Beclomethasone Dipropionate

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)

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)

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) ] .

Localized infections: Candida albicans infection of the mouth and throat may occur. Monitor patients periodically for signs of adverse effects on the oral cavity. Advise patients to rinse the mouth with water without swallowing after inhalation. (5.1) Deterioration of asthma and acute episodes: Do not use beclomethasone dipropionate HFA inhalation aerosol for relief of acute symptoms. Patients require immediate re-evaluation during rapidly deteriorating asthma. (5.2) Transferring patients from systemic corticosteroids: Risk of impaired adrenal function when transferring from oral steroids. Taper patients slowly from systemic corticosteroids if transferring to beclomethasone dipropionate HFA inhalation aerosol. (5.3) Immunosuppression: Potential worsening of existing tuberculosis, fungal, bacterial, viral, or parasitic infection; or ocular herpes simplex infections. More serious or even fatal course of chickenpox or measles can occur in susceptible patients. Use with caution in patients with these infections because of the potential for worsening of these infections. (5.4) Paradoxical Bronchospasm: Bronchospasm, with an immediate increase in wheezing, may occur after dosing. Treat bronchospasm immediately with inhaled, short-acting bronchodilator and discontinue beclomethasone dipropionate HFA inhalation aerosol. (5.5) Hypersensitivity Reactions: Hypersensitivity reactions, such as urticaria, angioedema, rash, and bronchospasm may occur. Discontinue beclomethasone dipropionate HFA inhalation aerosol if such reactions occur. (5.6) Hypercorticism and adrenal suppression: May occur with very high dosages or at the regular dosage in susceptible individuals. If such changes occur, discontinue beclomethasone dipropionate HFA inhalation aerosol slowly. (5.7) Effects on growth: Monitor growth of pediatric patients. (5.8) Decreases in bone mineral density: Monitor patients with major risk factors for decreased bone mineral content. (5.9) Eye Disorders: Monitor patients with change in vision or with a history of increased intraocular pressure, blurred vision, glaucoma, and/or cataracts closely. (5.10)

5.1 Local Effects Localized infections with Candida albicans have occurred in the mouth and pharynx in some patients receiving beclomethasone dipropionate HFA inhalation aerosol. If oropharyngeal candidiasis develops, it should be treated with appropriate local or systemic (i.e., oral) antifungal therapy while still continuing with beclomethasone dipropionate HFA inhalation aerosol therapy, but at times therapy with beclomethasone dipropionate HFA inhalation aerosol may need to be temporarily interrupted under close medical supervision. Rinsing the mouth with water without swallowing after inhalation is advised.

5.2 Deterioration of Asthma and Acute Episodes Beclomethasone dipropionate HFA inhalation aerosol is not indicated for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. An inhaled, short-acting beta-2 agonist, not beclomethasone dipropionate HFA inhalation aerosol, should be used to relieve acute symptoms such as shortness of breath. Instruct patients to contact their physician immediately if episodes of asthma that are not responsive to bronchodilators occur during the course of treatment with beclomethasone dipropionate HFA inhalation aerosol. During such episodes, patients may require therapy with oral corticosteroids.

5.3 Transferring Patients from Systemic Corticosteroid Therapy Particular care is needed in patients who are transferred from systemically active corticosteroids to beclomethasone dipropionate HFA inhalation aerosol because deaths due to adrenal insufficiency have occurred in asthmatic patients during and after transfer from systemic corticosteroids to less systemically available inhaled corticosteroids. After withdrawal from systemic corticosteroids, a number of months are required for recovery of hypothalamic-pituitary-adrenal (HPA) function. Patients who have been previously maintained on 20 mg or more per day of prednisone (or its equivalent) may be most susceptible, particularly when their systemic corticosteroids have been almost completely withdrawn. During this period of HPA suppression, patients may exhibit signs and symptoms of adrenal insufficiency when exposed to trauma, surgery, or infections (particularly gastroenteritis) or other conditions with severe electrolyte loss. Although beclomethasone dipropionate HFA inhalation aerosol may provide control of asthmatic symptoms during these episodes, in recommended doses it supplies less than normal physiological amounts of glucocorticoid systemically and does NOT provide the mineralocorticoid that is necessary for coping with these emergencies. During periods of stress or a severe asthmatic attack, patients who have been withdrawn from systemic corticosteroids should be instructed to resume oral corticosteroids (in large doses) immediately and to contact their physician for further instruction. These patients should also be instructed to carry a warning card indicating that they may need supplementary systemic steroids during periods of stress or a severe asthma attack. Patients requiring oral or other systemic corticosteroids should be weaned slowly from oral or other systemic corticosteroid use after transferring to beclomethasone dipropionate HFA inhalation aerosol. Lung function (FEV 1 or PEF), beta-agonist use, and asthma symptoms should be carefully monitored during withdrawal of oral or other systemic corticosteroids. In addition to monitoring asthma signs and symptoms, patients should be observed for signs and symptoms of adrenal insufficiency such as fatigue, lassitude, weakness, nausea and vomiting, and hypotension. Transfer of patients from systemic corticosteroid therapy to beclomethasone dipropionate HFA inhalation aerosol may unmask allergic conditions previously suppressed by the systemic corticosteroid therapy, e.g., rhinitis, conjunctivitis, eczema, arthritis, and eosinophilic conditions. During withdrawal from oral corticosteroids, some patients may experience symptoms of systemically active corticosteroid withdrawal, e.g., joint and/or muscular pain, lassitude, and depression, despite maintenance or even improvement of respiratory function.

