2.1 Recommended Dosage

• The recommended dosage is 2 mg orally twice daily for 12 weeks.

2.2 Preparation and Important Administration Instructions

• Do NOT take EOHILIA with food or liquid at the time of ingestion. Wait for at least 30 minutes to eat or drink after taking EOHILIA.
• Administer EOHILIA as follows:
  1. Do NOT mix EOHILIA with food or liquid.
  2. Shake the EOHILIA stick pack for at least 10 seconds prior to opening.
  3. Squeeze the stick pack from the bottom to the top directly into the mouth. Repeat 2 to 3 times until the EOHILIA stick pack is empty.
  4. Swallow all the EOHILIA suspension.
  5. Do not eat or drink for 30 minutes after taking EOHILIA. After 30 minutes, rinse mouth with water and spit out the contents without swallowing [see Warnings and Precautions (5.2)].
• Avoid consumption of grapefruit juice for the duration of therapy with EOHILIA [see Drug Interactions (7.1)].

5.1 Hypercorticism and Adrenal Axis Suppression

Systemic effects such as hypercorticism and adrenal axis suppression may occur with use of corticosteroids, including EOHILIA. Monitor patients for signs and symptoms of hypercorticism and adrenal axis suppression and consider reducing the dosage of EOHILIA [see Adverse Reactions (6.1), Clinical Pharmacology (12.2)].

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. Use is not recommended in patients with severe hepatic impairment (Child-Pugh Class C) and monitoring for signs and/or symptoms of hypercorticism is recommended in patients with moderate hepatic impairment (Child-Pugh Class B) [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

Corticosteroids, including EOHILIA, can reduce the response of the hypothalamus-pituitary-adrenal (HPA) axis to stress. In situations where patients are subject to trauma, surgery, infection, or other stress situations, supplementation with a systemic corticosteroid is recommended.

5.2 Immunosuppression and Increased Risk of Infection

Corticosteroids, including EOHILIA, suppress the immune system and increase the risk of infection with any pathogen, including viral, bacterial, fungal, protozoan, or helminthic pathogens. Corticosteroids can:

• Reduce resistance to new infections
• Exacerbate existing infections
• Increase the risk of disseminated infections
• Increase the risk of reactivation or exacerbation of latent infections
• Mask some signs of infection

Corticosteroid-associated infections can be mild but can be severe and at times fatal. The rate of infectious complications increases with increasing corticosteroid dosages.

Monitor patients for the development of infection and consider discontinuation of EOHILIA if the patient develops an infection while on treatment.

Tuberculosis

If corticosteroids are used in patients with latent tuberculosis or tuberculin reactivity, reactivation of tuberculosis may occur. Closely monitor such patients for reactivation while receiving EOHILIA.

Varicella Zoster and Measles Viral Infections

Varicella and measles can have a serious or even fatal course in non-immune pediatric and adult patients taking corticosteroids. In corticosteroid-treated patients who have not had these diseases or are non-immune, particular care should be taken to avoid exposure to varicella and measles:

• If an EOHILIA-treated patient is exposed to varicella, prophylaxis with varicella zoster immune globulin may be indicated. If varicella develops, treatment with antiviral agents may be considered.
• If an EOHILIA-treated patient is exposed to measles, prophylaxis with immunoglobulin may be indicated.

Hepatitis B Virus Reactivation

Hepatitis B virus reactivation can occur in patients who are hepatitis B carriers treated with immunosuppressive dosages of corticosteroids. Reactivation can also occur infrequently in corticosteroid-treated patients who appear to have resolved hepatitis B infection.

Prior to starting treatment with EOHILIA, for patients who show evidence of hepatitis B infection, recommend consultation with physicians with expertise in managing hepatitis B regarding monitoring and consideration for hepatitis B antiviral therapy.

Fungal Infections

Corticosteroids may exacerbate systemic fungal infections; therefore, avoid EOHILIA use in the presence of such infections.

Amebiasis

Corticosteroids may activate latent amebiasis. Therefore, it is recommended that latent amebiasis or active amebiasis be ruled out before initiating EOHILIA in patients who have spent time in the tropics or patients with unexplained diarrhea.

