ASMANEX

Dosage and Administration ( 2 ) 02/2021 Warnings and Precautions ( 5.1 , 5.2 ) 02/2021

1 INDICATIONS AND USAGE ASMANEX ® TWISTHALER ® is indicated for the maintenance treatment of asthma as prophylactic therapy in adult and pediatric patients 4 years of age and older. Limitations of Use ASMANEX TWISTHALER is not indicated for the relief of acute bronchospasm. ASMANEX TWISTHALER is not indicated in children less than 4 years of age. ASMANEX TWISTHALER is a corticosteroid indicated for maintenance treatment of asthma as prophylactic therapy in patients 4 years of age and older. ( 1 ) Limitations of Use: ASMANEX TWISTHALER is not indicated for the relief of acute bronchospasm ( 1 , 5.2 ) or in children less than 4 years of age ( 1 , 8.4 ).

2 DOSAGE AND ADMINISTRATION Administration Information Administer ASMANEX TWISTHALER by the orally inhaled route only. Instruct patients to inhale rapidly and deeply. After administration, advise patients to rinse the mouth with water and spit out contents without swallowing. Individual patients will experience a variable time to onset and degree of symptom relief. Maximum benefit may not be achieved for 1 to 2 weeks or longer after initiation of treatment. After asthma stability has been achieved, it is desirable to titrate to the lowest effective dosage to reduce the possibility of side effects. For patients ≥12 years of age who do not respond adequately to the starting dose after 2 weeks of therapy, higher doses may provide additional asthma control. The safety and efficacy of ASMANEX TWISTHALER when administered in excess of recommended doses have not been established. For oral inhalation only. ( 2 ) Instruct patients to inhale rapidly and deeply and, after administration, rinse mouth with water and spit out contents without swallowing. ( 2 ) Recommended Dosages for ASMANEX TWISTHALER Treatment Previous Therapy Recommended Starting Dose Highest Recommended Daily Dose , , , Please refer to section 2.1 for full dosage recommendations and details. Patients ≥12 years who received bronchodilators alone 220 mcg once daily in the evening 440 mcg Patients ≥12 years who received inhaled corticosteroids 220 mcg once daily in the evening 440 mcg Patients ≥12 years who received oral corticosteroids 440 mcg twice daily 880 mcg Children 4-11 years of age 110 mcg once daily in the evening 110 mcg 2.1 Recommended Dosages in Adult and Pediatric Patients 4 Years of Age and Older The recommended starting doses and highest recommended daily dose for ASMANEX TWISTHALER treatment based on prior asthma therapy are provided in Table 1 . Table 1: Recommended Dosages for ASMANEX TWISTHALER Treatment Previous Therapy Recommended Starting Dose Highest Recommended Daily Dose Patients ≥12 years who received bronchodilators alone 220 mcg once daily in the evening When administered once daily, ASMANEX TWISTHALER should be taken only in the evening. 440 mcg The 440 mcg daily dose may be administered in divided doses of 220 mcg twice daily or as 440 mcg once daily. Patients ≥12 years who received inhaled corticosteroids 220 mcg once daily in the evening 440 mcg Patients ≥12 years who received oral corticosteroids For Patients Currently Receiving Chronic Oral Corticosteroid Therapy: Prednisone should be reduced no faster than 2.5 mg/day on a weekly basis, beginning after at least 1 week of ASMANEX TWISTHALER therapy. Monitor patients carefully for signs of asthma instability, including serial objective measures of airflow, and for signs of adrenal insufficiency during steroid taper and following discontinuation of oral corticosteroid therapy [see Warnings and Precautions (5.5) ] . 440 mcg twice daily 880 mcg Children 4-11 years of age Recommended pediatric dosage is 110 mcg once daily in the evening regardless of prior therapy. 110 mcg once daily in the evening 110 mcg

3 DOSAGE FORMS AND STRENGTHS Inhalation powder: ASMANEX TWISTHALER 220 mcg delivers 200 mcg mometasone furoate per actuation from the mouthpiece. ASMANEX TWISTHALER 110 mcg delivers 100 mcg mometasone furoate per actuation from the mouthpiece. Inhalation powder: 220 mcg TWISTHALER: delivers 200 mcg mometasone furoate per actuation. ( 3 ) 110 mcg TWISTHALER: delivers 100 mcg mometasone furoate per actuation. ( 3 )

