QVAR REDIHALER

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 ( 5.7 )] Reduction in bone mineral density [see Warnings and Precautions ( 5.9 )] Growth effects [see Warnings and Precautions ( 5.8 ) and Use in Specific Populations ( 8.4 )] Glaucoma and cataracts [see Warnings and Precautions ( 5.10 )] Most common adverse reactions (incidence > 3% and > placebo) include oral candidiasis, upper respiratory tract infection, nasopharyngitis, allergic rhinitis, oropharyngeal pain and sinusitis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Teva Pharmaceuticals at 1-888-483-8279 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience A total of 1858 subjects participated in the QVAR REDIHALER clinical development program. 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 Adolescent Patients 12 years of Age and Older: The adverse reaction information presented in Table 1 is derived from 3 double-blind, placebo-controlled clinical trials in which 1230 patients (751 female and 479 male adults previously treated with as‑needed bronchodilators and/or inhaled corticosteroids) were treated with QVAR REDIHALER (doses of 40, 80, 160, or 320 mcg twice daily) or QVAR (beclomethasone dipropionate HFA) Inhalation Aerosol (QVAR MDI; doses of 160 or 320 mcg twice daily) or placebo. In considering these data, difference in average duration of exposure and clinical trial design should be taken into account. Table 1: Adverse Reactions Experienced by at Least 3% of Adult and Adolescent Patients in the QVAR REDIHALER or QVAR MDI Groups and Greater Than Placebo by Treatment and Daily Dose Preferred Term Number (%) of patients QVAR REDIHALER QVAR MDI Placebo 80 mcg N=90 160 mcg N=92 320 mcg N=214 640 mcg N=211 320 mcg N=212 640 mcg N=107 N=304 Oral Candidiasis 0 2 (2) 7 (3) 15 (7) 6 (3) 9 (8) 1 (<1) Upper Respiratory Tract Infection 3 (3) 3 (3) 9 (4) 6 (3) 17 (8) 4 (4) 6 (2) Nasopharyngitis 4 (4) 2 (2) 3 (1) 3 (1) 6 (3) 4 (4) 4 (1) Oropharyngeal Pain 2 (2) 2 (2) 1 (<1) 3 (1) 6 (3) 4 (4) 2 (<1) Viral Upper Respiratory Tract Infection 3 (3) 0 1 (<1) 3 (1) 4 (2) 2 (<1) 4 (1) Sinusitis 3 (3) 0 1 (<1) 2 (<1) 1 (<1) 1 (<1) 2 (<1) Rhinitis Allergic 0 3 (3) 0 2 (<1) 0 1 (<1) 0 *QVAR MDI=QVAR Inhalation Aerosol Other adverse reactions that occurred in clinical trials using QVAR REDIHALER with an incidence of 1% to 3% and which occurred at a greater incidence than placebo were back pain, headache, pain, nausea and cough. Pediatric Patients 4 to 11 Years of Age: The adverse reaction information presented in Table 2 concerning QVAR REDIHALER and QVAR MDI is derived from one 12‑week placebo-controlled study in pediatric patients 4 to 11 years of age with persistent asthma. Table 2: Adverse Reactions Experienced by at Least 3% of Patients 4 to 11 Years of Age in the QVAR REDIHALER or QVAR MDI Groups and Greater Than Placebo by Treatment and Daily Dose Preferred Term Number (%) of patients QVAR REDIHALER QVAR MDI Placebo 80 mcg N=126 160 mcg N=125 80 mcg N=125 160 mcg N=125 N=127 Upper Respiratory Tract Infection 3 (2.4) 1 (0.8) 6 (4.8) 5 (4.0) 5 (3.9) Nasopharyngitis 5 (4.0) 11 (8.8) 6 (4.8) 6 (4.8) 4 (3.1) Viral Upper Respiratory Tract Infection 5 (4.0) 5 (4.0) 3 (2.4) 1 (0.8) 4 (3.1) Pharyngitis 4 (3.2) 4 (3.2) 4 (3.2) 4 (3.2) 2 (1.6) Cough 1 (0.8) 3 (2.4) 9 (7.2) 6 (4.8) 4 (3.1) Vomiting 2 (1.6) 2 (1.6) 4 (3.2) 0 2 (1.6) Headache 2 (1.6) 5 (4.0) 0 4 (3.2) 5 (3.9) Pyrexia 1 (0.8) 4 (3.2) 4 (3.2) 3 (2.4) 3 (2.4) *QVAR MDI=QVAR Inhalation Aerosol Other adverse reactions that occurred in clinical trials using QVAR REDIHALER with an incidence of 1% to 3% and which occurred at a greater incidence than placebo were influenza, gastroenteritis viral, ear infection, oral candidiasis, diarrhea, and myalgia. 6.2 Postmarketing Experience In addition to the adverse reactions reported from clinical trials with QVAR REDIHALER, the following adverse reactions have been identified during post-approval use of QVAR MDI and other inhaled corticosteroids. 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. Local Effects: Localized infections with Candida albicans have occurred in patients treated with beclomethasone dipropionate or other orally inhaled corticosteroids [see Warnings and Precautions ( 5.1 )] . Psychiatric and Behavioral Changes: Aggression, depression, sleep disorders, psychomotor hyperactivity, and suicidal ideation have been reported (primarily in children). Eye Disorders: Blurred vision, central serous chorioretinopathy (CSC).

