Elderm

Beclomethasone Dipropionate:

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Elderm (Beclomethasone Dipropionate) reviews

1 INDICATIONS AND USAGE

Elderm Nasal Aerosol is a corticosteroid indicated for the treatment of nasal symptoms associated with seasonal and perennial allergic rhinitis in patients 4 years of age and older. ( 1.1 )

1.1 Treatment of Nasal Symptoms of Allergic Rhinitis

Elderm (Beclomethasone Dipropionate)^® Nasal Aerosol is indicated for the treatment of the nasal symptoms associated with seasonal and perennial allergic rhinitis in patients 4 years of age and older.

2 DOSAGE AND ADMINISTRATION

Administer Elderm Nasal Aerosol by the intranasal route only. Elderm (Beclomethasone Dipropionate) Nasal Aerosol must be primed prior to initial use by actuating four times. To do this, remove the protective dust cap from the device, hold the device upright between your thumb and forefinger (index finger) (the canister should be on top, pointing down), and spray 4 times into the air, away from your eyes and face. After the initial priming, the dose counter should read 120 for Elderm (Beclomethasone Dipropionate) 40 mcg Nasal Aerosol and Elderm (Beclomethasone Dipropionate) 80 mcg Nasal Aerosol 120-actuation products and 60 for Elderm (Beclomethasone Dipropionate) 40 mcg Nasal Aerosol 60-actuation product. If Elderm (Beclomethasone Dipropionate) Nasal Aerosol is not used for 7 consecutive days it should be primed by spraying 2 times. See accompanying illustrated Patient Information and Instructions for Use leaflet for proper use of Elderm (Beclomethasone Dipropionate) Nasal Aerosol.

Elderm (Beclomethasone Dipropionate) Nasal Aerosol is for intranasal use only.

• The recommended dose of Elderm (Beclomethasone Dipropionate) 80 mcg Nasal Aerosol in patients 12 years and older is 320 mcg per day administered as 2 actuations in each nostril once daily (maximum total daily dose of 4 actuations per day). ( 2.1 )
• The recommended dose of Elderm (Beclomethasone Dipropionate) 40 mcg Nasal Aerosol in children aged 4 to 11 years of age is 80 mcg per day administered as 1 actuation in each nostril once daily (maximum total daily dose of 2 actuations per day). ( 2.1 )

2.1 Allergic Rhinitis

Adults and Adolescents (12 Years of Age and Older): The recommended dose of Elderm (Beclomethasone Dipropionate) Nasal Aerosol is 320 mcg per day administered as 2 actuations in each nostril (QNASL 80 mcg Nasal Aerosol) once daily (maximum total daily dose of 4 actuations per day).

Children (4 to 11 Years of Age): The recommended dose of Elderm (Beclomethasone Dipropionate) Nasal Aerosol is 80 mcg per day administered as 1 actuation in each nostril (QNASL 40 mcg Nasal Aerosol) once daily (maximum total daily dose of 2 actuations per day).

3 DOSAGE FORMS AND STRENGTHS

Elderm (Beclomethasone Dipropionate) Nasal Aerosol is a nonaqueous nasal spray solution.

Each actuation of Elderm (Beclomethasone Dipropionate) 40 mcg Nasal Aerosol delivers 40 mcg of Elderm (Beclomethasone Dipropionate) and each actuation of Elderm (Beclomethasone Dipropionate) 80 mcg Nasal Aerosol delivers 80 mcg of Elderm (Beclomethasone Dipropionate). Each strength is supplied in an 8.7 g canister containing 120 actuations; Elderm (Beclomethasone Dipropionate) 40 mcg Nasal Aerosol is also supplied in a 4.9 g canister containing 60 actuations.

Elderm (Beclomethasone Dipropionate) Nasal Aerosol is available in two strengths:

• Each actuation of Elderm (Beclomethasone Dipropionate) 40 mcg Nasal Aerosol delivers 40 mcg of Elderm (Beclomethasone Dipropionate). ( 3 )
• Each actuation of Elderm (Beclomethasone Dipropionate) 80 mcg Nasal Aerosol delivers 80 mcg of Elderm (Beclomethasone Dipropionate). ( 3 )
• Each strength is supplied in an 8.7 g canister containing 120 actuations; Elderm (Beclomethasone Dipropionate) 40 mcg Nasal Aerosol is also supplied in a 4.9 g canister containing 60 actuations. ( 3 )

4 CONTRAINDICATIONS

Elderm (Beclomethasone Dipropionate) Nasal Aerosol is contraindicated in patients with a history of hypersensitivity to Elderm (Beclomethasone Dipropionate) and/or any other Elderm (Beclomethasone Dipropionate) Nasal Aerosol ingredients .

Patients with a history of hypersensitivity to Elderm (Beclomethasone Dipropionate) and/or any other Elderm (Beclomethasone Dipropionate) Nasal Aerosol ingredients. ( 4 )

5 WARNINGS AND PRECAUTIONS

• Nasal discomfort, epistaxis, nasal ulceration, Candida albicans infection, nasal septal perforation, impaired wound healing. Monitor patients periodically for signs of adverse effects on the nasal mucosa. Avoid use in patients with recent nasal ulcers, nasal surgery, or nasal trauma.
• Eye Disorders. Monitor patients closely with a change in vision or with a history of increased intraocular pressure, blurred vision, glaucoma, and/or cataracts. ( 5.2 )
• Hypersensitivity, rash, and urticaria may occur after administration of Elderm (Beclomethasone Dipropionate) Nasal Aerosol. ( 5.3 )
• Potential worsening of existing tuberculosis; fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex. More serious or even fatal course of chickenpox or measles in susceptible patients. Use caution in patients with the above because of the potential for worsening of these infections. ( 5.4 )
• Hypercorticism and adrenal suppression with very high dosages or at the regular dosage in susceptible individuals. If such changes occur, discontinue Elderm (Beclomethasone Dipropionate) Nasal Aerosol slowly. ( 5.5 )
• Potential reduction in growth velocity in pediatric patients. Monitor growth routinely in pediatric patients receiving Elderm (Beclomethasone Dipropionate) Nasal Aerosol. ( 5.6, 8.4 )

5.1 Local Nasal Effects

Nasal Discomfort, Epistaxis, and Nasal Ulceration: In clinical trials of 2 to 52 weeks duration, epistaxis and nasal ulcerations were observed more frequently and some epistaxis events were more severe in patients treated with Elderm (Beclomethasone Dipropionate) Nasal Aerosol than those who received placebo. In the 52-week safety trial in patients with perennial allergic rhinitis, nasal erosions were identified in 4 of 415 patients and a nasal ulceration was identified in 1 of 415 patients treated with Elderm (Beclomethasone Dipropionate) Nasal Aerosol. No nasal erosions or ulcerations were reported for patients who received placebo. In clinical trials conducted in pediatric patients ages 4 to 11 years, the local nasal effect was similar to those reported in patients 12 years of age and older. Patients using Elderm (Beclomethasone Dipropionate) Nasal Aerosol over several months or longer should be examined periodically for possible changes in the nasal mucosa. If an adverse reaction (e.g., erosion, ulceration) is noted, discontinue Elderm (Beclomethasone Dipropionate) Nasal Aerosol .

Candida Infection: In previous clinical trials with an aqueous formulation of Elderm (Beclomethasone Dipropionate) administered intranasally, localized infections of the nose and pharynx with Candida albicans had been reported. There were no instances of similar infections observed in clinical trials with Elderm (Beclomethasone Dipropionate) Nasal Aerosol. If such an infection develops, it may require treatment with appropriate local therapy and discontinuation of Elderm (Beclomethasone Dipropionate) Nasal Aerosol treatment. Thus, patients using Elderm (Beclomethasone Dipropionate) Nasal Aerosol over several months or longer should be examined periodically for evidence of Candida infection.

Nasal Septal Perforation: Instances of nasal septal perforation have been reported in patients following the intranasal application of Elderm (Beclomethasone Dipropionate). There were no nasal septal perforations reported during clinical trials in the indicated dose of Elderm (Beclomethasone Dipropionate) 80 mcg Nasal Aerosol administered as 320 mcg once daily in adults and adolescents. There was one report of nasal septal perforation observed in the dose-ranging pediatric clinical trial.

Impaired Wound Healing: Because of the inhibitory effect of corticosteroids on wound healing, patients who have experienced recent nasal septal ulcers, nasal surgery, or nasal trauma should not use Elderm (Beclomethasone Dipropionate) Nasal Aerosol until healing has occurred.

5.2 Eye Disorders

Use of intranasal and inhaled corticosteroids may result in the development of increased intraocular pressure, blurred vision, glaucoma and/or cataracts. Therefore, close monitoring is warranted in patients with a change in vision or with a history of increased intraocular pressure, blurred vision, glaucoma, and/or cataracts.

Glaucoma and cataract formation was evaluated with ocular assessments that included intraocular pressure measurements and slit lamp examinations in 245 adolescent and adult patients with perennial allergic rhinitis who were treated with Elderm (Beclomethasone Dipropionate) Nasal Aerosol 320 mcg daily (N=197) or placebo (N=48) for up to 52 weeks. In 94% of patients, intraocular pressure (IOP) remained within the normal range (<21 mmHg) during the treatment portion of the trial. There were 10 patients (5%) treated with Elderm (Beclomethasone Dipropionate) Nasal Aerosol and 1 patient (2%) treated with placebo that had intraocular pressure that increased above normal levels (≥21 mmHg) and greater than baseline during the treatment portion of the trial. Two of these occurrences in patients treated with Elderm (Beclomethasone Dipropionate) Nasal Aerosol were reported as adverse reactions, one serious. No instances of cataract formation or other clinically significant ocular incidents were reported in this 52-week safety trial .

