Eohilia

1 INDICATIONS AND USAGE EOHILIA ™ 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 [see Dosage and Administration (2.1) , Clinical Studies (14) ]. 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). ( 1 ) Limitations of Use EOHILIA has not been shown to be safe and effective for the treatment of EoE for longer than 12 weeks. ( 1 , 2.1 , 14 )

2 DOSAGE AND ADMINISTRATION Recommended dosage : 2 mg orally twice daily for 12 weeks. ( 2.1 ) See full prescribing information for preparation and important administration instructions. ( 2.2 ) 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: 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) ] .

4 CONTRAINDICATIONS EOHILIA is contraindicated in patients with hypersensitivity to budesonide. Serious hypersensitivity reactions, including anaphylaxis, have occurred with oral budesonide products [see Adverse Reactions (6.2) ] . Hypersensitivity to budesonide. ( 4 )

5 WARNINGS AND PRECAUTIONS Hypercorticism and Adrenal Axis Suppression : May occur with treatment; monitor for signs and symptoms and consider reducing the dosage. ( 5.1 , 8.6 ) 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 ) Erosive Esophagitis : Advise patients or caregivers to report new or worsening signs or symptoms of erosive esophagitis; consider endoscopic evaluation as appropriate. ( 5.3 ) Effect on Growth : Use of corticosteroids may cause a reduction in growth velocity in pediatric patients; monitor growth during treatment. ( 5.4 ) 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 ) Other Corticosteroid Effects : Monitor patients with concomitant conditions where corticosteroids may have unwanted effects (e.g., hypertension, diabetes mellitus). ( 5.6 ) Kaposi’s Sarcoma : Reported to occur in patients receiving corticosteroid therapy, most often for chronic conditions. ( 5.7 ) 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) ] .

7 DRUG INTERACTIONS CYP3A4 Inhibitors (e.g., ketoconazole, grapefruit juice): Can increase systemic budesonide concentrations. Avoid concomitant use. ( 2.2 , 7.1 ) 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) ] .

6 ADVERSE REACTIONS The following serious adverse reactions are described in greater detail in other sections of the labeling: Hypercorticism and adrenal axis suppression [see Warnings and Precautions (5.1) ] Immunosuppression and increased risk of infections [see Warnings and Precautions (5.2) ] Erosive esophagitis [see Warnings and Precautions (5.3) ] Effect on growth [see Warnings and Precautions (5.4) ] Symptoms of steroid withdrawal in those patients transferred from other systemic corticosteroids [see Warnings and Precautions (5.5) ] Other corticosteroid effects [see Warnings and Precautions (5.6) ] Kaposi’s sarcoma [see Warnings and Precautions (5.7) ] Most common adverse reactions (≥2%) are: respiratory tract infection, gastrointestinal mucosal candidiasis, headache, gastroenteritis, throat irritation, adrenal suppression, and erosive esophagitis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Takeda Pharmaceuticals America, Inc. at 1-877-TAKEDA-7 (1-877-825-3327) 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 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) ] . 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 [see Warnings and Precautions (5.3) ] . 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. 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

8.1 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 [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 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 [see Warnings and Precautions (5.1) ] . 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 [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/m 2 basis at maternal subcutaneous doses of 20 mcg/kg/day and higher). These findings occurred in the presence of maternal toxicity.