4 CONTRAINDICATIONS QVAR REDIHALER is contraindicated in: the primary treatment of status asthmaticus or other acute episodes of asthma where intensive measures are required [see Warnings and Precautions ( 5.2 )] . in patients with known hypersensitivity to beclomethasone dipropionate or any of the ingredients in QVAR REDIHALER [see Warnings and Precautions ( 5.6 )] . Primary treatment of status asthmaticus or other acute episodes of asthma where intensive measures are required. ( 4 ) Hypersensitivity to any of the ingredients of QVAR REDIHALER. ( 4 )

11 DESCRIPTION The active component of QVAR REDIHALER 40 mcg Inhalation Aerosol and QVAR REDIHALER 80 mcg Inhalation Aerosol is beclomethasone dipropionate, USP, a corticosteroid having the chemical name 9-chloro-11ß,17,21-trihydroxy-16ß-methylpregna-1,4-diene-3,20-dione 17,21-dipropionate. Beclomethasone dipropionate is a diester of beclomethasone, a synthetic corticosteroid chemically related to dexamethasone. Beclomethasone differs from dexamethasone in having a chlorine at the 9‑alpha carbon in place of a fluorine, and in having a 16‑beta-methyl group instead of a 16‑alpha-methyl group. Beclomethasone dipropionate is a white to creamy white, odorless powder with a molecular formula of C 28 H 37 ClO 7 and a molecular weight of 521.1. Its chemical structure is: Chemical Structure QVAR REDIHALER is a pressurized, breath‑actuated, metered‑dose aerosol with a dose counter intended for oral inhalation only. Each unit consists of a sealed breath‑actuated inhaler device enclosing a canister containing a solution of beclomethasone dipropionate in propellant HFA‑134a (1,1,1,2 tetrafluoroethane) and ethanol (0.85 g). QVAR REDIHALER 40 mcg delivers 40 mcg of beclomethasone dipropionate from the actuator mouthpiece and 50 mcg from the canister valve. QVAR REDIHALER 80 mcg delivers 80 mcg of beclomethasone dipropionate from the actuator mouthpiece and 100 mcg from the canister valve. Both products deliver 50 microliters (59 milligrams) of solution formulation as an aerosol from the canister valve with each actuation. The 40‑mcg canisters and the 80‑mcg canisters provide 120 inhalations each. Since the QVAR REDIHALER canister is fitted with a primeless valve, no priming actuations are required before use. For both products, an actuation was always triggered by a 20 L/min inspiratory flow rate. structure

2 DOSAGE AND ADMINISTRATION For oral inhalation only. ( 2.1 ) Starting dosage is based on prior asthma therapy and disease severity. ( 2.2 ) Treatment of asthma in patients 4 to 11 years of age: 40 mcg or 80 mcg twice daily. ( 2.2 ) Treatment of asthma in patients 12 years of age and older: 40 mcg, 80 mcg, 160 mcg, or 320 mcg twice daily ( 2.2 ) Discard QVAR REDIHALER inhaler when the dose counter displays 0 or after the expiration date on the product, whichever comes first. ( 2.1 ) Do not use a spacer or volume holding chamber ( 2.1 ) 2.1 General Overview Administration Administer QVAR REDIHALER by oral inhalation. After inhalation, rinse mouth with water without swallowing to help reduce the risk of oropharyngeal candidiasis. Consistent dose delivery is achieved, whether using the 40‑ or 80‑mcg strengths, due to proportionality of the 2 products (i.e., 2 actuations of 40‑mcg strength should provide a dose comparable to 1 actuation of the 80‑mcg strength). Inhaler Instructions Patients should be instructed on the proper use of their inhaler. Do not use QVAR REDIHALER with a spacer or volume holding chamber. Shaking the inhaler prior to use is not necessary. Do not shake the inhaler with the cap open to avoid possible actuation of the device. Priming QVAR REDIHALER does not require priming. Cleaning Keep the inhaler clean and dry at all times. Never wash or put any part of the inhaler in water. Routine maintenance is not required. If the mouthpiece needs cleaning, gently wipe the mouthpiece with a dry cloth or tissue as needed. Dose Counter QVAR REDIHALER has a dose counter attached to the actuator. When the patient receives the inhaler, the number 120 will be displayed. The dose counter will count down each time a spray is released. When the dose counter reaches 20, the color of the numbers will change to red to remind the patient to contact their pharmacist for a refill of medication or consult their physician for a prescription refill. When the dose counter reaches 0, the background will change to solid red. Discard QVAR REDIHALER inhaler when the dose counter displays 0 or after the expiration date on the product, whichever comes first [see Patient Counseling Information ( 17 )] . 2.2 Recommended Dosage Adults and Adolescents 12 years of age and older The recommended starting dosage for patients 12 years of age and older who are not on an inhaled corticosteroid is 40 to 80 mcg twice daily by oral inhalation, approximately 12 hours apart. The starting dosage is based on previous asthma therapy and disease severity, including consideration of the patients’ current control of asthma symptoms and risk of future exacerbation. For patients switching to QVAR REDIHALER from another inhaled corticosteroid product, select the appropriate starting dosage strength of QVAR REDIHALER based on the strength of the previous inhaled corticosteroid product and disease severity: 40, 80, 160 or 320 mcg twice daily. For patients who do not respond adequately to the initial dosage after 2 weeks of therapy, increasing the dosage may provide additional asthma control. The maximum recommended dosage for patients 12 years of age and older is 320 mcg twice daily. Pediatric Patients 4 to 11 years The recommended starting dosage for patients aged 4 to 11 years of age is 40 mcg twice daily by oral inhalation, approximately 12 hours apart. The starting dosage is based on previous asthma therapy and disease severity, including consideration of the patients’ current control of asthma symptoms and risk of future exacerbation. For patients who do not respond adequately to QVAR REDIHALER 40 mcg after 2 weeks of therapy, increasing the dosage to QVAR REDIHALER 80 mcg twice daily may provide additional asthma control. The maximum recommended dosage for patients 4 to 11 years of age is 80 mcg twice daily. General Dosing Recommendations The onset and degree of symptom relief will vary in individual patients. Improvement in asthma symptoms can occur within 24 hours of the beginning of treatment and should be expected within the first or second week, but maximum benefit should not be expected until 3 to 4 weeks of therapy. Improvement in pulmonary function is usually apparent within 1 to 4 weeks after the start of therapy. If a dosage regimen of QVAR REDIHALER fails to provide adequate control of asthma, the therapeutic regimen should be re-evaluated and additional therapeutic options (e.g., replacing the current strength of QVAR REDIHALER with a higher strength, or adding additional controller therapies) should be considered. As with any inhaled corticosteroid, physicians are advised to titrate the dose of QVAR REDIHALER downward over time to the lowest level that maintains proper asthma control. This is particularly important in children since a controlled study has shown that beclomethasone dipropionate has the potential to affect growth in children. The maximum number of inhalations should not exceed 8 per day.