5.3 Hypersensitivity Reactions Including Anaphylaxis

Hypersensitivity reactions including anaphylaxis, angioedema, urticaria, and rash have been reported following administration of Elderm (Beclomethasone Dipropionate) nasally administered and inhalationally administered products. Angioedema, urticaria, and rash have been reported following administration of Elderm (Beclomethasone Dipropionate) Nasal Aerosol. Discontinue Elderm (Beclomethasone Dipropionate) Nasal Aerosol if any such reactions occur .

5.4 Immunosuppression

Persons who are using drugs that 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 susceptible children or adults using corticosteroids. In children or adults who have not had these diseases or been properly immunized, particular care should be taken to avoid exposure. How the dose, route, and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If a patient is exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If a patient is exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. If chickenpox or measles develops, treatment with antiviral agents may be considered.

Corticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculous infections of the respiratory tract, untreated local or systemic fungal or bacterial infections, systemic viral or parasitic infections, or ocular herpes simplex because of the potential for worsening of these infections.

5.5 Hypothalamic-Pituitary-Adrenal Axis Effect

When intranasal steroids are used at higher-than-recommended dosages or in susceptible individuals at recommended dosages, systemic corticosteroid effects such as hypercorticism and adrenal suppression may appear. If such changes occur, the dosage of Elderm (Beclomethasone Dipropionate) Nasal Aerosol should be discontinued slowly, consistent with accepted procedures for discontinuing oral corticosteroid therapy.

The replacement of a systemic corticosteroid with a topical corticosteroid can be accompanied by signs of adrenal insufficiency. In addition, some patients may experience symptoms of corticosteroid withdrawal (e.g., joint and/or muscular pain, lassitude, and depression). Patients previously treated for prolonged periods with systemic corticosteroids and transferred to topical corticosteroids should be carefully monitored for acute adrenal insufficiency in response to stress. In patients who have asthma or other clinical conditions requiring long-term systemic corticosteroid treatment, rapid decreases in systemic corticosteroid dosages may cause a severe exacerbation of their symptoms.

5.6 Effect on Growth

Corticosteroids may cause a reduction in growth velocity when administered to pediatric patients. Routinely monitor the growth of pediatric patients receiving Elderm (Beclomethasone Dipropionate) Nasal Aerosol .

6 ADVERSE REACTIONS

Systemic and local corticosteroid use may result in the following:

• Epistaxis, nasal discomfort, nasal ulcerations, Candida albicans infection, and impaired wound healing
• Eye Disorders
• Hypercorticism, adrenal suppression, and growth reduction [see Warnings and Precautions (5.5) (5.6) , Use in Specific Populations (8.4)]
• Immunosuppression

The most common adverse reactions (≥ 1% and greater than placebo) in patients 12 years of age and older include nasal discomfort, epistaxis, and headache. ( 6.1 )

The most common adverse reactions (≥ 2% and greater than placebo) in children 4 to 11 years of age include headache, pyrexia, upper respiratory tract infection, and nasopharyngitis. ( 6.1 )

To report SUSPECTED ADVERSE REACTIONS, contact Teva Respiratory, LLC at 1-888-482-9522 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 with 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 data described below for adults and adolescents 12 years of age and older with seasonal or perennial allergic rhinitis are based on 4 placebo-controlled clinical trials of 2 to 6 weeks duration evaluating doses of beclomethasone nasal aerosol from 80 to 320 mcg once daily. These short-term trials included a total of 1394 patients with either seasonal or perennial allergic rhinitis. Of these, 575 (378 female and 197 male) received at least one dose of Elderm (Beclomethasone Dipropionate) Nasal Aerosol, 320 mcg once daily and 578 (360 female and 218 male) received placebo. Patient ages ranged from 12 to 82 years and the racial distribution of patients was 81% white, 16% black, and 4% other.

Short-Term (2–6 Weeks) Trials: Less than 2% of patients in the clinical trials discontinued treatment because of adverse reactions with the rate of withdrawal among patients who received Elderm (Beclomethasone Dipropionate) Nasal Aerosol similar to or lower than the rate among patients who received placebo. Table 1 displays the common adverse reactions (≥ 1% and greater than placebo-treated patients).

Nasal ulcerations occurred in 2 patients treated with placebo and in 1 patient treated with Elderm (Beclomethasone Dipropionate) Nasal Aerosol. There were no differences in the incidence of adverse reactions based on gender or race. Clinical trials did not have sufficient numbers of patients aged 65 years and older to determine whether they respond differently than younger patients.

Long-Term 52-Week Safety Trial: In a 52-week placebo-controlled long-term safety trial in patients with PAR, 415 patients (128 males and 287 females, aged 12 to 74 years) were treated with Elderm (Beclomethasone Dipropionate) Nasal Aerosol at a dose of 320 mcg once daily and 111 patients (44 males and 67 females, aged 12 to 67 years) were treated with placebo. Of the 415 patients treated with Elderm (Beclomethasone Dipropionate) Nasal Aerosol, 219 patients were treated for 52 weeks and 196 patients were treated for 30 weeks. While most adverse events were similar in type and rate between the treatment groups, epistaxis occurred more frequently in patients who received Elderm (Beclomethasone Dipropionate) Nasal Aerosol (45 out of 415, 11%) than in patients who received placebo (2 out of 111, 2%). Epistaxis also tended to be more severe in patients treated with Elderm (Beclomethasone Dipropionate) Nasal Aerosol. In 45 reports of epistaxis in patients who received Elderm (Beclomethasone Dipropionate) Nasal Aerosol, 27, 13, and 5 cases were of mild, moderate, and severe intensity, respectively, while the reports of epistaxis in patients who received placebo were of mild (1) and moderate (1) intensity. Seventeen patients treated with Elderm (Beclomethasone Dipropionate) Nasal Aerosol experienced adverse reactions that led to withdrawal from the trial compared to 3 patients treated with placebo. There were 4 nasal erosions and 1 nasal septum ulceration which occurred in patients who received Elderm (Beclomethasone Dipropionate) Nasal Aerosol, and no erosions or ulcerations noted in patients who received placebo. No patient experienced a nasal septum perforation during the trial.

Pediatric Patients Aged 4 to 11 Years:

The safety data described below for pediatric patients 4 to 11 years of age with seasonal or perennial allergic rhinitis are based on 3 placebo-controlled clinical trials. These trials were 2 to 12 weeks in duration, evaluated doses of beclomethasone nasal aerosol 80 mcg to 160 mcg once daily and included a total of 1360 patients with either seasonal or perennial allergic rhinitis. Of these, 668 (312 female and 356 male) received at least one dose of Elderm (Beclomethasone Dipropionate) Nasal Aerosol, 80 mcg once daily, 241 (116 female and 125 male) received Elderm (Beclomethasone Dipropionate) Nasal Aerosol 160 mcg once daily, and 451 (203 female and 248 male) received placebo. The racial distribution of patients was 73% white, 20% black, and 6% other. Based on the results from the dose ranging trial, 80 mcg once daily was chosen as the dose in pediatric patients.

Less than 1.5% of patients in the clinical trials discontinued treatment because of adverse reactions with the rate of withdrawal among patients who received Elderm (Beclomethasone Dipropionate) Nasal Aerosol 80 mcg once daily similar to or lower than the rate among patients who received placebo. Table 2 displays the common adverse reactions (≥ 2% and greater than placebo-treated patients). Additionally, epistaxis was reported at a rate of 4% for both Elderm (Beclomethasone Dipropionate) Nasal Aerosol 80 mcg once daily and placebo treated patients.

6.2 Postmarketing Experience

In addition to adverse reactions reported from clinical trials for Elderm (Beclomethasone Dipropionate) Nasal Aerosol, the following adverse events have been reported during postmarketing use of Elderm (Beclomethasone Dipropionate) Nasal Aerosol or other intranasal and inhaled formulations of Elderm (Beclomethasone Dipropionate). 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. These events have been chosen for inclusion due to either their seriousness, frequency of reporting, or causal connection to Elderm (Beclomethasone Dipropionate) or a combination of these factors.

Elderm (Beclomethasone Dipropionate) Nasal Aerosol: sneezing, burning sensation

Intranasal Elderm (Beclomethasone Dipropionate): Nasal septal perforation, blurred vision, glaucoma, cataracts, central serous chorioretinopathy (CSC), loss of taste and smell, and hypersensitivity reactions including anaphylaxis, angioedema, rash, and urticaria have been reported following intranasal administration of Elderm (Beclomethasone Dipropionate).

Inhaled Elderm (Beclomethasone Dipropionate): Hypersensitivity reactions, including anaphylaxis, angioedema, rash, urticaria, and bronchospasm have been reported following the oral inhalation of Elderm (Beclomethasone Dipropionate).

7 DRUG INTERACTIONS

No drug interaction studies have been performed with Elderm (Beclomethasone Dipropionate) Nasal Aerosol.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Teratogenic Effects: Pregnancy Category C

There are no adequate and well-controlled clinical trials in pregnant women treated with Elderm Nasal Aerosol. Elderm (Beclomethasone Dipropionate) was teratogenic and embryocidal in the mouse and rabbit although these effects were not observed in rats. Elderm (Beclomethasone Dipropionate) Nasal Aerosol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Experience with oral corticosteroids since their introduction in pharmacologic, as opposed to physiologic, doses suggests that rodents are more prone to teratogenic effects from corticosteroids than humans.

Elderm (Beclomethasone Dipropionate) administered subcutaneously was teratogenic and embryocidal in the mouse and rabbit at doses approximately twice the maximum recommended human daily intranasal dose (MRHDID) in adults (on a mg/m² basis at maternal doses of 0.1 and 0.025 mg/kg/day in mice and rabbits, respectively). No teratogenicity or embryocidal effects were seen in rats at approximately 460 times MRHDID (in adults on a mg/m² basis at a maternal inhalation dose of 15 mg/kg/day).

Non-teratogenic Effects: Hypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy. Such infants should be carefully monitored.

8.3 Nursing Mothers

It is not known whether Elderm (Beclomethasone Dipropionate) is excreted in human breast milk. However, other corticosteroids have been detected in human breast milk and thus caution should be exercised when Elderm (Beclomethasone Dipropionate) Nasal Aerosol is administered to a nursing mother.

