Atrasentan

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 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. 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.

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.

Carcinogenesis

In female rats orally administered atrasentan for 2 years, no atrasentan-related tumor findings were observed at exposures approximately 12 times the AUC at the MRHD. At a higher exposure (approximately 24 times the AUC at the MRHD, or 2 mg/kg/day), an increased incidence of benign uterine stromal polyps considered of low human relevance was observed. In male rats, no carcinogenic effects were observed at exposures approximately 100 times the AUC at the MRHD.

There were no atrasentan-related tumor findings observed in male and female transgenic mice administered atrasentan for 6 months at doses up to 60 mg/kg/day.

Mutagenesis

There was no evidence of mutagenicity or clastogenicity for atrasentan in in vitro bacteria reverse mutation and chromosomal aberration assays, or in an in vivo mouse micronucleus study.

Impairment of Fertility

In a fertility study, male rats were treated with atrasentan at doses of 5, 20, and 60 mg/kg/day and mated with untreated female rats. No adverse effects on male fertility were observed at 5 mg/kg/day, approximately 53 times the AUC at the MRHD. At higher doses, decreased numbers of implantation sites, reduced viable fetuses, and increased pre-implantation loss were observed in the untreated female rats mated with the treated male rats. These effects were reversible at 20 mg/kg/day, approximately 422 times the AUC at MRHD. In rats and dogs, testicular degeneration, dilatation of seminiferous tubules, interstitial edema of the testes, and prostate inflammation were observed at all doses tested, and a no adverse effect dose level could not be determined.

In a female rat fertility study, no reproductive toxicity was observed following oral administration during premating, mating, and early gestation at doses up to 100 mg/kg/day.

In female rats, cystic endometrial hyperplasia was observed at the lowest dose tested of 0.8 mg/kg/day.

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 atrasentan 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 atrasentan were peripheral edema and anemia. Table 1 describes the adverse reactions that occurred in ≥2% of patients treated with atrasentan and higher than placebo in the ALIGN study.

Table 1. Adverse Reactions Reported in ≥2% of Adult Patients with IgAN Treated with Atrasentan and Higher than Placebo in ALIGN:

^* Includes related terms
^** Elevations in ALT or AST >3-fold upper limit of normal (ULN)

Laboratory Tests and Vital Signs

Hemoglobin Decrease

At Week 36, the mean change in hemoglobin from baseline for those patients receiving atrasentan 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 atrasentan 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 atrasentan 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 atrasentan treated patients was mild or moderate in severity, rarely symptomatic, and did not necessitate treatment discontinuation.