregnancy.1 Exclude pregnancy before initiating atrasentan in females of reproductive potential.1 Advise females of reproductive potential to immediately inform their clinician if the onset of menses is delayed or if pregnancy is suspected.1 After a positive pregnancy test, the prescriber and patient must discuss the risks of atrasentan use.1
Females of reproductive potential must use an effective method of contraception prior to initiation of atrasentan, during treatment, and for 2 weeks after discontinuing the drug.1
Decreased sperm counts have been observed in some patients with diabetic kidney disease receiving atrasentan 0.75 mg once daily with return to normal levels within approximately 3 months after drug discontinuation.1 This effect has not been studied in patients with immunoglobulin A nephropathy (IgAN).1
Safety and efficacy of atrasentan have not been established in pediatric patients.1
In the ALIGN study, 7% of patients receiving atrasentan were ≥65 years of age.1 No overall difference in safety or effectiveness of atrasentan were observed between geriatric patients and younger adults.1
No clinically significant differences in the pharmacokinetics of atrasentan were observed based on mild to moderate hepatic impairment.1 The pharmacokinetics of atrasentan have not been studied in patients with severe hepatic impairment, and should not be initiated in this patient population.1
No clinically significant differences in the pharmacokinetics of atrasentan were observed based on mild to severe renal impairment.1 The pharmacokinetics of atrasentan have not been studied in patients with end-stage renal disease (ESRD).1
Most common adverse reactions (≥5%) reported with atrasentan in clinical studies were peripheral edema and anemia.1
Atrasentan is a cytochrome P-450 (CYP) 3A substrate.1 Atrasentan inhibits in vitro CYP3A, CYP2B6, CYP2C8, and CYP2C9 and induces CYP3A and CYP2B6.1
Atrasentan does not inhibit CYP1A2, CYP2C19, or CYP2D6 and is not an inducer of CYP1A2.1
Atrasentan is a substrate of P-glycoprotein (P-gp) and organic anion transporting polypeptides (OATP) 1B1/1B3 in vitro, but not a substrate of breast cancer resistance protein (BCRP), multidrug resistance-associated proteins (MRP) 2/4, sodium/taurocholate cotransporting polypeptide (NTCP), organic cation transporter (OCT) 1, or OATP2B1.1
Atrasentan inhibits P-gp, OATP1B1, and OATP1B3 and does not inhibit MRP, NTCP, OCT, OAT1, multidrug and toxin extrusion (MATE) 1, or MATE2K.1
Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes
Concomitant use with a moderate or strong CYP3A inducer is expected to decrease atrasentan exposure, which may reduce the efficacy of atrasentan.1 Avoid concomitant use with a moderate or strong CYP3A inducer.1
Concomitant use of a single 10 mg dose of atrasentan with rifampin, a strong CYP3A inducer, resulted in a 90% decrease in trough concentration of atrasentan.1
Concomitant use of a single 10 mg dose of atrasentan with ketoconazole, a strong CYP3A inhibitor, resulted in a 90% increase in the AUC of atrasentan.1
No clinically significant differences in the pharmacokinetics of midazolam, a CYP3A4 substrate, and losartan, a CYP2C9 and CYP3A4 substrate, were observed or expected when used concomitantly with atrasentan.1
Drugs Affecting or Affected by Transport Systems
Concomitant use with an OATP1B1/1B3 inhibitor increases atrasentan exposure, which may increase the risk of atrasentan adverse reactions.1 Concomitant use of a single 0.75 mg dose of atrasentan with cyclosporine, an OATP1B1/1B3 inhibitor, resulted in a 3.8-fold increase in AUC and a 4.3-fold increase in its maximum concentration.1
Avoid concomitant use with OATP1B1/1B3 inhibitors.1
No clinically significant differences in the pharmacokinetics of fexofenadine, a P-gp substrate, were observed or expected when administered with atrasentan.1 This is consistent with in vitro studies indicating that atrasentan does not cause clinically significant interactions through its inhibition of P-gp, OATP1B1, or OATP1B3.1
Atrasentan is an antagonist of the endothelin type A receptor (ETAR).1 Endothelin-1 is thought to contribute to the pathogenesis of immunoglobulin A nephropathy via the ETAR.1 Atrasentan shows high affinity for the ETAR, with >1800-fold selectivity for this receptor over the endothelin type B receptor.1
Increased atrasentan exposure was associated with an increased incidence of anemia, but no association was observed between atrasentan exposure and hypotension or peripheral edema.1
Steady state plasma concentrations are reached within 7 days with 2 to 3-fold accumulation.1 Atrasentan time to maximum plasma concentration is approximately 0.5 hour.1 In vitro, atrasentan is >99% bound to human plasma proteins.1 The effective half-life of atrasentan is approximately 24-41 hours.1 Atrasentan is extensively metabolized by CYP3A and multiple uridine 5'-diphospho-glucuronosyltransferases (UGTs).1 Following administration of a single radiolabeled dose of atrasentan 10 mg in healthy individuals, approximately 86% of the dose was recovered in feces (5.5% unchanged drug), and <4% recovered in urine (negligible amount of unchanged drug).1 Clinically significant differences in atrasentan pharmacokinetics have not been observed following administration with a high-fat meal in healthy subjects.1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Atrasentan is available through specialty pharmacies.5 Contact the manufacturer or consult the atrasentan website ([Web]) for more information.5
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets, film-coated | 0.75 mg (of atrasentan) | Vanrafia® | Novartis Pharmaceuticals |
AHFS® Drug Information. © Copyright, 1959-2025, Selected Revisions October 10, 2025. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
Only references cited for selected revisions after 1984 are available electronically.
1. Novartis Pharmaceuticals Corporation. VANRAFIA® (atrasentan) ORAL prescribing information. 2025 Apr. [Web]
2. Heerspink HJL, Jardine M, Kohan DE, et al. Atrasentan in patients with IgA nephropathy. N Engl J Med. 2025;392(6):544-554. doi:10.1056/NEJMoa2409415
3. US Food and Drug Administration. Center for Drug Evaluations and Research Application Number: 219208Orig1s000 Integrated Review. From FDA website. Accessed 2025 Jul 4.
4. Kidney Disease: Improving Global Outcomes (KDIGO) Glomerular Diseases Work Group. KDIGO 2021 clinical practice guideline for management of glomerular diseases. Kidney Int. 2021;100(4S):S1-S276.
5. Guide to Completing the Vanrafia (atrasentan) Start Form. From Vanfaria website. Accessed 2025 Jul 4. [Web]