1 INDICATIONS AND USAGE QVAR REDIHALER is indicated in the maintenance treatment of asthma as prophylactic therapy in adults and pediatric patients 4 years of age and older. Limitations of Use: QVAR REDIHALER is not indicated for the relief of acute bronchospasm. QVAR REDIHALER is a corticosteroid indicated for maintenance treatment of asthma as prophylactic therapy in adults and pediatric patients 4 years of age and older. ( 1 ) Limitations of Use : Not indicated for the relief of acute bronchospasm. ( 1 )

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Beclomethasone dipropionate is a corticosteroid demonstrating potent anti‑inflammatory activity. The precise mechanism of corticosteroid action on asthma is not known. Corticosteroids have been shown to have multiple anti‑inflammatory effects, inhibiting both inflammatory cells (e.g., mast cells, eosinophils, basophils, lymphocytes, macrophages, and neutrophils) and release of inflammatory mediators (e.g., histamine, eicosanoids, leukotrienes, and cytokines). These anti‑inflammatory actions of corticosteroids contribute to their efficacy in asthma. Beclomethasone dipropionate is a prodrug that is rapidly activated by hydrolysis to the active monoester, 17‑monopropionate (17‑BMP). Beclomethasone‑17‑monopropionate has been shown in vitro to exhibit a binding affinity for the human glucocorticoid receptor which is approximately 13 times that of dexamethasone, 6 times that of triamcinolone acetonide, 1.5 times that of budesonide and 25 times that of beclomethasone dipropionate. The clinical significance of these findings is unknown. Studies in patients with asthma have shown a favorable ratio between topical anti‑inflammatory activity and systemic corticosteroid effects with recommended doses of QVAR REDIHALER. 12.2 Pharmacodynamics HPA Axis Effects The effects of QVAR MDI on the hypothalamic‑pituitary‑adrenal (HPA) axis were studied in 40 corticosteroid-naive patients. QVAR MDI, at doses of 80, 160, or 320 mcg twice daily, was compared with placebo and 336 mcg twice daily of CFC‑BDP. Active treatment groups showed an expected dose‑related reduction in 24‑hour urinary-free cortisol (a sensitive marker of adrenal production of cortisol). Patients treated with the highest dose recommended of QVAR MDI (320 mcg twice daily) had a 37.3% reduction in 24‑hour urinary‑free cortisol compared to a reduction of 47.3% produced by treatment with 336 mcg twice daily of CFC‑BDP. There was a 12.2% reduction in 24‑hour urinary‑free cortisol seen in the group of patients that received 80 mcg twice daily of QVAR MDI and a 24.6% reduction in the group of patients that received 160 mcg twice daily. An open label study of 354 asthma patients given QVAR MDI at recommended doses for one year assessed the effect of treatment with this product on the HPA axis (as measured by both morning and stimulated plasma cortisol). Less than 1% of patients treated for one year with this product had an abnormal response (peak less than 18 mcg/dL) to a short-cosyntropin test. 12.3 Pharmacokinetics Beclomethasone dipropionate undergoes rapid and extensive conversion to beclomethasone‑17‑monopropionate (17‑BMP) during absorption. The pharmacokinetics of beclomethasone dipropionate and 17‑BMP were studied in subjects given single doses. Absorption The mean peak plasma concentration (C max ) of BDP was 6635 pg/mL at 2 minutes after inhalation of 320 mcg using QVAR REDIHALER (4 inhalations of the 80 mcg/inhalation strength). The mean peak plasma concentration of the major and most active metabolite, 17-BMP, was 1464 pg/mL at 10 minutes after inhalation of 320 mcg of QVAR REDIHALER. Distribution The in vitro protein binding for 17‑BMP was reported to be 94‑96% over the concentration range of 1000 to 5000 pg/mL. Protein binding was constant over the concentration range evaluated. There is no evidence of tissue storage of beclomethasone dipropionate or its metabolites. Elimination The major route of elimination of inhaled beclomethasone dipropionate appears to be via hydrolysis. More than 90% of inhaled beclomethasone dipropionate is found as 17‑BMP in the systemic circulation. The mean terminal half‑life of 17‑BMP is approximately 4 hours for QVAR REDIHALER. Metabolism Three major metabolites are formed via esterases: beclomethasone‑17‑monopropionate (17‑BMP) beclomethasone‑21‑monopropionate (21‑BMP) beclomethasone (BOH) Lung slices metabolize beclomethasone dipropionate rapidly to 17‑BMP and more slowly to BOH. 17‑BMP is the most active metabolite. Excretion Irrespective of the route of administration (injection, oral or inhalation), beclomethasone dipropionate and its metabolites are mainly excreted in the feces. Less than 10% of the drug and its metabolites are excreted in the urine. Specific Populations No pharmacokinetic studies for QVAR REDIHALER have been conducted in neonates or elderly subjects. Pediatric Patients: No pharmacokinetic studies for QVAR REDIHALER have been conducted in pediatric subjects aged of 4 to 17 years. However, the pharmacokinetics of 17‑BMP, including dose and strength proportionalities, is similar in children and adults using QVAR MDI, although the exposure is highly variable. In 17 children (mean age 10 years), the C max of 17‑BMP was 787 pg/mL at 0.6 hour after inhalation of 160 mcg (4 actuations of the 40 mcg/actuation strength of QVAR MDI). The systemic exposure to 17‑BMP from 160 mcg of QVAR MDI administered without a spacer was comparable to the systemic exposure to 17‑BMP from 336 mcg CFC‑BDP administered with a large volume spacer in 14 children (mean age 12 years). This implies that approximately twice the systemic exposure to 17‑BMP would be expected for comparable mg doses of QVAR MDI without a spacer and CFC‑BDP with a large volume spacer. Male and Female Patients : The influence of sex on the pharmacokinetics of QVAR REDIHALER has not been studied. Racial or Ethnic Groups : The influence of race on the pharmacokinetics of QVAR REDIHALER has not been studied. Patients with Renal Impairment : The effect of renal impairment on the pharmacokinetics of QVAR REDIHALER has not been evaluated. Patients with Hepatic Impairment : The effect of hepatic impairment on the pharmacokinetics of QVAR REDIHALER has not been evaluated. Drug Interaction Studies : In vitro and in vivo drug interaction studies have not been conducted with QVAR REDIHALER.

