ATRASENTAN: 15 Adverse Event Reports & Safety Profile

VANRAFIA contains atrasentan, an endothelin type A (ET A ) receptor antagonist. The chemical name of atrasentan hydrochloride is (2 R , 3 R , 4 S )-4-(1,3-benzodioxol-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)-3-pyrrolidinecarboxylic acid hydrochloride. Atrasentan hydrochloride has a molecular weight of 547.09 g/mol, a molecular formula of C 29 H 38 N 2 O 6 HCl and the following structural formula. Atrasentan is a slightly hygroscopic white to off-white powder that is slightly soluble in water. VANRAFIA is available as a film-coated tablet for oral administration. Each VANRAFIA tablet contains 0.75 mg atrasentan (equivalent to 0.803 mg of atrasentan hydrochloride) and contains the following excipients: crospovidone, glyceryl dibehenate, hypromellose, lactose monohydrate, L-cysteine hydrochloride monohydrate, polyethylene glycol, and silicon dioxide. Atrasentan structural formula

AND USAGE 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 [see Clinical Studies (14.1)] . 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. ( 1 ) 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. ( 1 )

AND ADMINISTRATION 0.75 mg orally once daily with or without food ( 2.2 )

2.1 Pregnancy Testing Exclude pregnancy before initiating VANRAFIA <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1), Use in Specific Populations (8.1, 8.3)]</span> .

2.2 Recommended Dosage The recommended dose of VANRAFIA is 0.75 mg administered orally once daily with or without food <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3)]</span> . 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.

Pregnancy ( 4.1 ) Hypersensitivity ( 4.2 )

4.1 Pregnancy Use of VANRAFIA is contraindicated in patients who are pregnant <span class="opacity-50 text-xs">[see Dosage and Administration (2.1), Warnings and Precautions (5.1), Use in Specific Populations (8.1)]</span> .

4.2 Hypersensitivity VANRAFIA is contraindicated in patients with a history of a hypersensitivity reaction to atrasentan or any component of the product.

REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Embryo-fetal Toxicity [see Warnings and Precautions (5.1)] Hepatotoxicity [see Warnings and Precautions (5.2)]

Fluid

Retention [see Warnings and Precautions (5.3)]

Decreased Sperm

Counts [see Warnings and Precautions (5.4)] Most common adverse reactions (incidence ≥ 5%) were peripheral edema and anemia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 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 <span class="opacity-50 text-xs">[see Clinical Studies (14.1)]</span> . 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.

AND PRECAUTIONS Hepatotoxicity ( 5.2 )

Fluid

Retention ( 5.3 )

Decreased Sperm

Counts ( 5.4 , 8.3 )

5.1 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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.1) and Use in Specific Populations (8.1, 8.3)]</span> . When pregnancy is detected, discontinue VANRAFIA as soon as possible <span class="opacity-50 text-xs">[see Dosage and Administration (2.1), Contraindications (4.1), Use in Specific Populations (8.1, 8.3)]</span> .

5.2 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 <span class="opacity-50 text-xs">[see Adverse Reactions (6.1)]</span> . Obtain liver enzyme testing before initiating VANRAFIA and repeat during treatment as clinically indicated. In patients with elevated aminotransferases at baseline (&gt;3 × upper limit of normal [ULN]), 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 &gt;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.

5.3 Fluid Retention Fluid retention may occur with ERAs and has been observed in clinical studies with VANRAFIA <span class="opacity-50 text-xs">[see Adverse Reactions (6.1)]</span> . 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.

5.4 Decreased Sperm Counts VANRAFIA, similar to other ERAs, may have an adverse effect on spermatogenesis. Counsel men about potential effects on fertility <span class="opacity-50 text-xs">[see Use in Specific Populations (8.3) and Nonclinical Toxicology (13.1)]</span> .

INTERACTIONS Strong or moderate CYP3A inducers: Avoid concomitant use. ( 7.1 ) OATP1B1/1B3 inhibitors: Avoid concomitant use. ( 7.1 )

7.1 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3)]</span> . Concomitant use with a strong and moderate CYP3A inducer is expected to decrease atrasentan exposure <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3)]</span> , 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3)]</span> . Concomitant use with a OATP1B1/1B3 inhibitor increases atrasentan exposure <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3)]</span> , which may increase the risk of VANRAFIA adverse reactions.