Eohilia Drug Information

™ is indicated for 12 weeks of treatment in adult and pediatric patients 11 years of age and older with eosinophilic esophagitis (EoE). Limitations of Use EOHILIA has not been shown to be safe and effective for the treatment of EoE for longer than 12 weeks. EOHILIA is a corticosteroid indicated for 12 weeks of treatment in adult and pediatric patients 11 years of age and older with eosinophilic esophagitis (EoE). Limitations of Use EOHILIA has not been shown to be safe and effective for the treatment of EoE for longer than 12 weeks.

Recommended Dosage

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

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 . Avoid consumption of grapefruit juice for the duration of therapy with EOHILIA .

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 . Common Adverse Reactions The most common adverse reactions reported in Study 1 are shown in Table 1. Table 1: Common Adverse Reactions reported in at least 2% of subjects in the EOHILIA group and at a rate greater than placebo. in Adult and Pediatric Subjects 11 Years of Age and Older with EoE in Study 1 ADVERSE REACTIONS EOHILIA 2 mg Twice Daily N = 213 Placebo N = 105 Respiratory tract infection includes acute sinusitis, sinusitis, nasopharyngitis, respiratory tract infection, respiratory tract infection viral, upper respiratory tract infection, viral upper respiratory tract infection, rhinitis 13% 11% Gastrointestinal mucosal candidiasis includes esophageal candidiasis, oropharyngeal candidiasis, oral candidiasis 8% 2% Headache includes headache, migraine 5% 2% Gastroenteritis 3% 1% Throat irritation includes throat irritation, oropharyngeal pain 3% 2% Adrenal suppression includes adrenal suppression, adrenal insufficiency 2% 0 Erosive esophagitis includes esophagitis only where erosions were present at the esophagogastroduodenoscopy conducted after 12 weeks of treatment 2% 0 Specific Adverse Reactions Erosive Esophagitis Erosive esophagitis occurred in 4/213 (2%) of EOHILIA-treated subjects in Study 1. These subjects had no erosions present at the baseline esophagogastroduodenoscopy (EGD). At EGD after 12 weeks of treatment with EOHILIA, 2 subjects had Los Angeles (LA) classification grade A, 1 subject had LA grade B, and 1 subject had LA grade C erosive esophagitis. All but one of the four subjects developed erosive esophagitis while receiving concomitant therapy with a PPI. No cases of erosive esophagitis were reported in Study 2 . Less Common Adverse Reactions Adverse reactions reported in less than 2% of subjects treated with EOHILIA and at a greater rate than placebo in Study 1 are listed below: Cardiac disorders: Palpitations Gastrointestinal disorders: Dry mouth, dyspepsia, erosive duodenitis, gastrointestinal motility disorder, esophageal food impaction, palatal swelling General disorders and administration site conditions: Fatigue, feeling abnormal Infections and infestations: Fungal skin infection, paronychia, pneumonia, sepsis, bronchitis Investigations: Transaminases increased, hyperkalemia Metabolism and nutrition disorders: Dyslipidemia Musculoskeletal and connective tissue disorders: Arthralgia, muscle spasms Nervous system disorders: Dysgeusia, syncope, tremor Psychiatric disorders: Depression, irritability, restlessness Respiratory, thoracic, and mediastinal disorders: Nasal congestion Skin and subcutaneous tissue disorders: Hirsutism, dermatitis acneiform Vascular disorders: Hypertension The safety profile of EOHILIA in Study 2 was generally similar to Study 1.

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

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 . Avoid concomitant use of CYP3A4 inhibitors, including grapefruit juice, with EOHILIA .

Pregnancy Risk Summary The 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 ) or pregnant rabbits (at doses approximately 0.14 times the maximum recommended human dose, based on body surface area ) 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 Considerations Fetal/Neonatal Adverse Reactions Hypoadrenalism 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 . Data Animal Data Budesonide 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, based on body surface area ). 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/m 2 basis at maternal subcutaneous doses of 20 mcg/kg/day and higher). These findings occurred in the presence of maternal toxicity.

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 . Systemic effects such as hypercorticism and adrenal axis suppression may occur with use of corticosteroids, including EOHILIA . 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 . The safety and effectiveness of EOHILIA in pediatric patients less than 11 years of age have not been established. Juvenile Animal Toxicity Data In a juvenile rat study, budesonide was administered orally at doses of 0.05, 0.2, 0.6, and 1.5 mg/kg/day starting on postnatal day (PND) 22 for 91 consecutive days. All of the effects noted were associated with the pharmacology of the drug and manifested in a dose related manner, typical of corticosteroids.

These included decreased body weight gain, adrenal atrophy, and effects on bone (decreased cellularity and bone length) and lymphoid tissues (decreased cellularity). The no observed adverse effect level (NOAEL) in juvenile rats was determined to be the 0.05 mg/kg/day. Plasma exposure (AUC) in rats at the NOAEL (0.05 mg/kg/day) was lower (approximately 0.8 times) than that in pediatric subjects (11 years to 17 years of age) at the MRHD. In a juvenile toxicity study in dogs, budesonide was orally administered at doses of 0.05, 0.2, and 0.6 mg/kg/day (starting at approximately 7 weeks of age) for 91 consecutive days. The observations were dose-related and consistent with corticosteroid treatment.

The effects included decreased body weight gain, distended abdomen and swelling associated with inguinal hernias, lymphocytic and leukocytic changes, adrenal atrophy, depletion in lymphoid organs (lymph nodes, spleen, thymus), and effects on skeletal development (decreased cellularity in bone marrow, bone growth, and skeletal muscle atrophy). The incidence and severity of the majority of the pharmacologically mediated effects decreased or resolved completely following the recovery period. A NOAEL could not be defined in juvenile dogs. Plasma exposure (AUC) at the lowest dose tested (0.05 mg/kg/day) was lower (approximately 0.4 times) than that in pediatric subjects (11 years to 17 years of age) at the MRHD.

is contraindicated in patients with hypersensitivity to budesonide. Serious hypersensitivity reactions, including anaphylaxis, have occurred with oral budesonide products . Hypersensitivity to budesonide.

Treatment of acute overdosage consists of immediate gastric lavage or emesis followed by supportive and symptomatic therapy. Use of corticosteroids, such as EOHILIA, at excessive doses or for prolonged periods, increases the risk of systemic corticosteroid effects such as hypercorticism and adrenal axis suppression .