20230607

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3 DOSAGE FORMS AND STRENGTHS Inhalation aerosol: a pressurized, breath‑actuated, metered-dose aerosol with a dose counter in 2 strengths 40 mcg in an aluminum canister contained within a beige plastic actuator and a hinged white cap 80 mcg in an aluminum canister contained within a maroon plastic actuator and a hinged white cap Inhalation aerosol: 40 mcg or 80 mcg per breath actuation. ( 3 )

QVAR REDIHALER Beclomethasone Dipropionate HFA BECLOMETHASONE DIPROPIONATE BECLOMETHASONE NORFLURANE ALCOHOL QVAR REDIHALER Beclomethasone Dipropionate HFA BECLOMETHASONE DIPROPIONATE BECLOMETHASONE NORFLURANE ALCOHOL

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility The carcinogenicity of beclomethasone dipropionate was evaluated in rats which were exposed for a total of 95 weeks, 13 weeks at inhalation doses up to 0.4 mg/kg/day and the remaining 82 weeks at combined oral and inhalation doses up to 2.4 mg/kg/day. There was no evidence of treatment‑related increases in the incidence of tumors in this study at the highest dose, which is approximately 37 and 72 times the MRHDID in adults and children, respectively, on a mg/m 2 basis. Beclomethasone dipropionate did not induce gene mutation in bacterial cells or mammalian Chinese hamster ovary (CHO) cells in vitro . No significant clastogenic effect was seen in cultured CHO cells in vitro or in the mouse micronucleus test in vivo . In rats, beclomethasone dipropionate caused decreased conception rates at an oral dose of 16 mg/kg/day (approximately 250 times the MRHDID in adults on a mg/m 2 basis). Impairment of fertility, as evidenced by inhibition of the estrous cycle in dogs, was observed following treatment by the oral route at a dose of 0.5 mg/kg/day (approximately 25 times the MRHDID in adults on a mg/m 2 basis). No inhibition of the estrous cycle in dogs was seen following 12 months of exposure to beclomethasone dipropionate by the inhalation route at an estimated daily dose of 0.33 mg/kg (approximately 17 times the MRHDID in adults on a mg/m 2 basis).

NDA207921

QVAR REDIHALER

Beclomethasone Dipropionate HFA

53002-3477

HUMAN PRESCRIPTION DRUG

RESPIRATORY (INHALATION)