8.4 Pediatric Use

The safety and effectiveness of Elderm Nasal Aerosol in children 4 years and older have been established . The safety and effectiveness of Elderm (Beclomethasone Dipropionate) Nasal Aerosol in children younger than 4 years of age have not been established. Controlled pediatric clinical trials with Elderm (Beclomethasone Dipropionate) Nasal Aerosol included 909 children 4 to 11 years of age and 188 adolescent patients 12 to 17 years of age .

Controlled clinical trials have shown that intranasal corticosteroids may cause a reduction in growth velocity in pediatric patients. This effect has been observed in the absence of laboratory evidence of hypothalamic-pituitary-adrenal (HPA) axis suppression, suggesting that growth velocity is a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA-axis function. The long-term effects of reduction in growth velocity associated with intranasal corticosteroids, including the impact on final adult height, are unknown. The potential for "catch-up" growth following discontinuation of treatment with intranasal corticosteroids has not been adequately studied. The growth of pediatric patients receiving intranasal corticosteroids, including Elderm (Beclomethasone Dipropionate) Nasal Aerosol, should be monitored routinely (e.g., via stadiometry).

A 12-month, randomized, controlled clinical trial evaluated the effects of QVAR^®, an orally inhaled HFA Elderm (Beclomethasone Dipropionate) product, without spacer versus chlorofluorocarbon-propelled (CFC) Elderm (Beclomethasone Dipropionate) with large volume spacer on growth in children with asthma ages 5 to 11 years. A total of 520 patients were enrolled, of whom 394 received HFA-beclomethasone dipropionate (100 to 400 mcg/day ex-valve) and 126 received CFC-beclomethasone dipropionate (200 to 800 mcg/day ex-valve). When comparing results at month 12 to baseline, the mean growth velocity in children treated with HFA-beclomethasone dipropionate was approximately 0.5 cm/year less than that noted with children treated with CFC-beclomethasone dipropionate via large volume spacer. The potential growth effects of prolonged treatment should be weighed against the clinical benefits obtained and the risks/benefits of treatment alternatives.

The potential for Elderm (Beclomethasone Dipropionate) Nasal Aerosol to cause reduction in growth velocity in susceptible patients or when given at higher than recommended dosages cannot be ruled out.

8.5 Geriatric Use

Clinical trials of Elderm (Beclomethasone Dipropionate) Nasal Aerosol did not include sufficient numbers of subjects aged 65 years and older to determine whether they responded differently than younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, administration to elderly patients should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

10 OVERDOSAGE

Chronic overdosage may result in signs/symptoms of hypercorticism . There are no data available on the effects of acute or chronic overdosage with Elderm (Beclomethasone Dipropionate) Nasal Aerosol.

11 DESCRIPTION

Elderm (Beclomethasone Dipropionate) USP, the active component of Elderm (Beclomethasone Dipropionate) Nasal Aerosol, is an anti-inflammatory steroid having the chemical name 9-chloro-11β,17,21-trihydroxy-16β-methylpregna-1,4-diene-3,20-dione 17, 21-dipropionate and the following chemical structure:

Elderm (Beclomethasone Dipropionate), a di-ester of beclomethasone (a synthetic corticosteroid chemically related to dexamethasone), is a white to almost white, odorless powder with a molecular formula of C₂₈H₃₇ClO₇ and a molecular weight of 521.1. It is practically insoluble in water, very soluble in chloroform, and soluble in acetone and in dehydrated alcohol.

Elderm (Beclomethasone Dipropionate) Nasal Aerosol is a pressurized, nonaqueous solution in a metered-dose aerosol device intended ONLY for intranasal use. It contains a solution of Elderm (Beclomethasone Dipropionate) in propellant HFA-134a (1,1,1,2-tetrafluoroethane) and dehydrated ethanol. Elderm (Beclomethasone Dipropionate) 40 mcg Nasal Aerosol delivers 40 mcg of Elderm (Beclomethasone Dipropionate) from the nasal actuator and 50 mcg from the valve. Elderm (Beclomethasone Dipropionate) 80 mcg Nasal Aerosol delivers 80 mcg of Elderm (Beclomethasone Dipropionate) from the nasal actuator and 100 mcg from the valve. Each strength delivers 59 mg of solution from the valve with each actuation. Each canister of Elderm (Beclomethasone Dipropionate) 40 mcg or 80 mcg Nasal Aerosol, contains 8.7 g of drug and excipients and each provides 120 actuations after priming. Additionally, Elderm (Beclomethasone Dipropionate) 40 mcg Nasal Aerosol contains 4.9 g of drug and excipients and provides 60 actuations after priming.

Chemical structure.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Elderm is a prodrug that is extensively converted to the active metabolite, beclomethasone-17-monopropionate. The precise mechanism through which Elderm (Beclomethasone Dipropionate) affects rhinitis symptoms is unknown. 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 the release of inflammatory mediators (e.g., histamine, eicosanoids, leukotrienes, and cytokines).

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 Elderm (Beclomethasone Dipropionate). The clinical significance of these findings is unknown.

12.2 Pharmacodynamics

Adrenal Function: The effects of Elderm (Beclomethasone Dipropionate) Nasal Aerosol on the HPA axis were evaluated in two 6-week, randomized, double-blind, parallel-group perennial allergic rhinitis trials – one in adult and adolescent patients 12 to 45 years of age and another in children 6 to 11 years of age. In the first study with adolescent and adult patients aged 12 to 45, Elderm (Beclomethasone Dipropionate) Nasal Aerosol 320 mcg, once daily, was compared with both placebo nasal aerosol and a positive control (a placebo/prednisone group that received prednisone 10 mg orally once daily for the final 7 days of the treatment period). In the second study with pediatric patients aged 6 to 11, Elderm (Beclomethasone Dipropionate) Nasal Aerosol 80 mcg once daily was compared to placebo nasal aerosol. HPA-axis function was assessed by 24-hour serial serum cortisol levels prior to the first dose and after 6 weeks of treatment. Patients were domiciled for the 24-hour serum cortisol assessments. The change from baseline in the 24-hour serum cortisol weighted mean for Elderm (Beclomethasone Dipropionate) Nasal Aerosol and placebo after 6 weeks of treatment were compared.

In the HPA–axis study in patients 12 to 45 years of age, baseline geometric mean serum cortisol weighted mean values were similar in the Elderm (Beclomethasone Dipropionate) Nasal Aerosol 320 mcg/day and placebo treatment groups (9.04 and 8.45 mcg/dL, respectively). After 6 weeks of treatment, the geometric mean values were 8.18 and 8.01 mcg/dL, respectively, with a change from baseline in 24-hour serum cortisol weighted mean for the Elderm (Beclomethasone Dipropionate) Nasal Aerosol and placebo groups of 0.86 and 0.44, resulting in a difference of 0.42. The geometric mean ratio for Elderm (Beclomethasone Dipropionate) Nasal Aerosol 320 mcg/day to placebo was 0.96 (95% CI: 0.87, 1.06). For comparison, in the positive-control (prednisone) treatment group, the geometric mean ratio for placebo to placebo/prednisone 10 mg/day was 3.17 (95% CI: 2.68, 3.74).

In the HPA-axis study in patients 6 to 11 years of age, baseline geometric mean serum cortisol weighted mean values were similar in the Elderm (Beclomethasone Dipropionate) Nasal Aerosol 80 mcg/day and placebo treatment groups (5.97 and 6.47 mcg/dL, respectively). After 6 weeks of treatment the geometric mean values were 6.19 and 7.13 mcg/dL, respectively with no decrease from baseline values in both treatment groups. The geometric mean ratio for Elderm (Beclomethasone Dipropionate) Nasal Aerosol 80 mcg/day to placebo was 0.91 (95% CI; 0.81, 1.03).

12.3 Pharmacokinetics

Absorption

Following intranasal administration, most of the Elderm (Beclomethasone Dipropionate) undergoes extensive conversion to its active metabolite, beclomethasone-17-monopropionate, during absorption. Plasma concentrations of Elderm (Beclomethasone Dipropionate) and beclomethasone-17-monopropionate have been measured with Elderm (Beclomethasone Dipropionate) Nasal Aerosol in 2 adult and/or adolescent clinical trials and 1 pediatric clinical trial.

The single-dose pharmacokinetics of Elderm (Beclomethasone Dipropionate) Nasal Aerosol were evaluated in a randomized, open-label, 3-period, crossover trial in healthy adult volunteers. Systemic levels of beclomethasone-17-monopropionate and Elderm (Beclomethasone Dipropionate) after single-dose intranasal administration of Elderm (Beclomethasone Dipropionate) at doses of 80 and 320 mcg were compared with the systemic levels of beclomethasone-17-monopropionate and Elderm (Beclomethasone Dipropionate) after administration of orally inhaled Elderm (Beclomethasone Dipropionate) HFA at a dose of 320 mcg (QVAR^® Inhalation Aerosol). The results of this trial demonstrated that the systemic bioavailability of Elderm (Beclomethasone Dipropionate) Nasal Aerosol 320 mcg was approximately 27.5% (approximately 4-fold lower) of that of orally inhaled Elderm (Beclomethasone Dipropionate) HFA 320 mcg/day based on the plasma concentrations of beclomethasone-17-monopropionate (AUC_last: 1139.7 vs 4140.3 hr*pg/mL; GMR: 0.275; 90% CI for the GMR: 0.214, 0.354). The peak exposure to Elderm (Beclomethasone Dipropionate) Nasal Aerosol 320 mcg/day was approximately 19.5% (approximately 5-fold lower) of that of orally inhaled Elderm (Beclomethasone Dipropionate) HFA 320 mcg/day as measured by beclomethasone-17-monopropionate (C_max: 262.7 vs 1343.7 pg/mL; GMR: 0.195; 90% CI for the GMR: 0.158, 0.241).