Strongyloides Infestation

Avoid EOHILIA in patients with known or suspected Strongyloides (threadworm) infection. Corticosteroid-induced immunosuppression may lead to Strongyloides superinfection and dissemination with widespread larval migration, often accompanied by severe enterocolitis and potentially fatal gram-negative septicemia.

Cerebral Malaria

Avoid corticosteroids, including EOHILIA, in patients with cerebral malaria.

Ocular Herpes Simplex

Avoid corticosteroids, including EOHILIA, in patients with active ocular herpes simplex.

Localized Infections

In clinical trials with EOHILIA, localized infections with Candida albicans occurred in the mouth, throat, and esophagus in some subjects [see Adverse Reactions (6.1)]. Do not eat or drink for 30 minutes after taking EOHILIA. After 30 minutes, rinse mouth with water and spit without swallowing [see Dosage and Administration (2.2)]. If oropharyngeal or esophageal candidiasis develops, treat with appropriate local or systemic antifungal therapy and consider discontinuing treatment with EOHILIA.

5.3 Erosive Esophagitis

Erosive esophagitis occurred in subjects who received EOHILIA in a 12-week clinical trial. None of the subjects had erosions at baseline esophagogastroduodenoscopy (EGD), and most were receiving concomitant therapy with a proton pump inhibitor (PPI) during the trial [see Adverse Reactions (6.1)].

Advise patients or caregivers to report new onset or worsening signs or symptoms of erosive esophagitis to their healthcare provider. Consider endoscopic evaluation as appropriate.

5.4 Effect on Growth

Use of corticosteroids may cause a reduction of growth velocity in pediatric patients. Monitor the growth of pediatric patients on EOHILIA. The maximum recommended duration of treatment with EOHILIA is 12 weeks [see Dosage and Administration (2.1)].

5.5 Symptoms of Steroid Withdrawal in Patients Transferred from Other Systemic Corticosteroids

Monitor patients who are transferred from corticosteroid treatment with high systemic effects to corticosteroids with lower systemic availability, such as EOHILIA, since symptoms attributed to withdrawal of steroid therapy, including those of acute adrenal axis suppression or benign intracranial hypertension, may develop. Adrenocortical function monitoring may be required in these patients and the dose of corticosteroid treatment with high systemic effects should be reduced cautiously.

Replacement of systemic corticosteroids with EOHILIA may unmask allergies (e.g., rhinitis and eczema), which were previously controlled by the systemic drug.

5.6 Other Corticosteroid Effects

Monitor patients with hypertension, 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.

5.7 Kaposi’s Sarcoma

Kaposi’s sarcoma has been reported to occur in patients receiving corticosteroid therapy, most often for chronic conditions. Discontinuation of corticosteroids may result in clinical improvement of Kaposi’s sarcoma. The maximum recommended duration of treatment with EOHILIA is 12 weeks [see Dosage and Administration (2.1)].

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 EOHILIA in 410 adults and pediatric subjects 11 years of age and older with EoE was evaluated in two 12-week, double-blind, placebo-controlled studies (Study 1 and Study 2). In these studies, 263 subjects received EOHILIA [see Clinical Studies (14)].

6.2 Postmarketing Experience

The following adverse reactions have been reported during post-approval use of oral budesonide products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Hypersensitivity Reactions: Anaphylaxis

Nervous System Disorders: Benign intracranial hypertension

Psychiatric Disorders: Mood swings

7.1 CYP3A4 Inhibitors

Budesonide is a substrate for CYP3A4. Concomitant use of budesonide with CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, erythromycin, cyclosporine, grapefruit juice) can increase systemic budesonide concentrations [see Clinical Pharmacology (12.3)]. Avoid concomitant use of CYP3A4 inhibitors, including grapefruit juice, with EOHILIA [see Dosage and Administration (2.2)].

