Baxdrostat

1 INDICATIONS AND USAGE BAXFENDY, in combination with other antihypertensive drugs, is indicated for the treatment of hypertension, to lower blood pressure in adults who are not adequately controlled on other agents. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes. There are no controlled trials demonstrating risk reduction of these events with BAXFENDY. Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the American College of Cardiology/American Heart Association (ACC/AHA). Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly. Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal. BAXFENDY is an aldosterone synthase inhibitor indicated for the treatment of hypertension in combination with other antihypertensive drugs, to lower blood pressure in adults who are not adequately controlled on other agents. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. (1)

12.1 Mechanism of Action Baxdrostat is an inhibitor of human aldosterone synthase. Aldosterone contributes to hypertension by promoting the retention of sodium and water by the kidneys, which increases blood volume and, consequently, raises blood pressure. Aldosterone can cause vascular dysfunction, inflammation, and fibrosis. Inhibition of aldosterone synthase by baxdrostat decreases plasma aldosterone concentrations, thereby reducing blood pressure. Baxdrostat has a higher potency and selectivity for aldosterone synthase compared to the closely related enzyme 11β-hydroxylase (final enzyme in cortisol synthesis). In nonclinical and clinical studies, baxdrostat significantly lowered aldosterone concentrations without affecting cortisol responses over a wide dose range. Baxdrostat does not inhibit synthesis of sex hormones such as testosterone and estrone.

2 DOSAGE AND ADMINISTRATION • Consider the patient’s risk of hyperkalemia and hyponatremia before initiating BAXFENDY. (2.1) • Recommended dosage is 2 mg orally once daily. (2.2) • For patients at increased risk of hyperkalemia or hyponatremia, the recommended dosage is 1 mg once daily. (2.2) • Take with or without food. (2.3) 2.1 Testing Prior to and After Initiation of BAXFENDY Consider the patient’s risk of hyperkalemia and hyponatremia before initiating BAXFENDY. Assess serum potassium and sodium before initiation of BAXFENDY and periodically thereafter. Correct serum potassium and sodium abnormalities prior to initiation of BAXFENDY [see Warnings and Precautions (5.1 , 5.2 )] . 2.2 Recommended Dosage The recommended dosage of BAXFENDY is 2 mg orally once daily. For patients at increased risk of hyperkalemia or hyponatremia, the recommended dosage is 1 mg orally once daily [see Warnings and Precautions (5.1 , 5.2) ] . 2.3 Administration Instructions Swallow tablets whole. Do not cut, crush, or chew tablets. BAXFENDY may be taken with or without food. If a dose is missed, take the next dose at the usual time. Do not take a double dose on the same day.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are also discussed elsewhere in the labeling: • Hyperkalemia [see Warnings and Precautions (5.1) ] • Hyponatremia [see Warnings and Precautions (5.2) ] The most common adverse reaction (more frequent than placebo and ≥ 5% in BAXFENDY-treated patients) was hyperkalemia. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca at 1-800-236-9933 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 BAXFENDY was evaluated over 12 weeks using the randomized, double-blind, placebo-controlled periods from three clinical trials in patients with hypertension not adequately controlled on other antihypertensive medications. Three of these trials [BaxHTN (NCT06034743), BrigHTN (NCT04519658), Bax24 (NCT06168409)] evaluated BAXFENDY 2 mg as add-on treatment and two trials [BaxHTN, BrigHTN] evaluated BAXFENDY 1 mg as add-on treatment. These data reflect exposure of 441 patients to BAXFENDY 2 mg and 333 patients to BAXFENDY 1 mg, with a mean treatment duration of 80 days for both BAXFENDY 2 mg and 1 mg. Analyses in this section are based on the 12‑week periods in these three trials. Uncontrolled, long-term safety data from 192 patients exposed to BAXFENDY 1 mg or 2 mg for a mean of 293 days and 172 patients exposed to BAXFENDY 2 mg for a mean of 327 days, were consistent with the safety profile observed during the 12-week, randomized, double-blind, placebo-controlled periods. Hyperkalemia was the most frequently reported adverse reaction to BAXFENDY in the three clinical trials [see Warnings and Precautions (5.1) ] . Hyperkalemia led to permanent discontinuation of treatment in 8 (1.8%) patients in the BAXFENDY 2 mg group, 2 (0.6%) patients in the BAXFENDY 1 mg group, and none in the placebo group. Table 1 shows the most frequently reported adverse reactions to BAXFENDY during the 12-week period in the three clinical trials. Table 1: Adverse Reactions Reported in ≥ 2% of Patients Treated with BAXFENDY and Greater (≥ 1%) than Placebo During the 12-Week, Randomized, Double-Blind Periods from Three Clinical Trials in Patients with Hypertension Adverse Reaction BAXFENDY 2 mg Frequencies derived from the pool of three hypertension studies (BaxHTN, BrigHTN, Bax24) with BAXFENDY 2 mg as add-on treatment. N=441 % BAXFENDY 1 mg Frequencies derived from the pool of two hypertension studies (BaxHTN, BrigHTN) with BAXFENDY 1 mg as add-on treatment. N=333 % Placebo Frequencies derived from the pool of three hypertension studies (BaxHTN, BrigHTN, Bax24) with BAXFENDY 1 mg and/or 2 mg as add‑on treatment. N=442 % Hyperkalemia 10.2 6.6 2.5 Hypotension 3.6 2.1 0.5 Hyponatremia 3.2 2.1 0.9 Dizziness 2.9 3.0 0.9 Muscle spasms 2.9 1.8 0.7 Laboratory Tests Serum Potassium During the 12-week, randomized, double-blind periods from BAXFENDY clinical trials in patients with hypertension, increases in serum potassium (> 5.5 mEq/L) were reported for 12.2% of patients administered BAXFENDY 2 mg, 6.3% of patients administered BAXFENDY 1 mg, and 0.9% of placebo-treated patients. Serum Sodium During the 12-week, randomized, double-blind periods from BAXFENDY clinical trials in patients with hypertension, decreases in serum sodium (< 130 mEq/L) were reported for 3.7% of patients administered BAXFENDY 2 mg, 3.3% of patients administered BAXFENDY 1 mg, and 0.9% of placebo-treated patients. Estimated Glomerular Filtration Rate (eGFR) A decrease in mean eGFR was observed in BAXFENDY clinical trials in patients with hypertension. At Week 12, the mean placebo-corrected decrease in eGFR was 8.0 mL/min/1.73 m 2 in the BAXFENDY 2 mg group and 7.1 mL/min/1.73 m 2 in the BAXFENDY 1 mg group. In BAXFENDY-