4 CONTRAINDICATIONS ASMANEX TWISTHALER is contraindicated: Status Asthmaticus: in the primary treatment of status asthmaticus or other acute episodes of asthma where intensive measures are required. Hypersensitivity: in patients with known hypersensitivity to milk proteins or any ingredients of ASMANEX TWISTHALER [see Warnings and Precautions (5.3) and Description (11) ]. Patients with status asthmaticus or other acute episodes of asthma where intensive measures are required. ( 4 ) Patients with a known hypersensitivity to milk proteins or any ingredients of ASMANEX TWISTHALER. ( 4 )

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Oropharyngeal Candidiasis [see Warnings and Precautions (5.1) ] Immunosuppression and Risk of Infections [see Warnings and Precautions (5.4) ] Hypercorticism and Adrenal Suppression [see Warnings and Precautions (5.6) ] Reduction in Bone Mineral Density [see Warnings and Precautions (5.7) ] Growth Effects [see Warnings and Precautions (5.8) and Use in Specific Populations (8.4) ] Glaucoma and Cataracts [see Warnings and Precautions (5.9) ] The most common adverse reactions (incidence ≥5%) are headache, allergic rhinitis, pharyngitis, upper respiratory tract infection, sinusitis, oral candidiasis, dysmenorrhea, musculoskeletal pain, back pain, and dyspepsia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Organon LLC, a subsidiary of Organon & Co., at 1-844-674-3200 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Studies Experience The safety data described below reflect exposure to ASMANEX TWISTHALER in 2380 patients with asthma exposed for 8 to 12 weeks and 627 patients with asthma exposed for 1 year in a total of 17 clinical trials. In adult and adolescent patients 12 years of age and older, ASMANEX TWISTHALER was studied in 10 placebo-controlled clinical trials of 8 to 12 weeks duration with a total of 1750 patients receiving ASMANEX TWISTHALER. There were also 3 trials with a total of 475 patients receiving ASMANEX TWISTHALER for 1 year. In the 8- to 12-week clinical trials, the population was 12 to 83 years of age; 38% males and 62% females; and 83% Caucasian, 8% black, 6% Hispanic, and 3% other race/ethnicity. Patients received ASMANEX TWISTHALER 110 mcg twice daily (n=133), 220 mcg once daily in the morning (n=209), 220 mcg once daily in the evening (n=232), 220 mcg twice daily (n=433), 440 mcg once daily in the morning (n=419), 440 mcg once daily in the evening (n=250), or 440 mcg twice daily (n=74). In 3 long-term safety trials (two 9-month extensions of efficacy trials and one 52-week active-controlled safety trial), 475 patients with asthma (12-83 years of age, 44% males, 56% females, 87% Caucasian, 8% black, 4% Hispanic, and 1% other race/ethnicity) received various doses of ASMANEX TWISTHALER for 1 year. In pediatric patients 4 to 11 years of age, ASMANEX TWISTHALER was studied in 3 placebo-controlled clinical trials of 12 weeks duration with a total of 630 patients receiving ASMANEX TWISTHALER and a 52-week, active-controlled safety trial with a total of 152 patients receiving ASMANEX TWISTHALER. In the 12-week clinical trials, the population was 4 to 11 years of age; 63% males and 37% females; and 67% Caucasian, 13% black, 17% Hispanic, and 3% other race/ethnicity. Patients received ASMANEX TWISTHALER 110 mcg once daily in the evening (n=98), 110 mcg once daily in the morning (n=181), 110 mcg twice daily (n=179), or 220 mcg once daily in the morning (n=172). In the long-term active-controlled safety trial (n=152), patients with asthma (4 to 11 years of age, 60% males and 40% females, 84% Caucasian, 11% Black, and 5% Hispanic) received ASMANEX TWISTHALER 110 mcg twice daily or 220 mcg once daily in the morning for 52 weeks. 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. Adults and Adolescents 12 Years of Age and Older: The safety results of the 10 trials that were 8 to 12 weeks in duration were pooled because patients with asthma in these studies were previously maintained on bronchodilators and/or inhaled corticosteroids. The safety results of the one 12-week clinical trial in patients with asthma previously treated with oral corticosteroids are presented separately. In the pooled 8- to 12-week clinical trials, adverse reactions were reported in 70% of patients tr …