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

The safety and effectiveness of EOHILIA for 12 weeks of treatment for EoE have been established in pediatric patients 11 years of age and older. Use of EOHILIA for this indication is supported by adequate and well controlled studies in adults and pediatric subjects 11 years of age and older (Studies 1 and 2) with pharmacokinetic data in pediatric subjects aged 11 to 17 years of age. In Studies 1 and 2, the safety of EOHILIA in pediatric subjects 11 to 17 years of age was similar to the safety profile in adults [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14)].

Systemic effects such as hypercorticism and adrenal axis suppression may occur with use of corticosteroids, including EOHILIA [see Warnings and Precautions (5.1), Adverse Reactions (6.1), and Clinical Pharmacology (12.2)].

Use of corticosteroids may cause a reduction of growth velocity in pediatric patients. Monitor the growth of pediatric patients on EOHILIA. The recommended duration of treatment with EOHILIA is 12 weeks [see Dosage and Administration (2.1)].

The safety and effectiveness of EOHILIA in pediatric patients less than 11 years of age have not been established.

8.5 Geriatric Use

Clinical studies of EOHILIA did not include sufficient numbers of subjects 65 years of age and older to determine whether they respond differently from younger adult subjects. In general, EOHILIA should be used with caution due to the potential for decreased hepatic function [see Warnings and Precautions (5.1)].

8.6 Hepatic Impairment

Patients with moderate to severe hepatic impairment (Child-Pugh Class B or Class C, respectively) could be at an increased risk of hypercorticism and adrenal axis suppression due to an increased systemic exposure to budesonide. Use is not recommended in patients with severe hepatic impairment (Child-Pugh Class C). The recommended dosage in patients with mild or moderate hepatic impairment (Child-Pugh Class A or Class B) is the same as the recommended dosage in patients with normal hepatic function. In patients with moderate hepatic impairment (Child-Pugh Class B), monitor for signs and/or symptoms of hypercorticism [see Warnings and Precautions (5.1), Clinical Pharmacology (12.3)].

12.1 Mechanism of Action

Budesonide is an anti-inflammatory corticosteroid and has a high glucocorticoid effect and a weak mineralocorticoid effect, and the affinity of budesonide to glucocorticoid receptors, which reflects the intrinsic potency of the drug, is about 200-fold that of cortisol and 15-fold that of prednisolone.

The precise mechanism of corticosteroid actions on inflammation in EoE is not known. Inflammation is an important component in the pathogenesis of EoE. Corticosteroids have a wide range of inhibitory activities against multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, and lymphocytes) and mediators (e.g., histamine, eicosanoids, leukocytes and cytokines) involved in allergic inflammation.

12.2 Pharmacodynamics

In Study 1, blood samples to detect cortisol levels (stimulated and unstimulated) were collected in the morning for all subjects [see Clinical Studies (14)]. At baseline, 4% of EOHILIA-treated subjects and 5% of placebo-treated subjects had abnormal peak adrenocorticotropic hormone (ACTH)-stimulated serum cortisol values, with abnormal defined as ≤18 mcg/dL. After 12 weeks of treatment, 9% of EOHILIA-treated subjects and 3% of placebo-treated subjects had abnormal peak ACTH-stimulated serum cortisol values [see Warnings and Precautions (5.1), Adverse Reactions (6.1)].

12.3 Pharmacokinetics

Budesonide geometric mean (%CV) maximum plasma concentration (Cmax) was 915 (59) pg/mL and area under the time concentration curve at 12 hours (AUC0-12h) was 5071 (58) pg•h/mL after repeated oral administration of EOHILIA 2 mg twice daily in adult subjects with EoE. Based on population pharmacokinetic analysis, there was no difference in pharmacokinetics between healthy adults and adult subjects with EoE.

Absorption

The median (range) time to reach budesonide peak plasma concentration (tmax) was 2 hours (range 0.5 to 4 hours) after oral administration of EOHILIA 2 mg twice daily in adult subjects with EoE. Following repeated (twice daily) oral administration of EOHILIA, the systemic exposure of budesonide was increased dose proportionally in the dose range of 0.5 to 2 mg (0.25 times the recommended dose and up to the recommended dose).

The oral bioavailability of budesonide in healthy subjects is estimated to be 14% under fasting state.

