Eohilia
(Budesonide)Dosage & Administration
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Eohilia Prescribing Information
EOHILIA™ is indicated for 12 weeks of treatment in adult and pediatric patients 11 years of age and older with eosinophilic esophagitis (EoE).
EOHILIA has not been shown to be safe and effective for the treatment of EoE for longer than 12 weeks
- The recommended dosage is 2 mg orally twice daily for 12 weeks.
The efficacy and safety of EOHILIA 2 mg twice daily were evaluated in two multicenter, randomized, double-blind, parallel-group, placebo-controlled 12-week studies (Study 1 [NCT02605837] and Study 2 [NCT01642212]). Eligible subjects in Study 1 and Study 2 had esophageal inflammation defined as ≥15 eosinophils/high-power field (hpf) from at least 2 levels of the esophagus at baseline following a treatment course of a proton pump inhibitor (PPI) either prior to or during screening and at least 4 days of dysphagia as measured by the Dysphagia Symptom Questionnaire (DSQ) over a 2-week period prior to randomization. Concomitant use of stable doses of inhaled or intranasal steroids (for conditions other than EoE), PPIs, H2-receptor antagonists, antacids, antihistamines or anti-leukotrienes, and maintenance immunotherapy was allowed. In Study 1, subjects were enrolled after maintaining a stable diet for at least 3 months prior to screening and were instructed to maintain a stable diet throughout the study. Subjects were excluded if they were on a full liquid or 6-food elimination diet. In Study 2, subjects were instructed to maintain a stable diet throughout the study. In Study 1 and Study 2, subjects were instructed to not eat or drink for 30 minutes after taking the drug and then to rinse their mouth with water and spit out the contents without swallowing prior to resuming normal oral intake.
A total of 318 subjects (277 adults and 41 pediatric subjects) were randomized and received at least one dose of study drug (EOHILIA or placebo) in Study 1. The mean age of the study population was 34 years (range 11 to 56 years). Sixty percent of subjects were male, 95% were White, and 3% were Hispanic or Latino. Over 80% of the subjects were on concomitant PPI. The mean (SD) DSQ combined scores at baseline were 30.3 (13.9) and 30.4 (13.1) in the EOHILIA and placebo groups, respectively.
A total of 92 subjects (58 adults and 34 pediatric subjects) were randomized and received at least one dose of study drug (EOHILIA or placebo) in Study 2. The mean age of the study population was 22 years (range 11 to 42 years). Sixty-eight percent of subjects were male, 95% were White, and 1% were Hispanic or Latino. Over 65% of the subjects were on concomitant PPI. The mean (SD) DSQ combined scores at baseline were 30.7 (16.0) and 29.0 (13.5) in the EOHILIA and placebo groups, respectively.
Study 1 and Study 2 evaluated efficacy endpoints of histologic remission (defined as a peak eosinophil count of ≤6/hpf across all available esophageal levels) and the absolute change from baseline in subject-reported DSQ combined score after 12 weeks of treatment.
Efficacy results for Study 1 and Study 2 are presented in Table 2.
| Study 1 | Study 2 | |||||
|---|---|---|---|---|---|---|
| EOHILIA 2 mg Twice Daily N=213 | Placebo N=105 | Treatment difference and 95% CIFor histological remission, the difference in percentages and 95% Newcombe confidence intervals are estimated using Mantel Haenszel weights, adjusting for age group and diet restriction. For absolute change in DSQ score, the LS mean changes, standard errors, and differences are estimated using an ANCOVA model with treatment group, age group, diet restriction, and baseline measurement as covariates. | EOHILIA 2 mg Twice Daily N=50 | Placebo N=42 | Treatment difference and 95%CI | |
Efficacy Endpoints | ||||||
| Proportion of subjects achieving histological remission (peak esophageal intraepithelial eosinophil count ≤6 eos/hpf) | 53.1% | 1.0% | 52.4% (43.3, 59.1) | 38.0% | 2.4% | 35.8% (17.2, 50.0) |
| Absolute change from baseline in DSQ combined score (0-84Total biweekly DSQ scores range from 0 to 84, higher scores indicate greater frequency and severity of dysphagia), LS mean (SE) | -10.2 (1.5) | -6.5 (1.8) | -3.7 (-6.8, -0.6) | -14.5 (1.8) | -5.9 (2.1) | -8.6 (-13.7, -3.5) |
During the last 2 weeks of the 12-week treatment periods in Study 1 and Study 2, a greater proportion of subjects randomized to EOHILIA experienced no dysphagia or only experienced dysphagia that “got better or cleared up on its own” compared to placebo, as measured by the subject-reported DSQ.
After completing Study 1, 48 subjects from the EOHILIA 2 mg treatment arm entered a double-blind randomized withdrawal extension study. These subjects received EOHILIA 2 mg twice daily or placebo for up to an additional 36 weeks. Treatment with EOHILIA did not demonstrate a statistically significant difference compared to subjects re-randomized to placebo for prespecified efficacy endpoints based on eosinophil count and/or clinical symptoms measured by the DSQ at Week 36.
- Recommended dosage: 2 mg orally twice daily for 12 weeks. ()
2.1 Recommended Dosage- The recommended dosage is 2 mg orally twice daily for 12 weeks.
- See full prescribing information for preparation and important administration instructions. ()
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:
- Do NOT mix EOHILIA with food or liquid.
- Shake the EOHILIA packet for at least 10 seconds prior to opening.
- Squeeze the packet from the bottom to the top directly into the mouth. Repeat 2 to 3 times until the EOHILIA packet is empty.
- Swallow all the EOHILIA suspension.
- 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)].
Oral suspension: 2 mg/10 mL unit-dose packets of a white to yellow viscous suspension with cherry flavoring.