Following repeated once-daily administration of Elderm (Beclomethasone Dipropionate) Nasal Aerosol, there was no accumulation or increase in plasma exposure to beclomethasone-17-monopropionate or Elderm (Beclomethasone Dipropionate), most likely due to the short plasma half-life relative to the dosing frequency.

Distribution

The in vitro protein binding for beclomethasone-17-monopropionate was reported to be 94% to 96% over the concentration range of 1000 to 5000 pg/mL. The volume of distribution at steady state for Elderm (Beclomethasone Dipropionate) is moderate (20 L) but more extensive for beclomethasone-17-monopropionate (424 L).

Metabolism

Elderm (Beclomethasone Dipropionate) undergoes extensive first-pass metabolism, forming three metabolites via CYP3A4, beclomethasone-17-monopropionate, beclomethasone-21-monopropionate, and beclomethasone. Beclomethasone-17-monopropionate is the major and most active metabolite.

Elimination

The major route of elimination of inhaled Elderm (Beclomethasone Dipropionate) appears to be via metabolism. More than 90% of inhaled Elderm (Beclomethasone Dipropionate) is found as beclomethasone-17-monopropionate in the systemic circulation. The mean elimination half-life of beclomethasone-17-monopropionate is 2.8 hours. The terminal elimination half-lives of Elderm (Beclomethasone Dipropionate) and beclomethasone-17-monopropionate following intranasal dosing with Elderm (Beclomethasone Dipropionate) Nasal Aerosol (320 mcg) were approximately 0.3 hours and 4.5 hours, respectively. Irrespective of the route of administration (injection, oral, or inhalation), Elderm (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. It is likely that intranasal Elderm (Beclomethasone Dipropionate) follows a similar elimination pathway.

Special Populations

Formal pharmacokinetic studies using Elderm (Beclomethasone Dipropionate) Nasal Aerosol were not conducted in any special populations.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

The carcinogenicity of Elderm (Beclomethasone Dipropionate) was evaluated in rats that were exposed for a total of 95 weeks: 13 weeks at inhalation doses up to 0.4 mg/kg and the remaining 82 weeks at combined oral and inhalation doses up to 2.4 mg/kg. In this trial, there was no evidence of carcinogenicity at the highest dose: approximately 70 and 120 times the maximum recommended human daily intranasal dose (MRHDID) in adults and children, respectively, on a mg/m² basis.

Elderm (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, Elderm (Beclomethasone Dipropionate) caused decreased conception rates at an oral dose of 16 mg/kg (approximately 490 times the MRHDID in adults on a mg/m² basis). There was no significant effect of Elderm (Beclomethasone Dipropionate) on fertility in rats at oral doses of 1.6 mg/kg (approximately 50 times the MRHDID in adults on a mg/m² basis). Inhibition of the estrous cycle in dogs was observed following oral doses of 0.5 mg/kg (approximately 50 times the MRHDID in adults on a mg/m² basis). No inhibition of the estrous cycle in dogs was seen following 12 months of exposure at an estimated inhalation dose of 0.33 mg/kg (approximately 35 times the MRHDID in adults on a mg/m² basis).

14 CLINICAL STUDIES

14.1 Seasonal and Perennial Allergic Rhinitis

Adult and Adolescent Patients Aged 12 Years and Older: The efficacy and safety of Elderm (Beclomethasone Dipropionate) Nasal Aerosol have been evaluated in 3 randomized, double-blind, parallel-group, multicenter, placebo-controlled clinical trials of 2 to 6 weeks duration in adult and adolescent patients 12 years and older with symptoms of seasonal or perennial allergic rhinitis. The 3 clinical trials included one 2-week dose-ranging trial in patients with seasonal allergic rhinitis, one 2-week efficacy trial in patients with seasonal allergic rhinitis, and one 6-week efficacy trial in patients with perennial allergic rhinitis. The trials included a total of 1049 patients (366 males and 683 females). About 81% of patients were Caucasian and 17% African American, the mean age was approximately 38 years. Of these patients 521 received Elderm (Beclomethasone Dipropionate) Nasal Aerosol 320 mcg once daily administered as 2 actuations in each nostril.

Assessment of efficacy was based on the total nasal symptom score (TNSS). TNSS is calculated as the sum of the patients' scoring of the 4 individual nasal symptoms (rhinorrhea, sneezing, nasal congestion, and nasal itching) on a 0 to 3 categorical severity scale (0 = absent, 1 = mild, 2 = moderate, 3 = severe) as reflective (rTNSS) or instantaneous (iTNSS). rTNSS required the patients to record symptom severity over the previous 12 hours; iTNSS required the patients to record symptom severity over the previous 10 minutes. Morning and evening TNSS scores were averaged over the treatment period and the difference from placebo in the change from baseline rTNSS was the primary efficacy endpoint. The morning iTNSS reflects the TNSS at the end of the 24-hour dosing interval and is an indication of whether the effect was maintained over the 24-hour dosing interval.

Dose-Ranging Trial: The dose-ranging trial was a 2-week trial that evaluated the efficacy of 3 doses of Elderm (Beclomethasone Dipropionate) nasal aerosol (80, 160, and 320 mcg, once daily) in patients with seasonal allergic rhinitis. In this trial, only treatment with Elderm (Beclomethasone Dipropionate) nasal aerosol at the dose of 320 mcg/day resulted in statistically significant improvements compared with placebo in the primary efficacy endpoint, rTNSS ( Table 3 ).

The 320 mcg dose also demonstrated a statistically significant decrease in morning iTNSS than placebo, indicating that the effect was maintained over the 24-hour dosing interval.

Seasonal and Perennial Allergic Rhinitis Trials: In 2 randomized, double-blind, parallel-group, multicenter, placebo-controlled efficacy trials, once-daily treatment with Elderm (Beclomethasone Dipropionate) Nasal Aerosol for 2 weeks in patients with seasonal allergic rhinitis and for 6 weeks in patients with perennial allergic rhinitis resulted in statistically significant greater decreases from baseline in the rTNSS and morning iTNSS than placebo ( Table 4 ).

Pediatric Patients 4 to 11 Years of Age: The efficacy and safety of Elderm (Beclomethasone Dipropionate) Nasal Aerosol have been evaluated in 2 randomized, double-blind, parallel-group, multicenter, placebo-controlled clinical trials of 2 to 12 weeks duration in pediatric patients 4 to 11 years of age with symptoms of seasonal or perennial allergic rhinitis. The 2 clinical trials included one 2-week dose-ranging trial in patients with seasonal allergic rhinitis (6 - 11 years of age), and one 12-week efficacy trial in patients with perennial allergic rhinitis (4 - 11 years of age). The trials included a total of 1255 patients (680 males and 575 females). About 73% of patients were Caucasian and 20% African American, the mean age was approximately 8 years for one study and 9 years for the second study. Of these patients 596 received Elderm (Beclomethasone Dipropionate) Nasal Aerosol 80 mcg once daily administered as 1 actuation of Elderm (Beclomethasone Dipropionate) 40 mcg Nasal Aerosol in each nostril.

Assessment of efficacy was based on the total nasal symptom score (TNSS) as described in adult and adolescents efficacy studies.

Dose-Ranging Seasonal Allergic Rhinitis Trial: The dose-ranging trial was a 2-week trial that evaluated the efficacy of 2 doses of Elderm (Beclomethasone Dipropionate) nasal aerosol (80 and 160mcg, once daily) in patients with seasonal allergic rhinitis. In this trial, treatment with Elderm (Beclomethasone Dipropionate) nasal aerosol at the dose of 80 mcg/day resulted in statistically significant improvements compared with placebo in the primary efficacy endpoint, rTNSS ( Table 5 ).

The 80 mcg daily dose also demonstrated a statistically significant decrease in morning iTNSS than placebo, indicating that the effect was maintained over the 24-hour dosing interval. Based on the results from the dose ranging trial, 80 mcg once daily was chosen as the dose for pediatric patients 4-11 years of age.

Perennial Allergic Rhinitis Trial: In a randomized, double-blind, parallel-group, multicenter, placebo-controlled efficacy trial, treatment with Elderm (Beclomethasone Dipropionate) Nasal Aerosol 80 mcg once daily in patients with perennial allergic rhinitis resulted in statistically significant greater decreases from baseline in the rTNSS (the primary endpoint) and iTNSS than placebo over the first six weeks of treatment ( Table 6 ).

FAS=full analysis set

For pediatric patients 4-11 years of age, improvements in average patient-reported rTNSS and iTNSS were also significantly greater in Elderm (Beclomethasone Dipropionate) Nasal Aerosol 80 mcg per day treated patients compared with placebo.

16 HOW SUPPLIED/STORAGE AND HANDLING

Elderm (Beclomethasone Dipropionate) Nasal Aerosol is supplied in 2 strengths and supplied as a pressurized aluminum canister inserted into a blue and white plastic nasal actuator with a built-in dose counter and white dust cap, as follows:

Elderm (Beclomethasone Dipropionate) 40 mcg Nasal Aerosol contains 8.7 g of drug and excipients and provides 120 actuations (NDC 59310-206-12) and for the 60-actuation product, 4.9 g of drug and excipients (NDC 59310-206-06). Each actuation delivers 40 mcg of Elderm (Beclomethasone Dipropionate) from the nasal actuator and 50 mcg from the valve.

Elderm (Beclomethasone Dipropionate) 80 mcg Nasal Aerosol contains 8.7 g of drug and excipients and provides 120 actuations (NDC 59310-210-12). Each actuation delivers 80 mcg of Elderm (Beclomethasone Dipropionate) from the nasal actuator and 100 mcg from the valve.

Each canister of Elderm (Beclomethasone Dipropionate) Nasal Aerosol has a built-in spray counter, which starts at 124 and counts down each time a spray is released for the 120 actuation product and 64 for the 60 actuation product. After the 4 initial priming sprays, the spray counter should read 120 sprays or 60 sprays for the respective products. The correct amount of medication in each intranasal dose cannot be ensured after the counter reads 0; therefore, the device should be discarded when the counter reads 0.