Qvar 40mcg HFA Redihaler Label Image

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA‑Approved Patient Labeling (Patient Information and Instructions for Use). Patients should be given the following information: Oropharyngeal Candidiasis Inform patients that localized infections with Candida albicans occurred in the mouth and pharynx in some patients. If oropharyngeal candidiasis develops, treat it with appropriate local or systemic (i.e., oral) antifungal therapy while still continuing therapy with QVAR REDIHALER, but at times therapy with QVAR REDIHALER may need to be temporarily interrupted under close medical supervision. Rinsing the mouth with water without swallowing after inhalation is advised to help reduce the risk of thrush. Status Asthmaticus and Acute Asthma Symptoms Inform patients that QVAR REDIHALER is not a bronchodilator and is not intended for use as rescue medicine for acute asthma exacerbations. Advise patients to treat acute asthma symptoms with an inhaled, short‑acting beta 2 ‑agonist such as albuterol. Instruct the patient to contact their physicians immediately if there is deterioration of their asthma. Immunosuppression and Risk of Infections Warn patients who are on immunosuppressant doses of corticosteroids to avoid exposure to chickenpox or measles and, if exposed, to consult their physicians without delay. Inform patients of potential worsening of existing tuberculosis; fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex. Hypercorticism and Adrenal Suppression Advise patients that QVAR REDIHALER may cause systemic corticosteroid effects of hypercorticism and adrenal suppression. Additionally, instruct patients that deaths due to adrenal insufficiency have occurred during and after transfer from systemic corticosteroids. Patients should taper slowly from systemic corticosteroids if transferring to QVAR REDIHALER. Immediate Hypersensitivity Reactions Advise patients that immediate hypersensitivity reactions (e.g., urticaria, angioedema, rash, bronchospasm, and hypotension), including anaphylaxis, may occur after administration of QVAR REDIHALER. Patients should discontinue QVAR REDIHALER if such reactions occur and contact their healthcare provider or get emergency medical help. Reduction in Bone Mineral Density Advise patients who are at an increased risk for decreased BMD that the use of corticosteroids may pose an additional risk. Reduced Growth Velocity Inform patients that orally inhaled corticosteroids, including QVAR REDIHALER, may cause a reduction in growth velocity when administered to pediatric patients. Physicians should closely follow the growth of adolescents taking corticosteroids by any route. Ocular Effects Long-term use of inhaled corticosteroids may increase the risk of some eye problems (cataracts, glaucoma or blurred vision); consider regular eye examinations. Pregnancy Inform patients who are pregnant or nursing that they should contact their physician about the use of QVAR REDIHALER. Use Daily for Best Effect Patients should use QVAR REDIHALER at regular intervals as directed. The daily dosage of QVAR REDIHALER should not exceed 8 inhalations per day. Advise patients, if they miss a dose, to take their next dose at the same time they normally do. Individual patients will experience a variable time to onset and degree of symptom relief and the full benefit may not be achieved until treatment has been administered for 1 to 2 weeks or longer. Patients should not increase the prescribed dosage but should contact their physicians if symptoms do not improve or if the condition worsens. Instruct patients to not stop use of QVAR REDIHALER abruptly. Patients should contact their physicians immediately if they discontinue use of QVAR REDIHALER. Caring for and Storing the Inhaler For normal hygiene, the mouthpiece of QVAR REDIHALER should be cleaned weekly with a clean, dry tissue or cloth. Never wash or put any part of QVAR REDIHALER in water. Patient should replace QVAR REDIHALER if washed or placed in water. Instruct patients to store the inhaler at room temperature and to avoid exposure to extreme heat and cold. Inform patients that shaking the inhaler prior to use is not necessary. Instruct patients not to shake the inhaler with the cap open to avoid possible actuation of the device. Instruct patients to never take QVAR REDIHALER apart. Inform patients that QVAR REDIHALER has a dose counter attached to the actuator at the rear of the mouth piece. When the patient receives the inhaler, the number 120 will be displayed. The dose counter will count down each time a spray is released. The dose-counter window displays the number of sprays left in the inhaler in units of two (e.g., 120, 118, 116, etc). When the counter displays 20, the color of the numbers will change to red to remind the patient to contact their pharmacist for a refill of medication or consult their healthcare provider for a prescription refill. When the dose counter reaches 0, the background will change to solid red. Inform patients to discard QVAR REDIHALER when the dose counter displays 0 or after the expiration date on the product, whichever comes first. Distributed by: Teva Pharmaceuticals USA Parsippany, NJ 07054 © 2021 Teva Respiratory, LLC U.S. Patent 7,637,260; 8,132,712; 8,931,476 QVARH-003

