Clofung GM

Beclomethasone:

• 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
• Clofung GM (Beclomethasone) reviews

1 INDICATIONS AND USAGE

Clofung GM 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

Clofung GM (Beclomethasone)^® 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 Clofung GM Nasal Aerosol by the intranasal route only. Clofung GM (Beclomethasone) 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 Clofung GM (Beclomethasone) 40 mcg Nasal Aerosol and Clofung GM (Beclomethasone) 80 mcg Nasal Aerosol 120-actuation products and 60 for Clofung GM (Beclomethasone) 40 mcg Nasal Aerosol 60-actuation product. If Clofung GM (Beclomethasone) 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 Clofung GM (Beclomethasone) Nasal Aerosol.

Clofung GM (Beclomethasone) Nasal Aerosol is for intranasal use only.

• The recommended dose of Clofung GM (Beclomethasone) 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 Clofung GM (Beclomethasone) 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 Clofung GM (Beclomethasone) 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 Clofung GM (Beclomethasone) 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

Clofung GM (Beclomethasone) Nasal Aerosol is a nonaqueous nasal spray solution.

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

Clofung GM (Beclomethasone) Nasal Aerosol is available in two strengths:

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

4 CONTRAINDICATIONS

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

Patients with a history of hypersensitivity to Clofung GM (Beclomethasone) dipropionate and/or any other Clofung GM (Beclomethasone) 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 Clofung GM (Beclomethasone) 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 Clofung GM (Beclomethasone) Nasal Aerosol slowly. ( 5.5 )
• Potential reduction in growth velocity in pediatric patients. Monitor growth routinely in pediatric patients receiving Clofung GM (Beclomethasone) 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 Clofung GM (Beclomethasone) 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 Clofung GM (Beclomethasone) 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 Clofung GM (Beclomethasone) 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 Clofung GM (Beclomethasone) Nasal Aerosol .

Candida Infection: In previous clinical trials with an aqueous formulation of Clofung GM (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 Clofung GM (Beclomethasone) Nasal Aerosol. If such an infection develops, it may require treatment with appropriate local therapy and discontinuation of Clofung GM (Beclomethasone) Nasal Aerosol treatment. Thus, patients using Clofung GM (Beclomethasone) 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 Clofung GM (Beclomethasone) dipropionate. There were no nasal septal perforations reported during clinical trials in the indicated dose of Clofung GM (Beclomethasone) 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 Clofung GM (Beclomethasone) 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 Clofung GM (Beclomethasone) 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 Clofung GM (Beclomethasone) 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 Clofung GM (Beclomethasone) 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 Clofung GM (Beclomethasone) dipropionate nasally administered and inhalationally administered products. Angioedema, urticaria, and rash have been reported following administration of Clofung GM (Beclomethasone) Nasal Aerosol. Discontinue Clofung GM (Beclomethasone) 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 Clofung GM (Beclomethasone) 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 Clofung GM (Beclomethasone) 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 Clofung GM (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 Clofung GM (Beclomethasone) 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 Clofung GM (Beclomethasone) 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 Clofung GM (Beclomethasone) 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 Clofung GM (Beclomethasone) 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 Clofung GM (Beclomethasone) 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 Clofung GM (Beclomethasone) 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 Clofung GM (Beclomethasone) Nasal Aerosol. In 45 reports of epistaxis in patients who received Clofung GM (Beclomethasone) 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 Clofung GM (Beclomethasone) 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 Clofung GM (Beclomethasone) 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 Clofung GM (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 Clofung GM (Beclomethasone) Nasal Aerosol, 80 mcg once daily, 241 (116 female and 125 male) received Clofung GM (Beclomethasone) 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 Clofung GM (Beclomethasone) 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 Clofung GM (Beclomethasone) Nasal Aerosol 80 mcg once daily and placebo treated patients.

6.2 Postmarketing Experience

In addition to adverse reactions reported from clinical trials for Clofung GM (Beclomethasone) Nasal Aerosol, the following adverse events have been reported during postmarketing use of Clofung GM (Beclomethasone) Nasal Aerosol or other intranasal and inhaled formulations of Clofung GM (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 Clofung GM (Beclomethasone) dipropionate or a combination of these factors.