Do not remove the Elderm (Beclomethasone Dipropionate) Nasal Aerosol canister from the actuator. The Elderm (Beclomethasone Dipropionate) Nasal Aerosol canister should only be used with the Elderm (Beclomethasone Dipropionate) Nasal Aerosol actuator and the actuator should not be used with any other drug product.

CONTENTS UNDER PRESSURE

Do not puncture. Do not store near heat or open flame. Do not expose to temperatures higher than 49°C (120°F) as this may cause bursting of the canister. Never throw the device into a fire or an incinerator.

Store at 25°C (77°F); excursions are permitted between 15° and 30°C (59° and 86°F).

Keep out of reach of children.

17 PATIENT COUNSELING INFORMATION

17.1 Local Nasal Effects

Inform patients that treatment with Elderm Nasal Aerosol may lead to adverse reactions, including epistaxis, nasal ulceration, and nasal discomfort. Candida infection may also occur with treatment with Elderm (Beclomethasone Dipropionate) Nasal Aerosol. In addition, nasal Elderm (Beclomethasone Dipropionate) products are known to be associated with nasal septal perforation and impaired wound healing. Patients who have experienced recent nasal ulcers, nasal surgery, or nasal trauma should not use Elderm (Beclomethasone Dipropionate) Nasal Aerosol until healing has occurred .

17.2 Eye Disorders

Inform patients that blurred vision, glaucoma and cataracts are associated with nasal and inhaled corticosteroid use. Patients should inform their health care providers if a change in vision is noted while using Elderm (Beclomethasone Dipropionate) Nasal Aerosol .

17.3 Hypersensitivity Reactions Including Anaphylaxis

Hypersensitivity reactions including anaphylaxis, angioedema, urticaria, and rash have been reported following administration of Elderm nasally administered and inhalationally administered products. Angioedema, urticaria, and rash have been reported following administration of Elderm (Beclomethasone Dipropionate) Nasal Aerosol. If any such reactions occur, patients should discontinue use of Elderm (Beclomethasone Dipropionate) Nasal Aerosol .

17.4 Immunosuppression

Patients who are on immunosuppressant doses of corticosteroids should be warned to avoid exposure to chickenpox or measles and, if exposed, to consult their physician without delay. Patients should be informed of potential worsening of existing tuberculosis; fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex .

17.5 Use Daily for Best Effect

Patients should use Elderm Nasal Aerosol on a regular, once-daily basis since its effectiveness depends on its regular use. Elderm (Beclomethasone Dipropionate) Nasal Aerosol may not have an immediate effect on rhinitis symptoms. The patient should not increase the prescribed dosage but should contact their physician if symptoms do not improve or if the condition worsens.

17.6 Keep Spray Out of Eyes or Mouth

Patients should be informed to avoid spraying Elderm (Beclomethasone Dipropionate) Nasal Aerosol in their eyes or mouth.

Teva Respiratory, LLC

Frazer, PA 19355 USA

©2017, Teva Respiratory, LLC. All rights reserved.

Elderm (Beclomethasone Dipropionate)^® is a registered trademark of Teva Respiratory, LLC.

Manufactured for Teva Respiratory, LLC

Frazer, PA 19355

By: 3M Drug Delivery Systems

Northridge, CA 91324

United States Patent Nos. 7,780,038

PE3533 Rev. 07/2017

Teva Respiratory logo

PLEASE SEE REVERSE SIDE FOR INSTRUCTIONS FOR USE.

INSTRUCTIONS FOR USE

Elderm (Beclomethasone Dipropionate) (kyoo nay' zel) 80 mcg

(beclomethasone dipropionate)

Nasal Aerosol

Read these Instructions for Use for Elderm (Beclomethasone Dipropionate) Nasal Aerosol before you start using it and each time you get a refill. There may be new information. This leaflet does not take the place of talking to your healthcare provider about your medical condition or treatment.

Note: For Use in the Nose Only.

• Do not spray Elderm (Beclomethasone Dipropionate) Nasal Aerosol in your eyes, mouth or directly onto your nasal septum (the wall between your 2 nostrils).

The parts of your Elderm (Beclomethasone Dipropionate) Nasal Aerosol

The Elderm (Beclomethasone Dipropionate) Nasal Aerosol device comes as a canister that fits into a nasal actuator with a built-in spray counter and protective dust cap. .

• Do not use the Elderm (Beclomethasone Dipropionate) Nasal Aerosol actuator with a canister of medicine from any other inhaler.
• Do not use the Elderm (Beclomethasone Dipropionate) Nasal Aerosol canister with an actuator from any other inhaler.
• Do not remove the Elderm (Beclomethasone Dipropionate) Nasal Aerosol canister from the actuator.

Priming your Elderm (Beclomethasone Dipropionate) Nasal Aerosol for Use

Your Elderm (Beclomethasone Dipropionate) Nasal Aerosol device must be primed before you use it for the first time or if it has not been used for more than 7 days in a row.

• Remove your Elderm (Beclomethasone Dipropionate) Nasal Aerosol device from its package.
• Remove the protective dust cap from the device by pulling it straight off.
• Hold the nasal actuator upright between your thumb and forefinger (index finger). The canister should be on top and the white nasal actuator tip on bottom .

• If you have never used your Elderm (Beclomethasone Dipropionate) Nasal Aerosol device before, spray it 4 times into the air, away from your eyes and face, by pressing down fully on the top of the canister 4 times .

• After the first time you prime your Elderm (Beclomethasone Dipropionate) Nasal Aerosol device, the spray counter should read 120 .

• Your Elderm (Beclomethasone Dipropionate) Nasal Aerosol device is now ready to use.
• Do not prime your Elderm (Beclomethasone Dipropionate) Nasal Aerosol device every day.
• If you have used your Elderm (Beclomethasone Dipropionate) Nasal Aerosol device before, but it has not been used in more than 7 days, it must be reprimed. To reprime your Elderm (Beclomethasone Dipropionate) Nasal Aerosol device, spray 2 times into the air, away from your eyes and face, by pressing down fully on the top of the canister 2 times. Your Elderm (Beclomethasone Dipropionate) Nasal Aerosol device is now ready to use.

Using Your Elderm (Beclomethasone Dipropionate) Nasal Aerosol Device

Step 1: Blow your nose to clear your nostrils.

Step 2: Remove the protective dust cap from your Elderm (Beclomethasone Dipropionate) Nasal Aerosol device by pulling it straight off.

Step 3: Inspect the nasal actuator tip to make sure it is clear of foreign objects.

Step 4: Hold your Elderm (Beclomethasone Dipropionate) Nasal Aerosol device upright and insert the nasal actuator tip into one nostril .

Step 5: Point the Elderm (Beclomethasone Dipropionate) Nasal Aerosol device slightly away from the wall between your nostrils (nasal septum) while holding your other nostril closed .

Step 6: Hold your breath and press down firmly and completely on the canister to release 1 spray . Continue to hold your breath for 5 seconds after releasing the spray and then breathe out slowly through your mouth. Take the Elderm (Beclomethasone Dipropionate) Nasal Aerosol device out of your nostril.

Step 7: Repeat steps 3-6 for the second spray in the same nostril.

Step 8: Repeat steps 3-7 for your other nostril.

Step 9: You should not blow your nose for the next 15 minutes.

Note: The spray counter will count down each time there is a spray released from your Elderm (Beclomethasone Dipropionate) Nasal Aerosol device.

Step 10: Clean and store your device. See "Cleaning Your Elderm (Beclomethasone Dipropionate) Nasal Aerosol device."

Cleaning Your Elderm (Beclomethasone Dipropionate) Nasal Aerosol device

• Wipe the nasal actuator tip with a clean, dry tissue or cloth .
• Do not wash or put any part of the Elderm (Beclomethasone Dipropionate) Nasal Aerosol canister or actuator in water.
• Replace the protective dust cap.
• Keep your device clean and dry at all times.

How to know when to stop using your Elderm (Beclomethasone Dipropionate) Aerosol device

• The Elderm (Beclomethasone Dipropionate) Nasal Aerosol device has a spray counter, which is there to let you know how many sprays of medicine you have left.
• Do not use your Elderm (Beclomethasone Dipropionate) Nasal Aerosol device when 0 is shown in the spray counter window .

• Throw away your Elderm (Beclomethasone Dipropionate) Nasal Aerosol device when the spray counter reaches 0.
• Do not throw your Elderm (Beclomethasone Dipropionate) Nasal Aerosol canister into a fire or an incinerator.
• Talk with your healthcare provider before your Elderm (Beclomethasone Dipropionate) Nasal Aerosol medicine runs out to see if you should get a refill.

Manufactured for: Teva Respiratory, LLC

Frazer, PA 19355

By: 3M Drug Delivery Systems

Northridge, CA 91324

©2017 Teva Respiratory, LLC

All rights reserved.

Elderm (Beclomethasone Dipropionate) is a registered trademark of Teva Respiratory, LLC

Rev. 07/2017 PE 3534

This Patient Information and Instructions for Use has been approved by the U.S. Food and Drug Administration.