INSTRUCTIONS FOR USE Instructions for Use QVAR REDIHALER ® (kue' var red-ee-haye’ ler ) (beclomethasone dipropionate HFA) inhalation aerosol Your QVAR REDIHALER Inhaler O verview When you are ready to use your QVAR REDIHALER for the first time, remove the inhaler from the carton. Important information: There is no button. You must close the white cap to prepare the inhaler with medicine before each inhalation . Do not shake. This breath-actuated device does not need to be shaken. This is not a press-and-breathe inhaler. Do not prime QVAR REDIHALER . The inhaler does not need to be primed. Do not use a spacer or volume holding chamber with QVAR REDIHALER. Always use the inhaler in the upright position (with the mouthpiece down). After the inhaler is prepared, it will deliver 1 inhalation of medicine when you breathe in (inhale) through the mouthpiece. Your dose might require more than 1 inhalation. Do not open the white cap or leave it open unless you are ready for your next inhalation. If the cap has been opened for more than 2 minutes or left in the open position, you will need to close the white cap before use. Do not breathe out or blow into any part of the inhaler. Breathing out or blowing into the inhaler can damage it. Do not suddenly stop using your QVAR REDIHALER. Contact your healthcare provider immediately if you stop using your QVAR REDIHALER. There are 2 main parts of your QVAR REDIHALER including: the inhaler body with the mouthpiece. See Figure A. the white cap that covers the mouthpiece of the inhaler. See Figure A. Figure A About the Dose Counter There is a dose counter in the back of the inhaler with a viewing window that shows you how many inhalations of medicine you have left. See Figure B. Your QVAR REDIHALER contains 120 inhalations. See Figure B. The counter on the back of your inhaler shows how many inhalations you have left. When there are 20 inhalations left, the numbers in the dose counter will change to red and you should refill your prescription or ask your healthcare provider for another prescription. When the dose counter shows ‘0’, the background will turn solid red and your inhaler is empty. You should stop using the inhaler and throw it away. Do not put your inhaler into a fire or incinerator. See Figure B. Figure B Important: The white cap must be closed to prepare the inhaler before each inhalation or you will not receive your medicine. See Figure C. If the white cap is open, close the white cap to prepare your inhaler and look at the dose counter window to make sure that your inhaler is not empty. See Figure B. Do not open the cap until you are ready to take your inhalation. Figure C Using your QVAR REDIHALER: Step 1. Open the white cap Open the white cap. See Figure D. Breathe out fully, away from the inhaler. Do not blow into the inhaler. Figure D Remember: Do not open the cap until you are ready to take your inhalation. Never breathe out or blow into the inhaler . Breathing out or blowing into the inhaler can damage it. Step 2. Inhale 1 Time Place the mouthpiece in your mouth and close your lips around it so you form a good seal. Inhale deeply to release the medicine. Remove the inhaler and hold your breath for 5 to 10 seconds, then breathe out slowly, away from the inhaler. Figure E Remember: Hold the inhaler upright as you take your inhalation. See Figure E. Step 3. Close the white cap Close the white cap after inhaling to prepare your next inhalation. See Figure F. Figure F If your healthcare provider has told you to take more than 1 inhalation per dose, make sure the white cap is closed and repeat Step 1 to Step 3. After taking your prescribed number of inhalations, rinse your mouth with water without swallowing to help reduce the risk of a fungal infection (thrush) in your mouth. How to store your QVAR REDIHALER Store QVAR REDIHALER at room temperature between 68ºF to 77ºF (20ºC to 25ºC). Avoid exposure to extreme heat or cold. Keep the white cap on the inhaler closed during storage. Keep your QVAR REDIHALER inhaler dry and clean at all times. If you drop your QVAR REDIHALER, inspect it for damage before use. If the QVAR REDIHALER is damaged, do not use the damaged QVAR REDIHALER. Call your doctor or pharmacist to replace the QVAR REDIHALER. Do not use or store your QVAR REDIHALER near heat or open flame. Exposure to temperatures above 120ºF (49ºC) may cause the canister to burst. Do not throw QVAR REDIHALER into fire or an incinerator. Throw away QVAR REDIHALER when the dose counter displays ‘0,’ or after the expiration date on the package, whichever comes first. Keep your QVAR REDIHALER and all medicines out of the reach of children. Cleaning your QVAR REDIHALER Do not wash or put any part of your QVAR REDIHALER in water. Clean the mouthpiece of your QVAR REDIHALER weekly with a clean, dry tissue or cloth. Support If you have any questions about QVAR REDIHALER or how to use your inhaler, go to www.QVAR.com or call 1-888-483-8279. This Instructions for Use has been approved by the U.S. Food and Drug Administration. Distributed by: Teva Pharmaceuticals USA, Inc. Parsippany, NJ 07054 ©2021Teva Respiratory, LLC. All rights reserved. QVARHIFU-003 Rev. 01/2021 Figure A Figure B Figure C Figure D Figure E Figure F