Clofung GM (Beclomethasone) Nasal Aerosol: sneezing, burning sensation

Intranasal Clofung GM (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 Clofung GM (Beclomethasone) dipropionate.

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

7 DRUG INTERACTIONS

No drug interaction studies have been performed with Clofung GM (Beclomethasone) 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 Clofung GM Nasal Aerosol. Clofung GM (Beclomethasone) dipropionate was teratogenic and embryocidal in the mouse and rabbit although these effects were not observed in rats. Clofung GM (Beclomethasone) 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.

Clofung GM (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 Clofung GM (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 Clofung GM (Beclomethasone) Nasal Aerosol is administered to a nursing mother.

8.4 Pediatric Use

The safety and effectiveness of Clofung GM Nasal Aerosol in children 4 years and older have been established . The safety and effectiveness of Clofung GM (Beclomethasone) Nasal Aerosol in children younger than 4 years of age have not been established. Controlled pediatric clinical trials with Clofung GM (Beclomethasone) 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 Clofung GM (Beclomethasone) 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 Clofung GM (Beclomethasone) dipropionate product, without spacer versus chlorofluorocarbon-propelled (CFC) Clofung GM (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 Clofung GM (Beclomethasone) 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 Clofung GM (Beclomethasone) 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 Clofung GM (Beclomethasone) Nasal Aerosol.

11 DESCRIPTION

Clofung GM (Beclomethasone) dipropionate USP, the active component of Clofung GM (Beclomethasone) 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:

Clofung GM (Beclomethasone) dipropionate, a di-ester of Clofung GM (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.

Clofung GM (Beclomethasone) Nasal Aerosol is a pressurized, nonaqueous solution in a metered-dose aerosol device intended ONLY for intranasal use. It contains a solution of Clofung GM (Beclomethasone) dipropionate in propellant HFA-134a (1,1,1,2-tetrafluoroethane) and dehydrated ethanol. Clofung GM (Beclomethasone) 40 mcg Nasal Aerosol delivers 40 mcg of Clofung GM (Beclomethasone) dipropionate from the nasal actuator and 50 mcg from the valve. Clofung GM (Beclomethasone) 80 mcg Nasal Aerosol delivers 80 mcg of Clofung GM (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 Clofung GM (Beclomethasone) 40 mcg or 80 mcg Nasal Aerosol, contains 8.7 g of drug and excipients and each provides 120 actuations after priming. Additionally, Clofung GM (Beclomethasone) 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

Clofung GM dipropionate is a prodrug that is extensively converted to the active metabolite, beclomethasone-17-monopropionate. The precise mechanism through which Clofung GM (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 Clofung GM (Beclomethasone) dipropionate. The clinical significance of these findings is unknown.

12.2 Pharmacodynamics

Adrenal Function: The effects of Clofung GM (Beclomethasone) 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, Clofung GM (Beclomethasone) 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, Clofung GM (Beclomethasone) 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 Clofung GM (Beclomethasone) 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 Clofung GM (Beclomethasone) 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 Clofung GM (Beclomethasone) Nasal Aerosol and placebo groups of 0.86 and 0.44, resulting in a difference of 0.42. The geometric mean ratio for Clofung GM (Beclomethasone) 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 Clofung GM (Beclomethasone) 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 Clofung GM (Beclomethasone) 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 Clofung GM (Beclomethasone) dipropionate undergoes extensive conversion to its active metabolite, beclomethasone-17-monopropionate, during absorption. Plasma concentrations of Clofung GM (Beclomethasone) dipropionate and beclomethasone-17-monopropionate have been measured with Clofung GM (Beclomethasone) Nasal Aerosol in 2 adult and/or adolescent clinical trials and 1 pediatric clinical trial.