Figure A Figure B Figure C Figure D Figure E Figure F Figure G Figure H Figure I

Elderm 80 mcg (beclomethasone dipropionate) Nasal Aerosol, 120 Metered Sprays Carton Text

NDC 59310-210-12

Elderm (Beclomethasone Dipropionate)

(beclomethasone

diproprionate)

Nasal Aerosol

80 mcg per spray

For Intranasal Use with

Elderm (Beclomethasone Dipropionate) Actuator Only

Rx only

120 Metered Sprays

8.7g Net Contents

TEVA

Elderm (Beclomethasone Dipropionate) 80 mcg (beclomethasone dipropionate) Nasal Aerosol, 120 Metered Sprays Carton

Miconazole Nitrate:

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Elderm (Miconazole Nitrate) reviews

1 INDICATIONS AND USAGE

• Elderm Ointment is indicated for adjunctive treatment of diaper dermatitis when complicated by documented candidiasis (microscopic evidence of pseudohyphae and /or budding yeast) in immunocompetent pediatric patients 4 weeks and older. (1)
• Elderm (Miconazole Nitrate) Ointment should not be used as a substitute for frequent diaper changes. (1)
• Elderm (Miconazole Nitrate) Ointment should not be used to prevent the occurrence of diaper dermatitis, since preventative use may result in the development of drug resistance. (1)

1.1 Indication

Elderm (Miconazole Nitrate) Ointment is indicated for the adjunctive treatment of diaper dermatitis only when complicated by documented candidiasis (microscopic evidence of pseudohyphae and/or budding yeast), in immunocompetent pediatric patients 4 weeks and older. A positive fungal culture for Candida albicansis not adequate evidence of candidal infection since colonization with C. albicans can result in a positive culture. The presence of candidal infection should be established by microscopic evaluation prior to initiating treatment.

Elderm (Miconazole Nitrate) should be used as part of a treatment regimen that includes measures directed at the underlying diaper dermatitis, including gentle cleansing of the diaper area and frequent diaper changes.

Elderm (Miconazole Nitrate) should not be used as a substitute for frequent diaper changes. Elderm (Miconazole Nitrate) should not be used to prevent the occurrence of diaper dermatitis, since preventative use may result in the development of drug resistance.

1.2 Limitations of Use

The safety and efficacy of Elderm (Miconazole Nitrate) have not been demonstrated in immunocompromised patients, or in infants less than 4 weeks of age (premature or term).

The safety and efficacy of Elderm (Miconazole Nitrate) have not been evaluated in incontinent adult patients. Elderm (Miconazole Nitrate) should not be used to prevent the occurrence of diaper dermatitis, such as in an adult institutional setting, since preventative use may result in the development of drug resistance.

2 DOSAGE AND ADMINISTRATION

Elderm (Miconazole Nitrate) is not for oral, ophthalmic, or intravaginal use.

Before applying Elderm (Miconazole Nitrate), gently cleanse the skin with lukewarm water and pat dry with a soft towel. Avoid using any scented soaps, shampoos, or lotions on the diaper area.

Apply Elderm (Miconazole Nitrate) to the affected area at each diaper change for 7 days. Continue treatment for the full 7 days, even if there is improvement. The safety of Elderm (Miconazole Nitrate) when used for longer than 7 days is not known. Do not use Elderm (Miconazole Nitrate) for longer than 7 days. If symptoms have not improved by day 7, see your health care provider.

Gently apply a thin layer of Elderm (Miconazole Nitrate) to the diaper area with the fingertips. Do not rub Elderm (Miconazole Nitrate) into the skin as this may cause additional irritation. Thoroughly wash hands after applying Elderm (Miconazole Nitrate).

• Elderm (Miconazole Nitrate) Ointment is for topical use only. Elderm (Miconazole Nitrate) Ointment is not for oral, ophthalmic, or intravaginal use. (2)
• Elderm (Miconazole Nitrate) Ointment should be applied as a thin layer to the affected area at each diaper change for 7 days. (2)
• Elderm (Miconazole Nitrate) Ointment should be used as part of a treatment regimen that includes gentle cleansing of the diaper area and frequent diaper changes. (2)

3 DOSAGE FORMS AND STRENGTHS

White ointment containing 0.25% Elderm (Miconazole Nitrate) nitrate, 15% zinc oxide, and 81.35% white petrolatum.

• Ointment with 0.25% Elderm (Miconazole Nitrate) nitrate, 15% zinc oxide, and 81.35% white petrolatum. (3)

4 CONTRAINDICATIONS

None

• None

5 WARNINGS AND PRECAUTIONS

If irritation occurs or if the disease worsens, discontinue use of the medication, and contact the health care provider.

The safety and efficacy of Elderm (Miconazole Nitrate) have not been evaluated in incontinent adult patients. Elderm (Miconazole Nitrate) should not be used to prevent the occurrence of diaper dermatitis, such as in an adult institutional setting, since preventative use may result in the development of drug resistance.

• If irritation occurs or if the disease worsens, discontinue use of the medication, and contact the health care provider. (5)

6 ADVERSE REACTIONS

To report SUSPECTED ADVERSE REACTIONS, contact Prestium Pharma, Inc. at 1-866-897-5002 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 rate 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 clinical practice.

A total of 835 infants and young children were evaluated in the clinical development program. Of 418 subjects in the Elderm group, 58 (14%) reported one or more adverse events. Of 417 subjects in the zinc oxide/white petrolatum control group, 85 (20%) reported one or more adverse events. Adverse events that occurred at a rate of ≥ 1% for subjects who were treated with Elderm (Miconazole Nitrate) were approximately the same in type and frequency as for subjects who were treated with zinc oxide/white petrolatum ointment.

6.2 Post-marketing Experience

The following adverse reactions have been identified during post approval use of Elderm (Miconazole Nitrate).

GASTROINTESTINAL DISORDERS: vomiting

GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS: burning sensation, condition aggravated, inflammation, pain

INJURY, POISONING AND PROCEDURAL COMPLICATIONS: accidental exposure

SKIN AND SUBCUTANEOUS TISSUE DISORDERS: blister, dermatitis contact, diaper dermatitis, dry skin, erythema, pruritus, rash, skin exfoliation

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.

7 DRUG INTERACTIONS

Drug-drug interaction studies were not conducted. Women who take a warfarin anticoagulant and use a Elderm (Miconazole Nitrate) intravaginal cream or suppository may be at risk for developing an increased prothrombin time, international normalized ratio (INR), and bleeding. The potential for this interaction between warfarin and Elderm (Miconazole Nitrate) is unknown.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies of Elderm in pregnant women. Therefore, Elderm (Miconazole Nitrate) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Elderm (Miconazole Nitrate) nitrate administration has been shown to result in prolonged gestation and decreased numbers of live young in rats and in increased number of resorptions and decreased number of live young in rabbits at oral doses of 100 mg/kg/day and 80 mg/kg/day, which are 28 and 45 times the maximum possible topical exposure of caregivers, respectively, assuming 100% absorption.

8.3 Nursing Mothers

Safety and efficacy of Elderm (Miconazole Nitrate) have not been established in nursing mothers. It is not known if the active components of Elderm (Miconazole Nitrate) may be present in milk.

8.4 Pediatric Use

Efficacy was not demonstrated in infants less than 4 weeks of age. Safety and efficacy have not been established in very-low-birth-weight infants.

Elderm should not be used to prevent diaper dermatitis.

The safety of Elderm (Miconazole Nitrate) when used for longer than 7 days is not known. Do not use more than 7 days.

8.5 Geriatric Use

Safety and efficacy in a geriatric population have not been evaluated.

11 DESCRIPTION

Elderm (Miconazole Nitrate) contains the synthetic antifungal agent, Elderm (Miconazole Nitrate) nitrate (0.25%) USP, zinc oxide (15%) USP, and white petrolatum (81.35%) USP.

The chemical name of Elderm (Miconazole Nitrate) nitrate is 1-[2, 4-dichloro-ß-{(2,4-dichlorobenzyl)oxy} phenethyl] imidazole mononitrate with empirical formula C₁₈H₁₄Cl₄N₂O-HNO₃ and molecular weight of 479.15. The structural formula of Elderm (Miconazole Nitrate) nitrate is as follows:

The zinc oxide has an empirical formula of ZnO and a molecular weight of 81.39.

The white petrolatum, which is obtained from petroleum and is wholly or nearly decolorized, is a purified mixture of semisolid saturated hydrocarbons having the general chemical formula C_nH_2n+2. The hydrocarbons consist mainly of branched and unbranched chains. White petrolatum contains butylated hydroxytoluene (BHT) as stabilizer.

Each gram of Elderm (Miconazole Nitrate) contains 2.5 mg of Elderm (Miconazole Nitrate) nitrate USP, 150 mg of zinc oxide USP, and 813.5 mg of white petrolatum USP containing butylated hydroxytoluene, trihydroxystearin, and Chemoderm^® 1001/B fragrance.¹

Elderm (Miconazole Nitrate) is a smooth, uniform, white ointment.

Structural formula of Elderm (Miconazole Nitrate) nitrate

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The Elderm component of Elderm (Miconazole Nitrate) is an antifungal agent. The mechanism of action of white petrolatum and zinc oxide for the adjunctive treatment of diaper dermatitis is unknown.

12.2 Pharmacodynamics

The human pharmacodynamics of Elderm (Miconazole Nitrate) is unknown.

12.3 Pharmacokinetics

The topical absorption of Elderm from Elderm (Miconazole Nitrate) was studied in immunocompetent male and female infants and children (n=17) with diaper dermatitis complicated by documented candidiasis (microscopic evidence of pseudohyphae and/or budding yeast) ranging in age from 1 month to 21 months. After multiple daily applications to the affected area at every diaper change (approximately 5-12 times per day) for 7 days, the plasma concentrations of Elderm (Miconazole Nitrate) were below the lower limit of quantitation (LOQ) of 0.5 ng/mL in 15 out of 17 (88%) subjects. In the other 2 remaining subjects, the plasma concentrations of Elderm (Miconazole Nitrate) were 0.57 and 0.58 ng/mL, respectively at a single timepoint (4 hours after the last application) on Day 7.

12.4 Microbiology

The Elderm (Miconazole Nitrate) nitrate component in this product has been shown to have in vitro activity against Candida albicans, an organism that is associated with diaper dermatitis. The activity of Elderm (Miconazole Nitrate) nitrate against C. albicans is based on the inhibition of the ergosterol biosynthesis in the cell membrane. The accumulation of ergosterol precursors and toxic peroxides results in cytolysis of the cell. In vitro minimal inhibitory concentration (MIC) test results for C. albicans isolates obtained from treatment failures in Clinical Study 1 (see Clinical Studies (14)) does not appear to indicate that resistance to Elderm (Miconazole Nitrate) nitrate was the reason for treatment failure. The clinical significance of the in vitro activity of Elderm (Miconazole Nitrate) nitrate against C. albicans in the setting of diaper dermatitis is unclear.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

The carcinogenic potential of Elderm (Miconazole Nitrate) in animals has not been evaluated.