14 CLINICAL STUDIES The safety and efficacy of QVAR REDIHALER were evaluated in 1,858 patients with asthma. The development program included 2 confirmatory trials of 12 weeks duration and 1 confirmatory trial of 6 weeks duration in patients 12 years of age and older, and 1 confirmatory trial of 12 weeks duration in patients 4 to 11 years of age. The efficacy of QVAR REDIHALER is based primarily on the confirmatory trials described below. 14.1 Trials in the Maintenance Treatment of Asthma Adult and Adolescent Patients 12 Years of Age and Older Two confirmatory clinical trials were conducted comparing QVAR REDIHALER with placebo in adult and adolescent patients with persistent asthma (Trial 1 and Trial 2). Trial 1 (NCT02040779): This randomized, double-blind, parallel-group, placebo-controlled, 12-week, efficacy and safety trial compared QVAR REDIHALER 40 and 80 mcg given as 1 inhalation twice daily with placebo in adult and adolescent patients with persistent symptomatic asthma despite low-dose inhaled corticosteroid or non-corticosteroid asthma therapy. Patients aged 12 years and older who met the entry criteria including FEV 1 40-85 percent of predicted normal, reversible bronchoconstriction of 15% with short-acting inhaled beta-agonist entered a 14-21 day run-in period. 270 patients (104 previously treated with inhaled corticosteroids) who met all the randomization criteria including asthma symptoms and rescue medication use were discontinued from asthma maintenance medication and randomized equally to treatment with QVAR REDIHALER 80 mcg/day, QVAR REDIHALER 160 mcg/day or placebo. Baseline FEV 1 values were similar across treatments. The primary endpoint for this trial was the standardized baseline-adjusted trough morning forced expiratory volume in 1 second (FEV 1 ) area under the effect curve from time zero to 12 weeks [FEV 1 AUEC(0-12wk)]. Patients in both treatment groups had significantly greater improvements in trough FEV 1 compared to placebo (QVAR REDIHALER 80 mcg/day, LS mean change of 0.124 L and QVAR REDIHALER 160 mcg/day, LS mean change of 0.116 L over 12 weeks) (Table 3). In addition, the mean change from baseline is displayed in Figure 1. Both doses of QVAR REDIHALER were effective in improving asthma control with significantly greater improvements in FEV 1 and morning PEF when compared to placebo. Reduction in asthma symptoms was also supportive of the efficacy of QVAR REDIHALER. Figure 1: A 12‑Week Clinical Trial in Patients with Asthma: Mean Change in FEV 1 Trial 2 (NCT02513160): This randomized, double-blind, parallel-group, placebo-controlled, 6-week, efficacy and safety trial compared QVAR REDIHALER 40 and 80 mcg given as 4 inhalations twice daily and placebo in adult and adolescent patients with persistent symptomatic asthma despite treatment with non-corticosteroid, inhaled corticosteroids (with or without a long acting beta agonist [LABA]), or combination asthma therapy. The study also included a reference treatment group, QVAR ® Inhalation Aerosol (QVAR MDI) 40 mcg, 4 inhalations twice daily. Patients aged 12 years and older who met the entry criteria including FEV 1 50-90% predicted normal, reversible bronchoconstriction of at least 10% with short-acting inhaled beta-agonist discontinued baseline asthma treatment and entered a 2-4 week run-in period. 425 patients (257 previously treated with ICS with or without LABA) who met all the randomization criteria including FEV 1 of 40-85% predicted and 15% reversibility with short-acting inhaled beta-agonist, and asthma symptoms were randomized equally to QVAR REDIHALER 320 mcg/day, QVAR REDIHALER 640 mcg/day, QVAR MDI 320 mcg/day or placebo. Baseline FEV 1 values were similar across treatments. The primary endpoint for this trial was the standardized baseline-adjusted trough morning forced expiratory volume in 1 second (FEV 1 ) area under the effect curve from time zero to 6 weeks [FEV 1 AUEC(0-6wk)]. Patients in both treatment groups had significantly greater improvements in trough FEV 1 compared to placebo (QVAR REDIHALER 320 mcg/day, LS mean change of 0.144 L and QVAR REDIHALER 640 mcg/day, LS mean change of 0.150 L over 6 weeks) (Table 3). Treatment with QVAR MDI was similar. The change from baseline in morning FEV 1 during the trial is displayed in Figure 2. Both doses of QVAR REDIHALER were effective in improving asthma control with significantly greater improvements in FEV 1 , morning PEF, weekly average of daily trough morning FEV 1 , reduced rescue medication use and improved asthma symptom scores than with placebo. Similar results were demonstrated with QVAR MDI. Figure 2: A 6‑Week Dose Response Clinical Trial in Patients with Inhaled Corticosteroid-Dependent Asthma: Mean Change in FEV 1 as Percent of Predicted Side-by-side comparison of the primary analysis of standardized baseline-adjusted trough morning FEV 1 from time zero to the end of the treatment period for both studies is shown below in Table 3. Table 3: Primary Analysis of Standardized Baseline-Adjusted Trough Morning FEV 1 (L) AUEC from Time Zero to the End of the Treatment Period 12-week Study and 6-week Dose Response Study 12 weeks; FAS 6 weeks; mITT Analysis set Parameter Statistic Placebo (N=90) QVAR REDIHALER 80 mcg/day (N=88) QVAR REDIHALER 160 mcg/day (N=92) Placebo (N=107) QVAR REDIHALER 320 mcg/day (N=108) QVAR REDIHALER 640 mcg/day (N=105) QVAR MDI * 320 mcg/day (N=105) Difference from placebo Difference of Least Square mean — 0.124 0.116 — 0.144 0.150 0.148 95% CI — 0.054, 0.193 0.048, 0.185 — 0.0807, 0.2066 0.0868, 0.2132 0.0847, 0.2114 *QVAR MDI=QVAR Inhalation Aerosol Pediatric Patients 4 to 11 Years of Age This randomized, double-blind, parallel-group, placebo controlled, 12-week, global efficacy and safety trial (NCT02040766) compared QVAR REDIHALER 40 or 80 mcg, QVAR MDI 40 or 80 mcg or placebo given as 1 inhalation twice daily in pediatric patients aged 4 through 11 years old with persistent symptomatic asthma despite treatment with non-corticosteroid or low dose inhaled corticosteroid (with or without a long acting beta agonist [LABA]). Patients aged 4 to 5 years who were technically unable to complete spirometry participated in the safety population. Patients who met the entry criteria including FEV 1 40-90% predicted normal and reversible bronchoconstriction of at least 12% with short acting inhaled beta agonist entered a 14-21 day run in period. Patients who met the randomization criteria including asthma symptoms and rescue medication use discontinued asthma therapy and were randomized equally across treatment groups. Five hundred sixty-eight (568) pediatric patients with symptomatic asthma of which 410 had previously been treated with low dose inhaled corticosteroids with or without a LABA were randomized to receive either 40 mcg or 80 mcg twice daily of QVAR REDIHALER, QVAR MDI or placebo. The primary endpoint was the change from baseline in trough percent predicted FEV 1 AUEC (0-12 weeks). While the primary endpoint, was not statistically significant, change in weekly average of daily morning peak expiratory flow (PEF, L/min) over the 12 week treatment period was 11.3 [95% CI: 5.58, 17.06] and 8.5 [95% CI: 2.71, 14.24] for the 80 mcg/day and 160 mcg/day doses of QVAR REDIHALER, respectively, at nominal significance. Similar results were seen with evening PEF. Figure 1 Figure 2