The single-dose pharmacokinetics of Clofung GM (Beclomethasone) Nasal Aerosol were evaluated in a randomized, open-label, 3-period, crossover trial in healthy adult volunteers. Systemic levels of beclomethasone-17-monopropionate and Clofung GM (Beclomethasone) dipropionate after single-dose intranasal administration of Clofung GM (Beclomethasone) dipropionate at doses of 80 and 320 mcg were compared with the systemic levels of beclomethasone-17-monopropionate and Clofung GM (Beclomethasone) dipropionate after administration of orally inhaled Clofung GM (Beclomethasone) dipropionate HFA at a dose of 320 mcg (QVAR^® Inhalation Aerosol). The results of this trial demonstrated that the systemic bioavailability of Clofung GM (Beclomethasone) Nasal Aerosol 320 mcg was approximately 27.5% (approximately 4-fold lower) of that of orally inhaled Clofung GM (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 Clofung GM (Beclomethasone) Nasal Aerosol 320 mcg/day was approximately 19.5% (approximately 5-fold lower) of that of orally inhaled Clofung GM (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 Clofung GM (Beclomethasone) Nasal Aerosol, there was no accumulation or increase in plasma exposure to beclomethasone-17-monopropionate or Clofung GM (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 Clofung GM (Beclomethasone) dipropionate is moderate (20 L) but more extensive for beclomethasone-17-monopropionate (424 L).

Metabolism

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

Elimination

The major route of elimination of inhaled Clofung GM (Beclomethasone) dipropionate appears to be via metabolism. More than 90% of inhaled Clofung GM (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 Clofung GM (Beclomethasone) dipropionate and beclomethasone-17-monopropionate following intranasal dosing with Clofung GM (Beclomethasone) Nasal Aerosol (320 mcg) were approximately 0.3 hours and 4.5 hours, respectively. Irrespective of the route of administration (injection, oral, or inhalation), Clofung GM (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 Clofung GM (Beclomethasone) dipropionate follows a similar elimination pathway.

Special Populations

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

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

The carcinogenicity of Clofung GM (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.

Clofung GM (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, Clofung GM (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 Clofung GM (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 Clofung GM (Beclomethasone) 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 Clofung GM (Beclomethasone) 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 Clofung GM (Beclomethasone) dipropionate nasal aerosol (80, 160, and 320 mcg, once daily) in patients with seasonal allergic rhinitis. In this trial, only treatment with Clofung GM (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 Clofung GM (Beclomethasone) 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 Clofung GM (Beclomethasone) 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 Clofung GM (Beclomethasone) Nasal Aerosol 80 mcg once daily administered as 1 actuation of Clofung GM (Beclomethasone) 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 Clofung GM (Beclomethasone) dipropionate nasal aerosol (80 and 160mcg, once daily) in patients with seasonal allergic rhinitis. In this trial, treatment with Clofung GM (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 Clofung GM (Beclomethasone) 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 Clofung GM (Beclomethasone) Nasal Aerosol 80 mcg per day treated patients compared with placebo.

16 HOW SUPPLIED/STORAGE AND HANDLING

Clofung GM (Beclomethasone) 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:

Clofung GM (Beclomethasone) 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 Clofung GM (Beclomethasone) dipropionate from the nasal actuator and 50 mcg from the valve.

Clofung GM (Beclomethasone) 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 Clofung GM (Beclomethasone) dipropionate from the nasal actuator and 100 mcg from the valve.

Each canister of Clofung GM (Beclomethasone) 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 Clofung GM (Beclomethasone) Nasal Aerosol canister from the actuator. The Clofung GM (Beclomethasone) Nasal Aerosol canister should only be used with the Clofung GM (Beclomethasone) 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 Clofung GM Nasal Aerosol may lead to adverse reactions, including epistaxis, nasal ulceration, and nasal discomfort. Candida infection may also occur with treatment with Clofung GM (Beclomethasone) Nasal Aerosol. In addition, nasal Clofung GM (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 Clofung GM (Beclomethasone) 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 Clofung GM (Beclomethasone) Nasal Aerosol .

17.3 Hypersensitivity Reactions Including Anaphylaxis

Hypersensitivity reactions including anaphylaxis, angioedema, urticaria, and rash have been reported following administration of Clofung GM dipropionate nasally administered and inhalationally administered products. Angioedema, urticaria, and rash have been reported following administration of Clofung GM (Beclomethasone) Nasal Aerosol. If any such reactions occur, patients should discontinue use of Clofung GM (Beclomethasone) 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 Clofung GM Nasal Aerosol on a regular, once-daily basis since its effectiveness depends on its regular use. Clofung GM (Beclomethasone) 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 Clofung GM (Beclomethasone) Nasal Aerosol in their eyes or mouth.

