Beclomethasone Dipropionate

1 INDICATIONS AND USAGE Beclomethasone dipropionate HFA inhalation aerosol is indicated in the maintenance treatment of asthma as prophylactic therapy in patients 5 years of age and older. Important Limitations of Use: Beclomethasone dipropionate HFA inhalation aerosol is NOT indicated for the relief of acute bronchospasm. Beclomethasone dipropionate HFA inhalation aerosol is a corticosteroid indicated for: Maintenance treatment of asthma as prophylactic therapy in patients 5 years of age and older. (1) Important Limitations: Not indicated for the relief of acute bronchospasm. (1)

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 12 years and older: 40 mcg, 80 mcg, 160 mcg, or 320 mcg twice daily. (2.2) Treatment of asthma in patients 5 to 11 years of age: 40 or 80 mcg twice daily. (2.2) Discard beclomethasone dipropionate HFA inhalation aerosol inhaler when the dose counter displays 0 or after the expiration date on the product, whichever comes first. (2.1) 2.1 Administration Information Administer beclomethasone dipropionate HFA inhalation aerosol by the orally inhaled route in patients 5 years of age and older. Beclomethasone dipropionate HFA inhalation aerosol does not require shaking prior to use. After inhalation, the patient should rinse his/her mouth with water without swallowing to help reduce the risk of oropharyngeal candidiasis. Use of beclomethasone dipropionate HFA inhalation aerosol with a spacer device in children less than 5 years of age is not recommended [see Use in Specific Populations (8.4) ] . Patients should be instructed on the proper use of their inhaler. 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). Priming : Patients should prime beclomethasone dipropionate HFA inhalation aerosol by actuating into the air twice before using for the first time or if beclomethasone dipropionate HFA inhalation aerosol has not been used for over 10 days. Avoid spraying in the eyes or face when priming beclomethasone dipropionate HFA inhalation aerosol. Dose Counter : Beclomethasone dipropionate HFA inhalation aerosol has a dose counter window located on the back of the actuator. When the patient receives the inhaler, “122” will appear in the viewing window until it has been primed 2 times, at which point the total number of actuations 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 one (e.g., 120, 119, 118, etc). When the dose counter reaches "20", it is a reminder to the patient to contact their pharmacist for a refill of medication or consult their physician for a prescription refill. Discard beclomethasone dipropionate HFA inhalation aerosol inhaler when the dose counter displays 0 or after the expiration date on the product, whichever comes first. 2.2 Recommended Dosage Adults and Adolescents 12 years of age and older 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. 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, approximately 12 hours apart. For patients switching to beclomethasone dipropionate HFA inhalation aerosol from another inhaled corticosteroid product, select the appropriate starting dosage strength of beclomethasone dipropionate HFA inhalation aerosol 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 5 to 11 years 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. The recommended starting dosage for patients aged 5 to 11 years of age is 40 mcg twice daily, approximately 12 hours apart. For patients who do not respond adequately to beclomethasone dipropionate HFA inhala …

3 DOSAGE FORMS AND STRENGTHS Inhalation Aerosol: Beclomethasone dipropionate HFA inhalation aerosol is a pressurized, metered-dose aerosol with a dose counter intended for oral inhalation containing beclomethasone dipropionate, USP in the following 2 strengths: Beclomethasone dipropionate HFA inhalation aerosol 40 mcg is supplied in a pressurized aluminum canister with a plastic actuator (beige actuator with light blue dust cap). Each actuation delivers 50 mcg of beclomethasone dipropionate, USP from the valve and 40 mcg from the actuator. Beclomethasone dipropionate HFA inhalation aerosol 40 mcg is available as a 120-inhalation/8.7 g canister. Beclomethasone dipropionate HFA inhalation aerosol 80 mcg is supplied in a pressurized aluminum canister with a plastic actuator (dark pink actuator with gray dust cap). Each actuation delivers 100 mcg of beclomethasone dipropionate, USP from the valve and 80 mcg from the actuator. Beclomethasone dipropionate HFA inhalation aerosol 80 mcg is available as a 120-inhalation/8.7 g canister. Inhalation aerosol: 40 or 80 mcg per actuation (3)

4 CONTRAINDICATIONS Primary treatment of status asthmaticus or other acute episodes of asthma where intensive measures are required. (4) Hypersensitivity to any of the ingredients of beclomethasone dipropionate HFA inhalation aerosol. (4) 4.1 Status Asthmaticus Beclomethasone dipropionate HFA inhalation aerosol is contraindicated in the primary treatment of status asthmaticus or other acute episodes of asthma where intensive measures are required. 4.2 Hypersensitivity Beclomethasone dipropionate HFA inhalation aerosol is contraindicated in patients with known hypersensitivity to beclomethasone dipropionate or any of the ingredients in beclomethasone dipropionate HFA inhalation aerosol [see Warnings and Precautions (5.6) ] .