7 DRUG INTERACTIONS In clinical studies, the concurrent administration of ASMANEX TWISTHALER and other drugs commonly used in the treatment of asthma was not associated with any unusual adverse reactions. Strong cytochrome P450 3A4 inhibitors (e.g., ritonavir): Use with caution. May cause increased systemic corticosteroid effects. ( 7.1 ) 7.1 Inhibitors of Cytochrome P450 3A4 Concomitant administration of CYP3A4 inhibitors may inhibit the metabolism of, and increase the systemic exposure to, mometasone furoate and potentially increase the risk for systemic corticosteroid side effects [see Clinical Pharmacology (12.3) ] . Caution should be exercised when considering the coadministration of ASMANEX TWISTHALER with long-term ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, cobicistat-containing products, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin). Consider the benefit of coadministration versus the potential risk of systemic corticosteroid effects, in which case patients should be monitored for systemic corticosteroid side effects.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no adequate and well-controlled studies of ASMANEX TWISTHALER in pregnant women. There are clinical considerations with the use of ASMANEX TWISTHALER in pregnant women [see Clinical Considerations ] . In animal reproduction studies with pregnant mice, rats, or rabbits, mometasone furoate caused increased fetal malformations and decreased fetal survival and growth following administration of doses that produced exposures approximately 1/3 to 8 times the maximum recommended human dose (MRHD) on a mcg/m 2 or AUC basis [see Data ] . However, experience with oral corticosteroids suggests that rodents are more prone to teratogenic effects from corticosteroid exposure than humans. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk In women with poorly or moderately controlled asthma, there is an increased risk of several perinatal adverse outcomes such as preeclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate. Pregnant women with asthma should be closely monitored and medication adjusted as necessary to maintain optimal asthma control. Data Animal Data In an embryofetal development study with pregnant mice dosed throughout the period of organogenesis, mometasone furoate produced cleft palate at an exposure approximately 1/3 of the MRHD (on a mcg/m 2 basis with maternal subcutaneous doses of 60 mcg/kg and above) and decreased fetal survival at an exposure approximately equivalent to the MRHD (on a mcg/m 2 basis with a maternal subcutaneous dose of 180 mcg/kg). No toxicity was observed with a dose that produced an exposure approximately 1/10 of the MRHD (on a mcg/m 2 basis with maternal topical dermal doses of 20 mcg/kg and above). In an embryofetal development study with pregnant rats dosed throughout the period of organogenesis, mometasone furoate produced fetal umbilical hernia at exposures approximately 6 times the MRHD (on a mcg/m 2 basis with maternal topical dermal doses of 600 mcg/kg and above) and delays in fetal ossification at exposures approximately 3 times the MRHD (on a mcg/m 2 basis with maternal topical dermal doses of 300 mcg/kg and above). In another reproductive toxicity study, pregnant rats were dosed with mometasone furoate throughout pregnancy or late in gestation. Treated animals had prolonged and difficult labor, fewer live births, lower birth weight, and reduced early pup survival at an exposure that was approximately 6 times the MRHD (on an area under the curve (AUC) basis with a maternal subcutaneous dose of 15 mcg/kg). There were no findings with an exposure approximately 3 times the MRHD (on an AUC basis with a maternal subcutaneous dose of 7.5 mcg/kg). Embryofetal development studies were conducted with pregnant rabbits dosed with mometasone furoate by either the topical dermal route or oral route throughout the period of organogenesis. In the study using the topical dermal route, mometasone furoate caused multiple malformations in fetuses (e.g., flexed front paws, gallbladder agenesis, umbilical hernia, hydrocephaly) at an exposure approximately 3 times the MRHD (on a mcg/m 2 basis with maternal topical dermal doses of 150 mcg/kg and above). In the study using the oral route, mometasone furoate caused increased fetal resorptions and cleft palate and/or head malformations (hydrocephaly and domed head) at an exposure approximately 1/2 of the MRHD (on an AUC basis with a maternal oral dose of 700 mcg/kg). At an exposure approximately 2 times the MRHD (on an AUC basis with a maternal oral dose of 2800 mcg/kg), most litters were aborted or resorbed. No effects were observed at an exposure approxi …

12.1 Mechanism of Action Mometasone furoate is a corticosteroid demonstrating potent anti-inflammatory activity. The precise mechanism of corticosteroid action on asthma is not known. Inflammation is an important component in the pathogenesis of asthma. Corticosteroids have been shown to have a wide range of inhibitory effects on multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, and lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, and cytokines) involved in inflammation and in the asthmatic response. These anti-inflammatory actions of corticosteroids may contribute to their efficacy in asthma. Mometasone furoate has been shown in vitro to exhibit a binding affinity for the human glucocorticoid receptor, which is approximately 12 times that of dexamethasone, 7 times that of triamcinolone acetonide, 5 times that of budesonide, and 1.5 times that of fluticasone. The clinical significance of these findings is unknown. Though effective for the treatment of asthma, corticosteroids do not affect asthma symptoms immediately. Maximum improvement in symptoms following inhaled administration of mometasone furoate may not be achieved for 1 to 2 weeks or longer after starting treatment. When corticosteroids are discontinued, asthma stability may persist for several days or longer.

