5.1 Hypercorticism and Adrenal Axis Suppression

When corticosteroids are used chronically, systemic effects such as hypercorticism and adrenal suppression may occur. Corticosteroids can reduce the response of the hypothalamus-pituitary-adrenal (HPA) axis to stress. In situations where patients are subject to surgery or other stress situations, supplementation with a systemic corticosteroid is recommended. When discontinuing therapy [see Dosing and Administration (2)] or switching between corticosteroids, monitor for signs of adrenal axis suppression.

Patients with moderate to severe hepatic impairment (Child-Pugh Class B and C respectively) could be at an increased risk of hypercorticism and adrenal axis suppression due to an increased systemic exposure of oral budesonide. Avoid use in patients with severe hepatic impairment (Child-Pugh Class C). Monitor for increased signs and/or symptoms of hypercorticism in patients with moderate hepatic impairment (Child-Pugh Class B) [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

5.2 Risks of Immunosupression

Patients who are on drugs that suppress the immune system are more susceptible to infection than healthy individuals. Chickenpox and measles, for example, can have a more serious or even fatal course in susceptible patients or patients on immunosuppressant doses of corticosteroids. Avoid corticosteroid therapy in patients with active or quiescent tuberculosis infection, untreated fungal, bacterial, systemic viral or parasitic infections, or ocular herpes simplex. Avoid exposure to active, easily-transmitted infections (e.g., chicken pox, measles). Corticosteroid therapy may decrease the immune response to some vaccines.

How the dose, route, and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If exposed to chickenpox, consider therapy with varicella zoster immune globulin (VZIG) or pooled intravenous immunoglobulin (IVIG). If exposed to measles, consider prophylaxis with pooled intramuscular immunoglobulin (IG). If chickenpox develops, consider treatment with antiviral agents.

5.3 Other Corticosteroid Effects

TARPEYO is a systemically available corticosteroid and is expected to cause related adverse reactions. Monitor patients with hypertension, prediabetes, diabetes mellitus, osteoporosis, peptic ulcer, glaucoma or cataracts, or with a family history of diabetes or glaucoma, or with any other condition where corticosteroids may have unwanted effects.

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 TARPEYO has been evaluated in a randomized controlled study in 197 patients.

The most common adverse reactions reported in greater than or equal to 5% of TARPEYO-treated patients are listed in Table 1.

The majority of adverse reactions were mild or moderate in severity.

Most adverse reactions that occurred at a greater incidence for TARPEYO compared to placebo were consistent with hypercortisolism.

7.1 Interaction with CYP3A4 Inhibitors

Budesonide is a substrate for CYP3A4. Avoid use with potent CYP3A4 inhibitors; e.g. ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, erythromycin, and cyclosporine [see Clinical Pharmacology (12.3)].

Avoid ingestion of grapefruit juice with TARPEYO. Intake of grapefruit juice, which inhibits CYP3A4 activity, can increase the systemic exposure to budesonide [see Clinical Pharmacology (12.3)].

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

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

8.5 Geriatric Use

Clinical studies of TARPEYO did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

8.6 Hepatic Impairment

Patients with moderate to severe hepatic impairment (Child-Pugh Class B and C, respectively) could be at an increased risk of hypercorticism and adrenal axis suppression due to an increased systemic exposure to budesonide [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)]. Avoid use in patients with severe hepatic impairments (Child-Pugh Class C). Monitor for increased signs and/or symptoms of hypercorticism in patients with moderate hepatic impairment (Child-Pugh Class B).

12.1 Mechanism of Action

Budesonide is a corticosteroid with potent glucocorticoid activity and weak mineralocorticoid activity that undergoes substantial first pass metabolism. Mucosal B-cells present in the ileum, including the Peyer's patches, express glucocorticoid receptors and are responsible for the production of galactose-deficient IgA1 antibodies (Gd-Ag1) causing IgA nephropathy. Through their anti-inflammatory and immunosuppressive effects at the glucocorticoid receptor, corticosteroids can modulate B-cell numbers and activity. It has not been established to what extent TARPEYO's efficacy is mediated via local effects in the ileum vs systemic effects.