6 ADVERSE REACTIONS Systemic and local corticosteroid use may result in the following: Candida albicans infection [see Warnings and Precautions (5.1) ] Immunosuppression [see Warnings and Precautions (5.4) ] Hypercorticism and adrenal suppression [see Warnings and Precautions (5.7) ] Growth effects [see Warnings and Precautions (5.8) and Use in Specific Populations (8.4) ] Eye Disorders [see Warnings and Precautions (5.10) ] Most common adverse reactions (incidence ≥3% and > placebo) include headache, pharyngitis, oral symptoms (inhalation route), and sinusitis. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 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 following reporting rates of common adverse experiences are based upon 4 clinical trials in which 1196 patients (671 female and 525 male adults previously treated with as-needed bronchodilators and/or inhaled corticosteroids) were treated with beclomethasone dipropionate HFA inhalation aerosol (doses of 40, 80, 160, or 320 mcg twice daily) or CFC-BDP (doses of 42, 168, or 336 mcg twice daily) or placebo. Table 1 below includes all events reported by patients taking beclomethasone dipropionate HFA inhalation aerosol (whether considered drug related or not) that occurred at a rate over 3% for beclomethasone dipropionate HFA inhalation aerosol. In considering these data, difference in average duration of exposure and clinical trial design should be taken into account. Table 1 Adverse Events Reported by at Least 3% of the Patients for Beclomethasone Dipropionate HFA Inhalation Aerosol by Treatment and Daily Dose Adverse Events Placebo (N=289) % Beclomethasone Dipropionate HFA Inhalation Aerosol Total (N=624) % 80 to 160 mcg (N=233) % 320 mcg (N=335) % 640 mcg (N=56) % Headache 9 12 15 8 25 Pharyngitis 4 8 6 5 27 Upper Respiratory Tract Infection 11 9 7 11 5 Rhinitis 9 6 8 3 7 Increased Asthma Symptoms 18 3 2 4 0 Oral Symptoms Inhalation Route 2 3 3 3 2 Sinusitis 2 3 3 3 0 Pain <1 2 1 2 5 Back Pain 1 1 2 <1 4 Dysphonia 2 <1 1 0 4 Other adverse events that occurred in these clinical trials using beclomethasone dipropionate HFA inhalation aerosol with an incidence of 1% to 3% and which occurred at a greater incidence than placebo were nausea, dysmenorrhea, and coughing. Oropharyngeal candidiasis occurred in <1% of patients in both beclomethasone dipropionate HFA inhalation aerosol and placebo treatment groups. Pediatric Studies In two 12-week placebo-controlled studies in steroid naive pediatric patients 5 to 12 years of age, no clinically relevant differences were found in the pattern, severity, or frequency of adverse events compared with those reported in adults, with the exception of conditions which are more prevalent in a pediatric population generally. 6.2 Postmarketing Experience In addition to adverse reactions experienced in the clinical trials, the following adverse events have been reported during post-approval use of beclomethasone dipropionate HFA inhalation aerosol. Because they 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 HFA inhalation aerosol 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).

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no adequate and well-controlled studies with beclomethasone dipropionate HFA inhalation aerosol 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 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% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryofetal 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 as necessary 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 rats 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 grea …

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 may 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 beclomethasone dipropionate HFA inhalation aerosol.

11 DESCRIPTION The active component of beclomethasone dipropionate HFA inhalation aerosol 40 mcg inhalation aerosol and beclomethasone dipropionate HFA inhalation aerosol 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, USP (BDP) 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, USP 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: Beclomethasone dipropionate HFA inhalation aerosol is a pressurized, metered-dose aerosol with a dose counter intended for oral inhalation only. Each unit contains a solution of beclomethasone dipropionate, USP in propellant HFA-134a (1,1,1,2 tetrafluoroethane) and ethanol. Beclomethasone dipropionate HFA inhalation aerosol 40 mcg delivers 40 mcg of beclomethasone dipropionate, USP from the actuator and 50 mcg from the valve. Beclomethasone dipropionate HFA inhalation aerosol 80 mcg delivers 80 mcg of beclomethasone dipropionate, USP from the actuator and 100 mcg from the valve. Both products deliver 50 microliters (59 milligrams) of solution formulation from the valve with each actuation. The 40 mcg canisters and the 80 mcg canisters provide 120 inhalations each. Beclomethasone dipropionate HFA inhalation aerosol should be "primed" or actuated twice prior to taking the first dose from a new canister, or when the inhaler has not been used for more than 10 days. Avoid spraying in the eyes or face while priming beclomethasone dipropionate HFA inhalation aerosol. This product does not contain chlorofluorocarbons (CFCs). Structural Formula

16 HOW SUPPLIED 16.1 How Supplied Beclomethasone dipropionate HFA inhalation aerosol is supplied in 2 strengths: Beclomethasone dipropionate HFA inhalation aerosol 40 mcg is available in a box of one 8.7 g canister containing 120 actuations with a beige plastic actuator with a dose counter and light blue dust cap, and Patient Information and Instructions for Use; box of one; 120 Actuations – NDC 69238-1289-4. Beclomethasone dipropionate HFA inhalation aerosol 80 mcg is available in a box of one 8.7 g canister containing 120 actuations with a dark pink plastic actuator with a dose counter and gray dust cap, and Patient Information and Instructions for Use; box of one; 120 Actuations – NDC 69238-1290-4. The correct amount of medication in each inhalation cannot be assured after 120 actuations from the 8.7 g canister even though the canister is not completely empty. Patients should be informed to discard the beclomethasone dipropionate HFA inhalation aerosol inhaler when the dose counter displays 0 or after the expiration date on the product, whichever comes first. 16.2 Storage and Handling Store at 20° to 25°C (68° to 77°F); excursions permitted between 15o to 30oC (59o to 86oF) (see USP Controlled Room Temperature). For optimal results, the canister should be at room temperature when used. Beclomethasone dipropionate HFA inhalation aerosol canister should only be used with the beclomethasone dipropionate HFA inhalation aerosol actuator and the actuator should not be used with any other inhalation drug product. Store beclomethasone dipropionate HFA inhalation aerosol when not being used, so that the product rests on the concave end of the canister with plastic actuator on top. CONTENTS UNDER PRESSURE Do not puncture. Do not use or store near heat or open flame. Exposure to temperatures above 49oC (120oF) may cause bursting. Never throw container into fire or incinerator. Keep out of reach of children.