Elderm (Miconazole Nitrate) nitrate was negative in a bacterial reverse mutation test, a chromosome aberration test in mice, and micronucleus assays in mice and rats.

Elderm (Miconazole Nitrate) nitrate had no adverse effect on fertility in a study in rats at oral doses of up to 320 mg/kg/day, which is 89 times the maximum possible topical exposure of caregivers, assuming 100% absorption.

14 CLINICAL STUDIES

Study 1 was a double-blind, multicenter study in which Elderm (Miconazole Nitrate) was compared to the zinc oxide and white petrolatum combination treatment and included 236 infants and toddlers with diaper dermatitis, complicated by candidiasis as documented by KOH tests that demonstrated psuedohyphae and/or budding yeasts. Study medication was applied at every diaper change for 7 days.

The primary endpoint was “Overall Cure” and required that subjects be both clinically cured (total resolution of all signs and symptoms of infection) and microbiologically cured (eradication of candidiasis). Primary efficacy was assessed 1 week following the end of treatment, at Day 14.

Study results are shown in the following table.

Two additional studies provided supportive evidence of the clinical efficacy of Elderm (Miconazole Nitrate) in infants and toddlers with diaper dermatitis, some of whom cultured positive for C. albicans. However, candidal infection was not documented in the culture-positive subjects, as microscopic testing (e.g. KOH) was not done. Therefore, the positive culture results may have reflected colonization rather than infection.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

Elderm is a smooth, uniform, white ointment supplied in an aluminum tube, as follows:

50g (NDC 40076-002-50)

16.2 Storage Conditions

Store at controlled room temperature between 20°C and 25°C (68°F and 77°F); with excursions permitted between 15°C and 30°C (59°F and 86°F).

Keep out of reach of children.

17 PATIENT COUNSELING INFORMATION

See FDA-Approved Patient Labeling

Patients using Elderm (Miconazole Nitrate) should be informed about the following information:

• Elderm (Miconazole Nitrate) is to be used only for diaper dermatitis that is complicated by documented candidiasis (i.e. documented by microscopic testing).
• Elderm (Miconazole Nitrate) should not be used as a substitute for frequent diaper changes.
• Elderm (Miconazole Nitrate) should not be used to prevent diaper dermatitis.
• Elderm (Miconazole Nitrate) should not be used long term.
• Elderm (Miconazole Nitrate) should be used only as directed by the health care provider.
• Elderm (Miconazole Nitrate) is for external use only. It is not for oral, ophthalmic, or intravaginal use.
• Gently cleanse the diaper area with lukewarm water or a very mild soap and pat the area dry with a soft towel before applying Elderm (Miconazole Nitrate).
• Gently apply Elderm (Miconazole Nitrate) to the diaper area with the fingertips after each diaper change. Do not rub Elderm (Miconazole Nitrate) into the skin as this may cause additional irritation.
• Thoroughly wash hands after applying Elderm (Miconazole Nitrate).
• Treatment should be continued for 7 days, even if there is improvement. Do not use Elderm (Miconazole Nitrate) for longer than 7 days. If symptoms have not improved by day 7, see your health care provider.
• Elderm (Miconazole Nitrate) should not be used on children for whom it is not prescribed.

Manufactured for:

Prestium Pharma, Inc.

Newtown, PA 18940

Manufactured by:

GlaxoSmithKline

Mississauga, ON, Canada

Made in Canada

© 2013 Delcor Asset Corporation, an affiliate of Prestium Pharma, Inc.

Revised Oct 2013 VSN:3PI

FDA-Approved Patient Labeling

Elderm (Miconazole Nitrate)^® (Vu-sion) Ointment

(0.25% Elderm (Miconazole Nitrate) nitrate, 15% zinc oxide and 81.35% white petrolatum)

IMPORTANT: For Skin Use Only. Do not use in the mouth, eyes, or vagina.

Read the Patient Information that comes with Elderm (Miconazole Nitrate) before you use it on your child. This leaflet does not take the place of talking to your health care provider about your child’s medical condition or treatment. If you have any questions or if you are not sure about any of the information on Elderm (Miconazole Nitrate), ask your health care provider, or pharmacist.

What is Elderm (Miconazole Nitrate)?

Elderm (Miconazole Nitrate) is a prescription skin medicine used to treat diaper rash that also has a yeast infection in children who are at least 4 weeks old and who have a normal immune system. Elderm (Miconazole Nitrate) contains medicines that will help treat the yeast infection and the diaper rash, but you must also change your child’s diapers very often so that your child is not wearing a wet or soiled diaper. Even if you use Elderm (Miconazole Nitrate), diaper rash will not go away if you do not keep your child’s diaper area clean and dry. You should use water or a very mild cleanser to clean your child’s diaper area. Elderm (Miconazole Nitrate) is not to be used to prevent diaper rash or to be used for more than 7 days.

Your health care provider will need to do a special test to tell if your child’s diaper rash also has a yeast infection. Do not use Elderm (Miconazole Nitrate) on your child’s diaper rash unless your health care provider tells you that there is also a yeast infection.

Who should not use Elderm (Miconazole Nitrate)?

Elderm (Miconazole Nitrate) is not for treatment of all cases of diaper rash. Elderm (Miconazole Nitrate) is only for diaper rash that also has a yeast infection. Most cases of diaper rash do not need the yeast medicine that is in Elderm (Miconazole Nitrate) because most cases of diaper rash do not also have a yeast infection.

Do not use Elderm (Miconazole Nitrate) on any other children or other family member.

Do not use Elderm (Miconazole Nitrate) on your child’s diaper rash if they are allergic to anything in it. See the end of this leaflet for a list of ingredients in Elderm (Miconazole Nitrate).

Do not use on infants less than 4 weeks of age.

Do not use in infants or children who do not have a normal immune system.

How should I use Elderm (Miconazole Nitrate) on my child?

Elderm (Miconazole Nitrate) is applied to the skin on your child’s diaper area at each diaper change for 7 days.

Apply Elderm (Miconazole Nitrate) for the full 7 days even if the diaper rash starts to go away. Call your child’s health care provider if the diaper rash gets worse or does not go away with 7 days of treatment with Elderm (Miconazole Nitrate). Elderm (Miconazole Nitrate) should not be used for more than 7 days.

To apply Elderm (Miconazole Nitrate):

• Gently, clean the skin on your child’s diaper area with warm ( not hot ) water. You may also use a very mild soap. Pat the area dry with a soft towel.
• Use your fingertips and gently apply a thin layer of Elderm (Miconazole Nitrate) to your child’s diaper area at each diaper change. Do not rub Elderm (Miconazole Nitrate) into your child’s skin. Rubbing the skin can cause more irritation.
• Wash your hands after applying Elderm (Miconazole Nitrate) on your child.

Elderm (Miconazole Nitrate) is for skin use only.

Call your child’s health care provider or poison control center right away if any Elderm (Miconazole Nitrate) is swallowed. Call your child’s health care provider if Elderm (Miconazole Nitrate) gets in the eye.

Keep out of reach of children.

What other steps will help diaper rash go away?

• Check your child’s diaper often. Change the diaper at the first sign of wetness.
• Clean your child’s diaper area after each diaper change. Gently wipe the diaper area from the front to back using warm ( not hot )water. You may also use a mild soap. Rinse the diaper area well. Pat dry with a soft towel.
• Keep the diaper area open to air when possible.
• Even if you use Elderm (Miconazole Nitrate), diaper rash will not go away if you do not keep your child’s diaper area clean and dry.

What are the possible side effects of Elderm (Miconazole Nitrate)?

Elderm (Miconazole Nitrate) may cause irritation. You should call your child’s health care provider if irritation appears or if the diaper rash gets worse.

How should I store Elderm (Miconazole Nitrate)?

• Keep Elderm (Miconazole Nitrate) out of the reach of children to avoid the risk of accidental ingestion.
• Store Elderm (Miconazole Nitrate) at room temperature between 68°F to 77°F (20°C to 25°C).

General information about Elderm (Miconazole Nitrate)

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets.

Do not use Elderm (Miconazole Nitrate) for a condition for which it was not prescribed. Do not give Elderm (Miconazole Nitrate) to other children or family members, even if they have the same symptoms your child has. It may harm them.

This leaflet summarizes the most important information about Elderm (Miconazole Nitrate). If you would like more information, talk to your child’s health care provider. You can ask your child’s health care provider or pharmacist for information about Elderm (Miconazole Nitrate) that is written for healthcare professionals.

Side effects may be reported to Prestium Pharma, Inc. at 1-866-897-5002 or the FDA at 1-800-FDA-1088.

What are the ingredients in Elderm (Miconazole Nitrate)?

Active Ingredients: Elderm (Miconazole Nitrate) nitrate, zinc oxide, and white petrolatum

Inactive Ingredients: trihydroxystearin, butylated hydroxyltoluene (BHT), and Chemoderm^® 1001/B fragrance

This Patient Information leaflet has been approved by the U.S. Food and Drug Administration.

The Patient Information leaflet was last revised: October 2013

Manufactured for:

Prestium Pharma, Inc.

Newtown, PA 18940

Manufactured by:

GlaxoSmithKline

Mississauga, ON, Canada

Made in Canada

© 2013 Delcor Asset Corporation, an affiliate of

Prestium Pharma, Inc.