Effect of Food

A high-fat, high-calorie meal (800-1000 calories and approximately 50% fat) administered to healthy subjects increased the AUC of budesonide by 26% and decreased the Cmax by 13% following a single dose of EOHILIA compared to fasting conditions. Median time to reach peak plasma concentration was delayed approximately 1 hour with the intake of a high-fat, high-calorie meal. The increase in systemic exposure of budesonide due to food effect is not expected to be clinically meaningful.

Distribution

The mean volume of distribution (Vss/F) of budesonide is 1886 L after repeated oral administration of EOHILIA. Plasma protein binding was estimated to be 85% to 90% in the concentration range 0.43 to 99.02 ng/mL. The erythrocyte/plasma partition ratio at clinically relevant concentrations was about 0.8.

Elimination

Budesonide has a high plasma clearance, 0.9 to 1.8 L/min approaching the estimated liver blood flow, suggesting that budesonide is a high hepatic clearance drug. The mean plasma elimination half-life (t1/2) of budesonide after administration of EOHILIA was 3.3 hours.

Metabolism

Following oral absorption, budesonide is subject to high first pass metabolism (80% to 90%). In vitro, budesonide is biotransformed, mainly by CYP3A4, to its 2 major metabolites, 6beta-hydroxy budesonide and 16alpha-hydroxy prednisolone. The corticosteroid activity of these metabolites was negligible (less than1/100) in relation to that of the parent compound.

Excretion

Budesonide is excreted in urine and feces in the form of metabolites. After oral as well as intravenous administration of micronized [3H]-budesonide, approximately 60% of the recovered radioactivity was found in urine. The major metabolites, including 6beta-hydroxy budesonide and 16alpha-hydroxy prednisolone, are mainly renally excreted, intact or in conjugated forms. No unchanged budesonide was detected in urine.

Specific Populations

Pediatric Patients

The pharmacokinetics of budesonide were evaluated in pediatric subjects aged 11 years to 17 years (n=10) following oral administration of EOHILIA 2 mg twice a day. The median (range) time to peak plasma concentration of budesonide was 1 (0.5, 2) hour, the mean (%CV) Cmax was 946 (61%) pg/mL and the mean (%CV) AUC0-8h was 3849 (51%) pg•h/mL.

Based on a population pharmacokinetic analysis, the steady-state exposure following EOHILIA 2 mg twice daily is predicted to be comparable between pediatric subjects (11 to less than 18 years) and adults (18 years and older).

Patients with Hepatic Impairment

In subjects with mild (Child-Pugh Class A, n=4) or moderate (Child-Pugh Class B, n=4) hepatic impairment, budesonide 4 mg was administered orally as a single dose. The subjects with moderate hepatic impairment had a 3.5-fold higher AUC compared to the healthy subjects with normal hepatic function while the subjects with mild hepatic impairment had an approximately 1.4-fold higher AUC. The Cmax values demonstrated similar increases [see Warnings and Precautions (5.1)]. The increased systemic exposure in subjects with mild hepatic impairment was not considered to be clinically relevant. Subjects with severe hepatic impairment (Child-Pugh Class C) were not studied [see Use in Specific Populations (8.6)].

Drug Interaction Studies

Budesonide is a substrate of CYP3A4. Inhibitors of CYP3A4 can increase the plasma concentrations of budesonide several-fold. Conversely, induction of CYP3A4 potentially could result in the lowering of budesonide plasma concentrations [see Dosage and Administration (2.2) and Drug Interactions (7.1)].

Budesonide is a substrate of P-gp, but not a substrate of BCRP, OATP1B1, OATP1B3, OAT1, OAT3, or OCT2. The role of P-gp on budesonide disposition is anticipated to be minimal due to CYP3A-mediated clearance.

Effects of Other Drugs on Budesonide

Ketoconazole

In an open, non-randomized, cross-over study, 6 healthy subjects were given budesonide 10 mg as a single dose (5-times the recommended dose of EOHILIA), either alone or concomitantly with the last ketoconazole dose of 3 days treatment with ketoconazole 100 mg twice daily. Co-administration of ketoconazole resulted in an eight-fold increase in AUC of budesonide, compared to budesonide alone [see Drug Interactions (7.1)].