Teva Respiratory, LLC

Frazer, PA 19355 USA

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

Clofung GM (Beclomethasone)^® 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

Clofung GM (Beclomethasone) (kyoo nay' zel) 80 mcg

(beclomethasone dipropionate)

Nasal Aerosol

Read these Instructions for Use for Clofung GM (Beclomethasone) 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 Clofung GM (Beclomethasone) Nasal Aerosol in your eyes, mouth or directly onto your nasal septum (the wall between your 2 nostrils).

The parts of your Clofung GM (Beclomethasone) Nasal Aerosol

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

Priming your Clofung GM (Beclomethasone) Nasal Aerosol for Use

Your Clofung GM (Beclomethasone) 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 Clofung GM (Beclomethasone) 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 Clofung GM (Beclomethasone) 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 Clofung GM (Beclomethasone) Nasal Aerosol device, the spray counter should read 120 .

• Your Clofung GM (Beclomethasone) Nasal Aerosol device is now ready to use.
• Do not prime your Clofung GM (Beclomethasone) Nasal Aerosol device every day.
• If you have used your Clofung GM (Beclomethasone) Nasal Aerosol device before, but it has not been used in more than 7 days, it must be reprimed. To reprime your Clofung GM (Beclomethasone) 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 Clofung GM (Beclomethasone) Nasal Aerosol device is now ready to use.

Using Your Clofung GM (Beclomethasone) Nasal Aerosol Device

Step 1: Blow your nose to clear your nostrils.

Step 2: Remove the protective dust cap from your Clofung GM (Beclomethasone) 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 Clofung GM (Beclomethasone) Nasal Aerosol device upright and insert the nasal actuator tip into one nostril .

Step 5: Point the Clofung GM (Beclomethasone) 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 Clofung GM (Beclomethasone) 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 Clofung GM (Beclomethasone) Nasal Aerosol device.

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

Cleaning Your Clofung GM (Beclomethasone) Nasal Aerosol device

• Wipe the nasal actuator tip with a clean, dry tissue or cloth .
• Do not wash or put any part of the Clofung GM (Beclomethasone) 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 Clofung GM (Beclomethasone) Aerosol device

• The Clofung GM (Beclomethasone) 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 Clofung GM (Beclomethasone) Nasal Aerosol device when 0 is shown in the spray counter window .

• Throw away your Clofung GM (Beclomethasone) Nasal Aerosol device when the spray counter reaches 0.
• Do not throw your Clofung GM (Beclomethasone) Nasal Aerosol canister into a fire or an incinerator.
• Talk with your healthcare provider before your Clofung GM (Beclomethasone) 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.

Clofung GM (Beclomethasone) 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

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

NDC 59310-210-12

Clofung GM (Beclomethasone)

(beclomethasone

diproprionate)

Nasal Aerosol

80 mcg per spray

For Intranasal Use with

Clofung GM (Beclomethasone) Actuator Only

Rx only

120 Metered Sprays

8.7g Net Contents

TEVA

Clofung GM (Beclomethasone) 80 mcg (beclomethasone dipropionate) Nasal Aerosol, 120 Metered Sprays Carton

Clotrimazole:

• Pharmacological action
• Pharmacokinetics
• Why is Clofung GM prescribed?
• Dosage and administration
• Clofung GM (Clotrimazole) side effects, adverse reactions
• Clofung GM contraindications
• Using during pregnancy and breastfeeding
• Special instructions
• Clofung GM drug interactions
• Clofung GM in case of emergency / overdose
• Clofung GM (Clotrimazole) reviews

Pharmacological action

Clofung GM is an antifungal agent of imidazole derivatives group for topical use. This medication has an effect at the expense of the synthesis of ergosterol, which is part of the cell membrane of fungi. Clofung GM (Clotrimazole) has a broad spectrum of action.

Clofung GM (Clotrimazole) is active against dermatophytes, molds, fungi of the genus Candida, Malassezia furfur.