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no adequate and well‑controlled studies with QVAR REDIHALER or beclomethasone dipropionate in pregnant women. There are clinical considerations with the use of inhaled corticosteroids (ICS), including beclomethasone dipropionate, in pregnant women [see Clinical Considerations] . Also, no published studies, including studies of large birth registries, have to date related the use of ICS to any increases in congenital malformations or other adverse perinatal outcomes. Thus, available human data do not establish the presence or absence of drug‑associated risk to the fetus. In animal reproduction studies, beclomethasone dipropionate resulted in adverse developmental effects in mice and rabbits at subcutaneous doses equal to or greater than approximately 0.75 times the maximum recommended human daily inhalation dose (MRHDID) in adults (0.64 mg/day) [see Data] . In rats exposed to beclomethasone dipropionate by inhalation, dose‑related gross injury to the fetal adrenal glands was observed at doses greater than 180 times the MRHDID, but there was no evidence of external or skeletal malformations or embryolethality at inhalation doses of up to 440 times the MRHDID. The estimated background risk of major birth defects and miscarriage for the indicated population(s) are unknown. In the US general population, the estimated risk of major birth defects and miscarriage in clinically recognized pregnancies is 2‑4% and 15‑20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk The risk of complications to the mother and developing fetus from inadequate control of asthma must be balanced against the risks from exposure to beclomethasone dipropionate. In women with poorly or moderately controlled asthma, evidence demonstrates that there is an increased risk of preeclampsia in the mother and prematurity, low birth weight, and small for gestational age for the neonate. The level of asthma control should be closely monitored in pregnant women and treatment adjusted to maintain optimal control. Labor or Delivery There are no specific human data regarding any adverse effects of inhaled beclomethasone dipropionate on labor and delivery. Data Animal Data In an embryofetal development study in pregnant rats, beclomethasone dipropionate administration during organogenesis from gestation days 6 to 15 at inhaled doses 180 times the MRHDID in adults and higher (on a mg/m 2 basis at maternal doses of 11.5 and 28.3 mg/kg/day) produced dose‑dependent gross injury (characterized by red foci) of the adrenal glands in fetuses. There were no findings in the adrenal glands of rat fetuses at an inhaled dose that was 40 times the MRHDID in adults (on a mg/m 2 basis at a maternal dose of 2.4 mg/kg/day). There was no evidence of external or skeletal malformations or embryolethality in rat at inhaled doses up to 440 times the MRHDID (on a mg/m 2 basis at maternal doses up to 28.3 mg/kg/day). In an embryofetal development study in pregnant mice, beclomethasone dipropionate administration from gestation days 1 to 18 at subcutaneous doses equal to and greater than 0.75 times the MRHDID in adults (on a mg/m 2 basis at maternal doses of 0.1 mg/kg/day and higher) produced adverse developmental effects (increased incidence of cleft palate). A no-effect dose in mice was not identified. In a second embryofetal development study in pregnant mice, beclomethasone dipropionate administration from gestation days 1 to 13 at subcutaneous doses equal to and greater than 2.3 times the MRHDID in adults (on a mg/m 2 basis at a maternal dose of 0.3 mg/kg/day) produced embryolethal effects (increased fetal resorptions) and decreased pup survival. In an embryofetal development study in pregnant rabbits, beclomethasone dipropionate administration during organogenesis from gestation days 7 to 16 at subcutaneous doses equal to and greater than 0.75 times the MRHDID in adults (on a mg/m 2 basis at maternal doses of 0.025 mg/kg/day and higher) produced external and skeletal malformations and embryolethal effects (increased fetal resorptions). There were no effects in fetuses of pregnant rabbits administered a subcutaneous dose 0.2 times the MRHDID in adults (on a mg/m 2 basis at a maternal dose of 0.006 mg/kg/day). 8.2 Lactation Risk Summary There are no data available on the presence of beclomethasone dipropionate in human milk, the effects on the breastfed child, or the effects on milk production. However, other inhaled corticosteroids have been detected in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for QVAR REDIHALER and any potential adverse effects on the breastfed child from beclomethasone dipropionate or from the underlying maternal condition. 8.3 Females and Males of Reproductive Potential Impairment of fertility was observed in rats and dogs at oral doses of beclomethasone dipropionate corresponding to 250 and 25 times the MRHDID for adults on a mg/m 2 basis, respectively. [see Nonclinical Toxicology ( 13.1 )] . 8.4 Pediatric Use The safety and effectiveness of QVAR REDIHALER for the maintenance treatment of asthma as prophylactic therapy have been established in pediatric patients aged 4 years and older. Use of QVAR REDIHALER for this indication is supported by evidence from adequate and well-controlled studies. Five-hundred and one children between the ages of 4 and 11 were treated with at least one dose of QVAR REDIHALER or QVAR MDI in one 12‑week clinical trial. The safety and effectiveness of QVAR REDIHALER in children below 4 years of age have not been established. Controlled clinical studies have shown that inhaled corticosteroids may cause a reduction in growth velocity in pediatric patients. A 12‑month, randomized, controlled clinical trial evaluated the effects of QVAR MDI versus beclomethasone dipropionate in a CFC propellant‑based formulation (CFC‑BDP) on growth in children age 5 to 11. A total of 520 patients were enrolled, of whom 394 received QVAR MDI (100 to 400 mcg/day ex‑valve) and 126 received CFC‑BDP (200 to 800 mcg/day ex‑valve). Similar control of asthma was noted in each treatment arm. When comparing results at month 12 to baseline, the mean growth velocity in children treated with QVAR MDI was approximately 0.5 cm/year less than that noted with children treated with CFC‑BDP via large‑volume spacer. The long‑term effects of the reduction in growth velocity associated with orally inhaled corticosteroids, including the impact on final adult height, are unknown. The potential for "catch‑up" growth following discontinuation of treatment with orally inhaled corticosteroids has not been adequately studied. The growth of children and adolescents receiving orally inhaled corticosteroids, including QVAR REDIHALER, should be monitored routinely (e.g., via stadiometry). If a child or adolescent on any corticosteroid appears to have growth suppression, the possibility that he/she is particularly sensitive to this effect should be considered. The potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the risks associated with alternative therapies. To minimize the systemic effects of orally inhaled corticosteroids, including QVAR REDIHALER, each patient should be titrated to his/her lowest effective dose [see Dosage and Administration ( 2.2 )] . 8.5 Geriatric Use Clinical studies of QVAR REDIHALER did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

16 HOW SUPPLIED/STORAGE AND HANDLING Product: 53002-2436 NDC: 53002-2436-3 1 AEROSOL, METERED in a INHALER / 1 in a CARTON Product: 53002-3477 NDC: 53002-3477-3 1 AEROSOL, METERED in a INHALER / 1 in a CARTON