11 DESCRIPTION Mometasone furoate, the active component of the ASMANEX TWISTHALER product, is a corticosteroid with the chemical name 9,21-dichloro-11(Beta),17-dihydroxy-16(alpha)-methylpregna-1,4-diene-3,20-dione 17-(2-furoate) and the following chemical structure: Mometasone furoate is a white powder with an empirical formula of C 27 H 30 Cl 2 O 6 , and molecular weight of 521.44 Daltons. The ASMANEX TWISTHALER 110 mcg and 220 mcg products are cap-activated, inhalation-driven, multidose dry powder inhalers containing mometasone furoate and anhydrous lactose (which contains trace amounts of milk proteins). Each actuation of the ASMANEX TWISTHALER 110 mcg or 220 mcg inhaler provides a measured dose of approximately 0.75 or 1.5 mg mometasone furoate inhalation powder, containing 110 or 220 mcg of mometasone furoate, respectively. This results in delivery of 100 or 200 mcg mometasone furoate from the mouthpiece, respectively, based on in vitro testing at flow rates of 30 L/min and 60 L/min with constant volume of 2 L. The amount of mometasone furoate emitted from the inhaler in vitro does not differ significantly for flow rates ranging from 28.3 L/min to 70 L/min at a constant volume of 2 L. However, the amount of drug delivered to the lung will depend on patient factors such as inspiratory flow and peak inspiratory flow through the device. In adult and adolescent patients (aged ≥12 years) with varied asthma severity, mean peak inspiratory flow rate through the device was 69 L/min (range: 54–77 L/min). In pediatric patients (aged 5-12 years) diagnosed with asthma, mean peak inspiratory flow rate in the 5- to 8-year-old subgroup was >50 L/min (minimum of 46 L/min) and for the 9- to 12-year-old subgroup was >60 L/min (minimum of 48 L/min). Chemical Structure

10 OVERDOSAGE Chronic overdosage may result in signs/symptoms of hypercorticism [see Warnings and Precautions (5.6) ]. Because of low systemic bioavailability and an absence of acute drug-related systemic findings in clinical studies, acute overdose is unlikely to require any treatment other than observation.

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied ASMANEX TWISTHALER 220 mcg: delivers 200 mcg mometasone furoate from the mouthpiece comprised of an assembled plastic cap–activated dosing mechanism with dose counter, drug-product storage unit, drug-product formulation (135 mg for the 14 and 30 inhalation units and 240 mg for the 60 and 120 inhalation units), and mouthpiece, covered by a white screw cap that bears the product label. body of the inhaler is white and the turning grip is pink with a clear plastic window indicating the number of doses remaining. The inhaler will not deliver subsequent doses once the counter reaches zero (“00”). 14 inhalation units (Institutional Use Only; NDC# 78206-114-03) 30 inhalation units (NDC# 78206-114-04) 60 inhalation units (for more than 1 inhalation daily; NDC# 78206-114-02) 120 inhalation units (for more than 2 inhalations daily; NDC# 78206-114-01) ASMANEX TWISTHALER 110 mcg: delivers 100 mcg mometasone furoate from the mouthpiece comprised of an assembled plastic cap–activated dosing mechanism with dose counter, drug-product storage unit, drug-product formulation (135 mg), and mouthpiece, covered by a white screw cap that bears the product label. body of the inhaler is white and the turning grip is gray with a clear plastic window indicating the number of doses remaining. The inhaler will not deliver subsequent doses once the counter reaches zero (“00”). 30 inhalation units (NDC# 78206-115-01) Each inhaler is supplied in a protective foil pouch with Patient’s Instructions for Use. Storage and Handling Store in a dry place at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Discard the inhaler 45 days after opening the foil pouch or when dose counter reads "00", whichever comes first.