- Pregnancy: Based on animal data, may cause fetal harm. ()
8.1 PregnancyRisk SummaryThe available data from published case series, epidemiological studies, and reviews with oral budesonide use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or other adverse maternal outcomes. Infants exposed to in-utero corticosteroids, including EOHILIA, are at risk for hypoadrenalism
(see Clinical Considerations). In animal reproduction studies, subcutaneous administration of budesonide during organogenesis in pregnant rats (at doses up to approximately 1.2 times the maximum recommended human dose, based on body surface area [BSA]) or pregnant rabbits (at doses approximately 0.14 times the maximum recommended human dose, based on body surface area [BSA]) resulted in increased fetal loss, decreased pup weights, and skeletal abnormalities. Maternal toxicity was observed in both rats and rabbits at these dose levels(see Data). Based on animal data, advise pregnant women of the potential risk to a fetus.The background risk of major birth defects and miscarriage in the indicated population is unknown. All pregnancies have a background risk of birth defect, 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.
Clinical ConsiderationsFetal/Neonatal Adverse ReactionsHypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy. Infants should be carefully observed for signs of hypoadrenalism, such as poor feeding, irritability, weakness, and vomiting, and managed accordingly
[see Warnings and Precautions (5.1)].DataAnimal DataBudesonide was teratogenic and embryolethal in rabbits and rats.
In an embryo-fetal development study in pregnant rats dosed subcutaneously with budesonide during the period of organogenesis from gestation days 6-15, there were effects on fetal development and survival at subcutaneous doses up to approximately 500 mcg/kg/day in rats (approximately 1.2 times the maximum recommended human dose [MRHD], based on body surface area [BSA]). In an embryo-fetal development study in pregnant rabbits dosed during the period of organogenesis from gestation days 6-18, there was an increase in maternal abortion, and effects on fetal development and reduction in litter weights at subcutaneous doses up to approximately 25 mcg/kg/day (approximately 0.14 times the MRHD, based on BSA). Maternal toxicity, including reduction in body weight gain, was observed at subcutaneous doses of 5 mcg/kg in rabbits (approximately 0.03 times the MRHD, based on BSA) and 500 mcg/kg in rats (approximately 1.2 times the MRHD, based on BSA).
In a peri- and post-natal development study, rats dosed subcutaneously with budesonide during the period of Day 15 post coitum to Day 21 postpartum, budesonide had no effects on delivery but did have an effect on growth and development of offspring. In addition, offspring survival was reduced and surviving offspring had decreased mean body weights at birth and during lactation at exposures 0.05 times the MRHD (on a mg/m2basis at maternal subcutaneous doses of 20 mcg/kg/day and higher). These findings occurred in the presence of maternal toxicity.
- Hepatic Impairment:Use is not recommended in severe hepatic impairment. Monitor patients with moderate hepatic impairment for signs and/or symptoms of hypercorticism. (,
5.1 Hypercorticism and Adrenal Axis SuppressionSystemic 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.
)8.6 Hepatic ImpairmentPatients 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)].
EOHILIA is contraindicated in patients with hypersensitivity to budesonide. Serious hypersensitivity reactions, including anaphylaxis, have occurred with oral budesonide products
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.
- Hypercorticism and Adrenal Axis Suppression: May occur with treatment; monitor for signs and symptoms and consider reducing the dosage. (,
5.1 Hypercorticism and Adrenal Axis SuppressionSystemic 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.
)8.6 Hepatic ImpairmentPatients 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)]. - Immunosuppression and Increased Risk of Infection: Increased risk of viral, bacterial, fungal, protozoan, and helminthic infections, including potentially fatal varicella and measles infection. Monitor patients for new or worsening localized or systemic infection, including oropharyngeal and esophageal candidiasis and consider drug discontinuation. Avoid use in patients with fungal infections, Strongyloides infestation, cerebral malaria, and ocular herpes simplex. Screen for hepatitis B infection. ()
5.2 Immunosuppression and Increased Risk of InfectionCorticosteroids, 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.
TuberculosisIf 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 InfectionsVaricella 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 ReactivationHepatitis 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 InfectionsCorticosteroids may exacerbate systemic fungal infections; therefore, avoid EOHILIA use in the presence of such infections.
AmebiasisCorticosteroids 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 InfestationAvoid 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 MalariaAvoid corticosteroids, including EOHILIA, in patients with cerebral malaria.
Ocular Herpes SimplexAvoid corticosteroids, including EOHILIA, in patients with active ocular herpes simplex.
Localized InfectionsIn clinical trials with EOHILIA, localized infections with
Candida albicansoccurred 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. - Erosive Esophagitis: Advise patients or caregivers to report new or worsening signs or symptoms of erosive esophagitis; consider endoscopic evaluation as appropriate. ()
5.3 Erosive EsophagitisErosive 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.
- Effect on Growth: Use of corticosteroids may cause a reduction in growth velocity in pediatric patients; monitor growth during treatment. ()
5.4 Effect on GrowthUse 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)]. - Symptoms of Steroid Withdrawal in Patients Transferred from Other Systemic Corticosteroids: Taper slowly from corticosteroids with high systemic effects; monitor for withdrawal symptoms and unmasking of allergies (rhinitis, eczema). ()
5.5 Symptoms of Steroid Withdrawal in Patients Transferred from Other Systemic CorticosteroidsMonitor 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.
- Other Corticosteroid Effects: Monitor patients with concomitant conditions where corticosteroids may have unwanted effects (e.g., hypertension, diabetes mellitus). ()
5.6 Other Corticosteroid EffectsMonitor 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.
- Kaposi’s Sarcoma: Reported to occur in patients receiving corticosteroid therapy, most often for chronic conditions. ()
5.7 Kaposi’s SarcomaKaposi’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)].