5 WARNINGS AND PRECAUTIONS • Hyperkalemia : Assess serum potassium before initiation and periodically thereafter. Assess more frequently in patients at increased risk of hyperkalemia. ( 5.1 ) • Hyponatremia : Assess serum sodium before initiation and periodically thereafter. Assess more frequently in patients at increased risk of hyponatremia. ( 5.2 ) 5.1 Hyperkalemia BAXFENDY can cause hyperkalemia [see Adverse Reactions (6.1) ] . Assess serum potassium prior to initiation of BAXFENDY and monitor periodically during treatment. Correct serum potassium abnormalities prior to initiation of BAXFENDY [see Dosage and Administration (2.1 , 2.2) ] . More frequent monitoring is recommended for patients at increased risk of hyperkalemia (e.g., patients ≥ 65 years of age, those with diabetes mellitus or chronic kidney disease, and those receiving concomitant medications that increase serum potassium) [see Drug Interactions (7.1) and Geriatric Use (8.5) ] . If hyperkalemia occurs, treat hyperkalemia and consider interrupting or discontinuing BAXFENDY. Consider more frequent monitoring of serum potassium in patients who restart BAXFENDY after experiencing hyperkalemia. Permanently discontinue BAXFENDY if clinically significant hyperkalemia recurs. 5.2 Hyponatremia BAXFENDY can cause hyponatremia [see Adverse Reactions (6.1) ] . Assess serum sodium prior to initiation of BAXFENDY and monitor periodically during treatment. Correct serum sodium abnormalities prior to initiation of BAXFENDY [see Dosage and Administration (2.1 , 2.2 )] . More frequent monitoring is recommended for patients with low baseline serum sodium concentrations and those at risk of hyponatremia, such as those receiving concomitant medications that may cause hyponatremia. If clinically significant hyponatremia occurs, treat the hyponatremia and consider interrupting or discontinuing BAXFENDY. Consider more frequent monitoring of serum sodium in patients who restart BAXFENDY after experiencing hyponatremia. Permanently discontinue BAXFENDY if clinically significant hyponatremia recurs.

4 CONTRAINDICATIONS None. None. (4)

10 OVERDOSAGE BAXFENDY did not show any toxicity in healthy subjects at single oral doses up to 360 mg. In the event of an overdose, consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations. It is also reasonable to employ supportive measures as dictated by the patient’s clinical status. The removal of baxdrostat by hemodialysis has not been studied.