Grapefruit Juice

In an open, randomized, cross-over study, 8 healthy subjects were given budesonide delayed-release capsules 3 mg (1.5-times the recommended dose of EOHILIA), either alone, or concomitantly with 600 mL concentrated grapefruit juice (which inhibits CYP3A4 activity predominantly in the intestinal mucosa), on the last of 4 daily administrations. Concomitant administration of grapefruit juice resulted in a 2-fold increase of the bioavailability of budesonide compared to budesonide alone [see Drug Interactions (7.1)].

Oral Contraceptives (CYP3A4 Substrates)

In a parallel study, the pharmacokinetics of budesonide were not significantly different between healthy female subjects who received oral contraceptives containing desogestrel 0.15 mg and ethinyl estradiol 30 mcg and healthy female subjects who did not receive oral contraceptives. Budesonide 4.5 mg (2.3-times the recommended dose of EOHILIA) once daily for one week did not affect the plasma concentrations of ethinyl estradiol, a CYP3A4 substrate.

Omeprazole

In a study in 11 healthy subjects, performed in a double-blind, randomized, placebo-controlled manner, the effect of 5 to 6 days treatment with omeprazole 20 mg once daily on the pharmacokinetics of budesonide administered as budesonide delayed-release capsules 9 mg (4.5-times the recommended dose of EOHILIA) as a single dose was investigated. Omeprazole 20 mg once daily did not affect the absorption or pharmacokinetics of budesonide.

Cimetidine

In an open, non-randomized, cross-over study, the potential effect of cimetidine on the pharmacokinetics of budesonide was studied. Six healthy subjects received cimetidine 1 gram daily (200 mg with meals and 400 mg at night) for 2 separate 3-day periods. Budesonide 4 mg (2-times the recommended dose of EOHILIA) was administered either alone or on the last day of one of the cimetidine treatment periods. Co-administration of cimetidine resulted in a 52% and 31% increase in the budesonide peak plasma concentration and the AUC of budesonide, respectively.

Effect of Budesonide on Other Drugs

Budesonide is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 and CYP2D6 in vitro. Budesonide is not an inducer of CYP3A4, CYP1A2 or CYP2B6 at clinically relevant concentrations.

In vitro, budesonide is not a significant inhibitor of P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, or OCT2 at clinically relevant concentrations.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity

Carcinogenicity studies with budesonide were conducted in rats and mice. In a 2-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/day (approximately 0.1 times the maximum recommended human dose [MRHD], based on the body surface area [BSA]). In addition, there were increased incidences of primary hepatocellular tumors in male rats at 25 mcg/kg (approximately 0.06 times the MRHD, based on BSA) and above. No tumorigenicity was seen in female rats at oral doses up to 50 mcg/kg/day (approximately 0.1 times the MRHD, based on BSA).

In an additional 2-year study in male Sprague-Dawley rats, budesonide caused no gliomas at an oral dose of 50 mcg/kg/day (approximately 0.1 times the MRHD, based on BSA); however, it caused a statistically significant increase in the incidence of hepatocellular tumors at this same oral dose of 50 mcg/kg/day. 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/day (approximately 0.2 times the MRHD, based on BSA).

Mutagenesis

Budesonide showed no evidence of genotoxic potential in the Ames test, the mouse lymphoma cell forward gene mutation (TK+/-) test, the human lymphocyte chromosome aberration test, the Drosophila melanogaster sex-linked recessive lethality test, the rat hepatocyte UDS test or the mouse micronucleus test.

Impairment of Fertility

In rats, budesonide had no effect on fertility at subcutaneous doses up to 80 mcg/kg/day (approximately 0.1 times the MRHD, based on BSA). However, it caused a decrease in prenatal viability and viability in pups at birth and during lactation, along with a decrease in maternal body weight gain, at subcutaneous doses of 20 mcg/kg/day (approximately 0.04 times the MRHD, based on BSA) and above. No such effects were noted at 5 mcg/kg/day (approximately 0.01 times the MRHD on a body surface area basis).