Atrasentan (Monograph)

Brand name: Vanrafia
Drug class: Endothelin receptor antagonists

Introduction

Atrasentan hydrochloride is an endothelin type A (ET_A) receptor antagonist.

Uses for Atrasentan

Atrasentan has the following uses:

Atrasentan 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 atrasentan 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.

Atrasentan Dosage and Administration

General

Atrasentan hydrochloride is available in the following dosage form(s) and strength(s):

• Tablets: 0.75 mg of atrasentan

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

Dosage and Administration

• Recommended dosage is 0.75 mg orally once daily with or without food.

• Swallow tablets whole; do not cut, crush, or chew.

Cautions for Atrasentan

Contraindications

• Patients who are pregnant.

• Patients with a history of hypersensitivity reaction to atrasentan or any component of the product.

Warnings/Precautions

Embryo-fetal Toxicity

Based on data from animal reproduction studies, atrasentan 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 atrasentan. Counsel patients who can become pregnant of the potential risk to a fetus. Exclude pregnancy prior to initiation of treatment with atrasentan. Advise patients to use effective contraception prior to initiation of treatment, during treatment, and for two weeks after discontinuation of treatment with atrasentan. When pregnancy is detected, discontinue atrasentan 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 atrasentan. Obtain liver enzyme testing before initiating atrasentan and repeat during treatment as clinically indicated. In patients with elevated aminotransferases at baseline (>3 × upper limit of normal [ULN]), consider periodic liver test monitoring. Do not initiate atrasentan 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 atrasentan. Consider re-initiation of atrasentan 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 atrasentan. Atrasentan has not been evaluated in IgAN patients with heart failure. If clinically significant fluid retention develops, consider initiating or increasing diuretic treatment and interrupting atrasentan treatment.

Decreased Sperm Counts

Atrasentan, similar to other ERAs, may have an adverse effect on spermatogenesis. Counsel men about potential effects on fertility.

Specific Populations

Pregnancy

Based on data from animal reproductive toxicity studies, atrasentan 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 atrasentan 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 postmarketing 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. 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.

Lactation

There are no data on the presence of atrasentan in human milk, the effects on the breastfed infant, or the effect on milk production. Because of the potential for adverse reactions, such as fluid retention in breastfed infants, advise patients not to breastfeed during treatment with atrasentan.

Females and Males of Reproductive Potential

Based on data from animal reproductive toxicity studies, atrasentan may cause fetal harm, including birth defects and fetal death, when administered to a pregnant patient and is contraindicated during pregnancy.

Exclude pregnancy before initiating atrasentan in females of reproductive potential. The patient should contact their physician immediately for pregnancy testing if onset of menses is delayed or pregnancy is suspected. If pregnancy is confirmed, the physician should discuss with the patient the risks to the pregnancy and the fetus.

Patients who can become pregnant while using atrasentan should use effective contraception prior to initiation of treatment, during treatment, and for two weeks after discontinuation of treatment with atrasentan to prevent pregnancy.

Decreased sperm counts have been observed in some patients with diabetic kidney disease (DKD) receiving atrasentan 0.75 mg once daily with return to normal levels within approximately 3 months after drug discontinuation. This effect has not been studied in patients with IgAN.

Pediatric Use

The safety and efficacy of atrasentan in pediatric patients have not been established.

Geriatric Use

There were 29 (7%) patients 65 years of age and older in the ALIGN study of atrasentan. Of the total number of atrasentan-treated patients, 15 (7%) were 65 to 75 years of age, and 3 (2%) were 75 years of age and older. No overall differences in safety and effectiveness were observed between these patients and younger patients.

Hepatic Impairment

No dose adjustment is required for patients with mild or moderate hepatic impairment. Do not initiate atrasentan in patients with severe hepatic impairment.

Common Adverse Effects

Most common adverse reactions (incidence ≥ 5%) were peripheral edema and anemia.

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

• Strong or moderate CYP3A inducers: Avoid concomitant use.

• OATP1B1/1B3 inhibitors: Avoid concomitant use.

Actions

Mechanism of Action

Atrasentan is an ET_A receptor antagonist (Ki = 0.034 nM) with >1800-fold selectivity for the ET_A receptor compared to the endothelin type B receptor (Ki = 63.3 nM). Endothelin (ET)-1 is thought to contribute to the pathogenesis of IgAN via the ET_A receptor.

Advice to Patients

• Advise the patient to read the FDA-approved patient labeling (Medication Guide).

• Educate and counsel female patients of reproductive potential to use effective contraception prior to starting treatment with atrasentan, during treatment and for two weeks after treatment discontinuation. Patients who can become pregnant should have a negative pregnancy test prior to treatment with atrasentan.

• Patients should be instructed to immediately contact their physician if they suspect they may be pregnant. Patients should seek additional contraceptive advice as needed.

• Educate and counsel patients who can become pregnant on the use of emergency contraception in the event of unprotected sex or contraceptive failure.

• Advise patients to contact their healthcare provider if they want to change the form of birth control to ensure that another acceptable form of birth control is selected.

• Some members of this pharmacological class are hepatotoxic. Educate patients on signs of hepatotoxicity. Advise patients that they should contact their doctor if they have unexplained nausea, vomiting, right upper quadrant pain, fatigue, anorexia, jaundice, dark urine, fever, or itching.

• Educate patients on signs of fluid retention. Advise patients that they should contact their doctor if they have unusual weight increase or swelling of the ankles or legs.

• Advise patients not to breastfeed during treatment with atrasentan.

• Advise patients of the risk of decreased sperm count.

Additional Information

AHFSfirstRelease^™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

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.

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