5.4 Immunosuppression Persons who are on drugs which suppress the immune system are more susceptible to infections than healthy individuals. Chickenpox and measles, for example, can have a more serious or even fatal course in non-immune children or adults on corticosteroids. In such children or adults who have not had these diseases or been properly immunized, particular care should be taken to avoid exposure. It is not known how the dose, route and duration of corticosteroid administration affects the risk of developing a disseminated infection. Nor is the contribution of the underlying disease and/or prior corticosteroid treatment known. If exposed to chickenpox, prophylaxis with varicella-zoster immune globulin (VZIG) may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information.) If chickenpox develops, treatment with antiviral agents may be considered. Inhaled corticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infection of the respiratory tract; untreated systemic fungal, bacterial, parasitic or viral infections; or ocular herpes simplex.

5.5 Paradoxical Bronchospasm Inhaled corticosteroids may produce inhalation induced bronchospasm with an immediate increase in wheezing after dosing that may be life-threatening. If inhalation induced bronchospasm occurs following dosing with beclomethasone dipropionate HFA inhalation aerosol, it should be treated immediately with an inhaled, short-acting bronchodilator. […]

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).

8.1 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 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 beclomethasone dipropionate HFA inhalation aerosol 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 Eight-hundred and thirty-four children between the ages of 5 and 12 were treated with HFA beclomethasone dipropionate (HFA-BDP) in clinical trials. The safety and effectiveness of beclomethasone dipropionate HFA inhalation aerosol in children below 5 years of age have not been established. Use of beclomethasone dipropionate HFA inhalation aerosol with a spacer device in children less than 5 years of age is not recommended. In vitro dose characterization studies were performed with beclomethasone dipropionate HFA inhalation aerosol 40 mcg/actuation with the OptiChamber and AeroChamber Plus ® spacer utilizing inspiratory flows representative of children under 5 years old. These studies indicated that the amount of medication delivered through the spacing device decreased rapidly with increasing wait times of 5 to 10 seconds as shown in Table 2. If beclomethasone dipropionate HFA inhalation aerosol is used with a spacer device, it is important to inhale immediately. Based on the average inspiratory flow rates generated by children 6 months to 5 years old, the projected daily dose derived from beclomethasone dipropionate HFA inhalation aerosol 40 mcg at one puff per day at various wait times is depicted in Table 2 below: Table 2 Average Daily Dose Based on Wait Time in Pediatric Patients Wait time, seconds Mean medication delivery through AeroChamber mcg/actuation i Body Weight 50 th percentile, kg ii Medication delivered per dose, mcg/kg iii, iv Age 6 months, Flow rate 4.8 L/min 0 11.5 7.6

1.2 Age 2 years, Flow rate 8.2 L/min 0 14.1 13.5

0.83 Age 2 years, Flow rate 8.2 L/min 5 5.4 13.5

0.32 Age 2 years, Flow rate 8.2 L/min 10 3.9 13.5

0.23 Age 5 years, Flow rate 11.0 L/min 0 17.5 18 0.78 i Summary Report; Pediatric Dose Characterization of beclomethasone dipropionate HFA inhalation aerosol with Spacer; 3M Pharmaceutical Development, July 21, 2004 ii CDC Growth charts, developed by the National Center for Health Statistics in collaboration with the National Center for Chronic Disease Prevention and Health Promotion (2000). iii Includes an estimated 20% loss in the masks iv Beclomethasone dipropionate HFA inhalation aerosol 40mcg in an average adult without using a spacer delivers approximately 0.4 mcg/kg, or bid, 0.8 mcg/kg/day. 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 HFA beclomethasone dipropionate without spacer versus CFC beclomethasone dipropionate with large-volume spacer on growth in children age 5 to 11. A total of 520 patients were enrolled, of whom 394 received HFA-BDP (100 to 400 mcg/day ex-valve) and 126 received CFC-BDP (200 to 800 mcg/day ex-valve). […]

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.