12.2 Pharmacodynamics

Treatment with corticosteroids, including TARPEYO, is associated with a suppression of endogenous cortisol concentrations and an impairment of the hypothalamus-pituitary-adrenal (HPA) axis function.

12.3 Pharmacokinetics

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies with budesonide were conducted in rats and mice. In a two-year study in Sprague-Dawley rats, budesonide caused a statistically significant increase in the incidence of gliomas in male rats at an oral dose of 50 mcg/kg (approximately 0.03 times the maximum recommended human dose (MRHD) on a body surface area basis). In addition, there were increased incidences of primary hepatocellular tumors in male rats at 25 mcg/kg (approximately 0.015 times the MRHD on a body surface area basis) and above. No tumorigenicity was seen in female rats at oral doses up to 50 mcg/kg (approximately 0.03 times the MRHD on a body surface area basis). In an additional two-year study in male Sprague-Dawley rats, budesonide caused no gliomas at an oral dose of 50 mcg/kg (approximately 0.03 times the MRHD on a body surface area basis). However, it caused a statistically significant increase in the incidence of hepatocellular tumors at an oral dose of 50 mcg/kg (approximately 0.03 times the MRHD of a body surface area basis). The concurrent reference corticosteroids (prednisolone and triamcinolone acetonide) showed similar findings. In a 91-week study in mice, budesonide caused no treatment-related carcinogenicity at oral doses up to 200 mcg/kg (approximately 0.06 times the MRHD on a body surface area basis).

Budesonide was not genotoxic in the Ames text, the mouse lymphoma cell forward gene mutation (TK+/-) test, the human lymphocyte chromosome aberration test, the Drosophila melanogaster sex-linked recessive lethal test, the rat hepatocyte UDS test and the mouse micronucleus test.

In rats, budesonide had no effect on fertility at subcutaneous doses up to 80 mcg/kg (approximately 0.05 times the MRHD on a body surface area basis). However, it caused a decrease in prenatal viability and viability in pups at birth and during lactation, along with a decrease in maternal food consumption and body weight gain, at subcutaneous doses of 20 mcg/kg (approximately 0.012 times the MRHD on a body surface area basis) and above. No such effects were noted at 5 mcg/kg (approximately 0.003 times the MRHD on a body surface area basis).

14.1 Treatment of IgAN

The effect of TARPEYO on proteinuria was assessed in a randomized, double-blind, multicenter study (Nef-301, NCT: 03643965) in patients with biopsy-proven IgAN, eGFR ≥35 mL/min/1.73 m2, and proteinuria (defined as either ≥1 g/day or UPCR ≥0.8 g/g) who were on a stable dose of maximally-tolerated RAS inhibitor therapy. Patients with other glomerulopathies, nephrotic syndrome, or those who had been treated with systemic immunosuppressive medications were excluded. Patients were randomized 1:1 to either TARPEYO 16 mg once daily or placebo and treated for nine months followed by a 2-week taper of either TARPEYO 8 mg once daily or placebo.

Of the 199 patients who completed the Month 9 visit, 68% were male, 86% were Caucasian, 12% were Asian, and 16% were from the US. The median age was 44 years (range 23 to 73 years). At baseline, the mean eGFR was approximately 58 mL/min/1.73 m2, with 62% of patients having an eGFR <60 mL/min/1.73 m2. The mean baseline UPCR was 1.6 g/g and 25% of patients had proteinuria >3.5 g/24 hours. Approximately 73% of patients had a history of hypertension and 5% had a history of type 2 diabetes mellitus. At baseline, 98% were treated with an ACE inhibitor or ARB and <1% of patients were on an SGLT2 inhibitor.

The primary endpoint was the percentage reduction in UPCR at 9 months compared to baseline. The results are shown in Table 2.

The treatment effect for the UPCR endpoint at 9 months were consistent across key subgroups, including key demographic (such as age, sex, race) and baseline disease (such as baseline proteinuria) characteristics.