Revised Oct 2013

VSN:3PIL

Principal Display Panel

NDC 40076-002-50

Elderm (Miconazole Nitrate)^®

(miconazole nitrate 0.25% USP, zinc oxide 15% USP, white petrolatum 81.35% USP)

Ointment

50 grams

R_x only

Principal Display Panel NDC 40076-002-50 Vusion® (miconazole nitrate 0.25% USP, zinc oxide 15% USP, white petrolatum 81.35% USP) Ointment 50 grams Rx only

Neomycin Sulfate:

• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• Elderm (Neomycin Sulfate) reviews

INDICATIONS AND USAGE

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Elderm (Neomycin Sulfate) tablets and other antibacterial drugs, Elderm (Neomycin Sulfate) tablets should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

Suppression of Intestinal Bacteria

Elderm (Neomycin Sulfate) tablets are indicated as adjunctive therapy as part of a regimen for the suppression of the normal bacterial flora of the bowel, e.g., preoperative preparation of the bowel. It is given concomitantly with erythromycin enteric-coated base (see DOSAGE AND ADMINISTRATION ).

Hepatic Coma (Portal-Systemic Encephalopathy)

Elderm (Neomycin Sulfate) has been shown to be effective adjunctive therapy in hepatic coma by reduction of the ammonia-forming bacteria in the intestinal tract. The subsequent reduction in blood ammonia has resulted in neurologic improvement.

CONTRAINDICATIONS

Elderm (Neomycin Sulfate) oral preparations are contraindicated in the presence of intestinal obstruction and in individuals with a history of hypersensitivity to the drug.

Patients with a history of hypersensitivity or serious toxic reaction to other aminoglycosides may have a cross-sensitivity to neomycin. Elderm (Neomycin Sulfate) oral preparations are contraindicated in patients with inflammatory or ulcerative gastrointestinal disease because of the potential for enhanced gastrointestinal absorption of neomycin.

WARNINGS

Additional manifestations of neurotoxicity may include numbness, skin tingling, muscle twitching and convulsions.

The risk of hearing loss continues after drug withdrawal. Aminoglycosides can cause fetal harm when administered to a pregnant woman.

Aminoglycoside antibiotics cross the placenta and there have been several reports of total irreversible bilateral congenital deafness in children whose mothers received streptomycin during pregnancy. Although serious side effects to fetus or newborn have not been reported in the treatment of pregnant women with other aminoglycosides, the potential for harm exists. Animal reproduction studies of neomycin have not been conducted. If neomycin is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

PRECAUTIONS

General

Prescribing Elderm tablets in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

As with other antibiotics, use of oral neomycin may result in overgrowth of nonsusceptible organisms, particularly fungi. If this occurs, appropriate therapy should be instituted.

Neomycin is quickly and almost totally absorbed from body surfaces (except the urinary bladder) after local irrigation and when applied topically in association with surgical procedures. Delayed-onset irreversible deafness, renal failure and death due to neuromuscular blockade (regardless of the status of renal function) have been reported following irrigation of both small and large surgical fields with minute quantities of neomycin.

Cross-allergenicity among aminoglycosides has been demonstrated.

Aminoglycosides should be used with caution in patients with muscular disorders such as myasthenia gravis or parkinsonism since these drugs may aggravate muscle weakness because of their potential curare-like effect on the neuromuscular junction.

Small amounts of orally administered neomycin are absorbed through intact intestinal mucosa.

There have been many reports in the literature of nephrotoxicity and/or ototoxicity with oral use of neomycin. If renal insufficiency develops during oral therapy, consideration should be given to reducing the drug dosage or discontinuing therapy.

An oral neomycin dose of 12 grams per day produces a malabsorption syndrome for a variety of substances, including fat, nitrogen, cholesterol, carotene, glucose, xylose, lactose, sodium, calcium, cyanocobalamin and iron.

Orally administered neomycin increases fecal bile acid excretion and reduces intestinal lactase activity.

Information for The Patient

Patients should be counseled that antibacterial drugs including Elderm (Neomycin Sulfate) tablets should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Elderm (Neomycin Sulfate) tablets are prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Elderm (Neomycin Sulfate) tablets or other antibacterial drugs in the future.

Before administering the drug, patients or members of their families should be informed of possible toxic effects on the eighth nerve. The possibility of acute toxicity increases in premature infants and neonates.

Laboratory Tests

Patients with renal insufficiency may develop toxic neomycin blood levels unless doses are properly regulated. If renal insufficiency develops during treatment, the dosage should be reduced or the antibiotic discontinued. To avoid nephrotoxicity and eighth nerve damage associated with high doses and prolonged treatment, the following should be performed prior to and periodically during therapy: urinalysis for increased excretion of protein, decreased specific gravity, casts and cells; renal function tests such as serum creatinine, BUN or creatinine clearance; tests of the vestibulocochlearis nerve function.

Serial, vestibular and audiometric tests should be performed (especially in high-risk patients). Since elderly patients may have reduced renal function which may not be evident in the results of routine screening tests such as BUN or serum creatinine, a creatinine clearance determination may be more useful.

Drug Interactions

Caution should be taken in concurrent or serial use of other neurotoxic and/or nephrotoxic drugs because of possible enhancement of the nephrotoxicity and/or ototoxicity of neomycin (see boxed WARNINGS ).

Caution should also be taken in concurrent or serial use of other aminoglycosides and polymyxins because they may enhance neomycin’s nephrotoxicity and/or ototoxicity and potentiate neomycin sulfate’s neuromuscular blocking effects.

Oral neomycin inhibits the gastrointestinal absorption of penicillin V, oral vitamin B-12, methotrexate and 5-fluorouracil. The gastrointestinal absorption of digoxin also appears to be inhibited. Therefore, digoxin serum levels should be monitored.

Oral Elderm (Neomycin Sulfate) may enhance the effect of coumarin in anticoagulants by decreasing vitamin K availability.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No long-term animal studies have been performed with Elderm to evaluate carcinogenic or mutagenic potential or impairment of fertility.

Pregnancy Category D

See WARNINGS section.

Nursing Mothers

It is not known whether neomycin is excreted in human milk, but it has been shown to be excreted in cow milk following a single intramuscular injection. Other aminoglycosides have been shown to be excreted in human milk. Because of the potential for serious adverse reactions from the aminoglycosides in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

The safety and efficacy of oral Elderm (Neomycin Sulfate) in patients less than 18 years of age have not been established. If treatment of a patient less than 18 years of age is necessary, neomycin should be used with caution and the period of treatment should not exceed two weeks because of absorption from the gastrointestinal tract.

ADVERSE REACTIONS

The most common adverse reactions to oral Elderm (Neomycin Sulfate) are nausea, vomiting and diarrhea. The "Malabsorption Syndrome" characterized by increased fecal fat, decreased serum carotene and fall in xylose absorption has been reported with prolonged therapy. Nephrotoxicity, ototoxicity and neuromuscular blockage have been reported (see boxed WARNINGS and PRECAUTIONS sections).

OVERDOSAGE

Because of low absorption, it is unlikely that acute overdosage would occur with oral Elderm (Neomycin Sulfate). However, prolonged administration could result in sufficient systemic drug levels to produce neurotoxicity, ototoxicity and/or nephrotoxicity.

Hemodialysis will remove Elderm (Neomycin Sulfate) from the blood.

DOSAGE AND ADMINISTRATION

To minimize the risk of toxicity, use the lowest possible dose and the shortest possible treatment period to control the condition. Treatment for periods longer than two weeks is not recommended.

Hepatic Coma

For use as an adjunct in the management of hepatic coma, the recommended dose is 4 to 12 grams per day given in the following regimen:

• Withdraw protein from diet. Avoid use of diuretic agents.
• Give supportive therapy, including blood products, as indicated.
• Give Elderm (Neomycin Sulfate) tablets in doses of 4 to 12 grams of Elderm (Neomycin Sulfate) per day (eight to 24 tablets) in divided doses. Treatment should be continued over a period of five to six days, during which time protein should be returned incrementally to the diet.
• If less potentially toxic drugs cannot be used for chronic hepatic insufficiency, neomycin in doses of up to four grams daily (eight tablets per day) may be necessary. The risk for the development of neomycin-induced toxicity progressively increases when treatment must be extended to preserve the life of a patient with hepatic encephalopathy who has failed to fully respond. Frequent periodic monitoring of these patients to ascertain the presence of drug toxicity is mandatory (see PRECAUTIONS ). Also, neomycin serum concentrations should be monitored to avoid potentially toxic levels. The benefits to the patient should be weighed against the risks of nephrotoxicity, permanent ototoxicity and neuromuscular blockade following the accumulation of neomycin in the tissues.

Preoperative Prophylaxis for Elective Colorectal Surgery

Listed below is an example of a recommended bowel preparation regimen. A proposed surgery time of 8:00 a.m. has been used.

Pre-op Day 3: Minimum residue or clear liquid diet. Bisacodyl, 1 tablet orally at 6:00 p.m.

Pre-op Day 2: Minimum residue or clear liquid diet. Magnesium sulfate, 30 mL, 50% solution (15 g) orally at 10:00 a.m., 2:00 p.m., and 6:00 p.m. Enema at 7:00 p.m. and 8:00 p.m.

Pre-op Day 1: Clear liquid diet. Supplemental (IV) fluids as needed. Magnesium sulfate, 30 mL, 50% solution (15 g) orally at 10:00 a.m., and 2:00 p.m. Elderm (Neomycin Sulfate) (1 g) and erythromycin base (1 g) orally at 1:00 p.m., 2:00 p.m. and 11:00 p.m. No enema.

Day of Operation: Patient evacuates rectum at 6:30 a.m. for scheduled operation at 8:00 a.m.

HOW SUPPLIED

Elderm (Neomycin Sulfate) tablets USP, 500 mg (equivalent to 350 mg of neomycin base per tablet) are available as white to off-white, round, standard convex tablets debossed "LCI" on one side and "1210", on the other side and are supplied in:

Bottles of 100 (NDC 0527-1210-01)

Store at 20° to 25°C (68° to 77°F).

Dispense in tight containers as defined in the USP/NF.

Distributed By:

Lannett Company, Inc.

Philadelphia, PA 19154

Made in the USA

Rev. 01/17

CIB71710A