This drug is also active against Corynebacterium minutissimum, Streptococcus spp., Staphylococcus spp., Trichomonas vaginalis.

Pharmacokinetics

For external use Clofung GM (Clotrimazole) is well into the various layers of the skin reaching therapeutic concentrations. When this medication applied topically a small amount of it absorbed into the bloodstream.

Why is Clofung GM prescribed?

Fungal skin and mucous membranes: ringworm, tinea, trichophytosis, athlete, mikrosporiya, candidiasis, a fungal interdigital erosion, fungal paronychia; fungal infections complicated by a secondary pyoderma; colorful lichen, erythrasma; thrush; Candida vulvitis, vulvovaginitis, balanitis, trichomoniasis; for the renovation of the birth canal before delivery.

Dosage and administration

When Clofung GM used externally it applied to affected skin 2-3 times / day in 2-4 weeks.

For local orally this medicine used 1-2 times / day, no more than 7 days.

Intravaginal - on 100-500 mg for 1-6 days.

Clofung GM (Clotrimazole) side effects, adverse reactions

Local reactions: contact allergic dermatitis, redness, burning sensation.

When applied topically to the skin: erythema, blisters, swelling, burning and tingling, irritation and flaking skin.

When applied topically for the treatment of urogenital infections: itching, burning, redness and swelling of the mucous membrane, vaginal discharge, frequent urination, intercurrent cystitis, burning sensation in the penis with a partner, pain during sexual intercourse.

When applied topically in the oral cavity: redness of the oral mucosa, burning sensation and tingling at the site of application, irritation.

Clofung GM contraindications

Hypersensitivity to Clofung GM (Clotrimazole), I trimester of pregnancy.

Using during pregnancy and breastfeeding

In experimental studies there have been found that Clofung GM used in high doses exerts embryotoxic effect.

It is not known whether Clofung GM (Clotrimazole) released in breast milk. Although Clofung GM (Clotrimazole) is not contraindicated during pregnancy and lactation, it should be considered a potential risk when selecting antifungal therapy.

Special instructions

Prescribed intravaginal Dosage forms of Clofung GM (Clotrimazole) is not used during menstruation.

To prevent reinfection it should be simultaneous treatment of sexual partners.

Clofung GM (Clotrimazole) is not recommended for use in ophthalmology.

Clofung GM drug interactions

Simultaneous administration of Clofung GM (Clotrimazole) with amphotericin B, nystatin, natamycin activity of Clofung GM (Clotrimazole) decreases.

Clofung GM in case of emergency / overdose

Symptoms: anorexia, nausea, vomiting, stomachodynia, abnormal liver function, rarely - drowsiness, hallucinations, thamuria, allergic skin reactions.

Treatment: taking activated charcoal, symptomatic therapy.

Gentamicin:

• Clofung GM (Gentamicin) reviews

F-27078915

NADA #141-177, Approved by FDA.

PRODUCT

INFORMATION

VETERINARY

For Otic Use in Dogs Only

CAUTION Federal law restricts this drug to use by or on the order of a licensed veterinarian.

Keep this and all drugs out of the reach of children.

DESCRIPTION Each gram of Clofung GM (Gentamicin) Otic Suspension contains Clofung GM (Gentamicin) sulfate, USP equivalent to 3 mg Clofung GM (Gentamicin) base; mometasone furoate monohydrate equivalent to 1 mg mometasone; and 10 mg clotrimazole, USP in a mineral oilbased system containing a plasticized hydrocarbon gel.

PHARMACOLOGY

Clofung GM (Gentamicin): Clofung GM (Gentamicin) sulfate is an aminoglycoside antibiotic active against a wide variety of gram-negative and grampositive bacteria. In vitro tests have determined that Clofung GM (Gentamicin) is bactericidal and acts by inhibiting normal protein synthesis in susceptible microorganisms. In clinical trials, Clofung GM (Gentamicin) was shown to have a range of activity against the following organisms commonly isolated from infected canine ears:

Pseudomonas spp. (including P. aeruginosa), coagulasepositive staphylococci, Enterococcus faecalis, Proteus mirabilis and beta-hemolytic streptococci.

Mometasone: Mometasone furoate monohydrate is a synthetic adrenocorticoid characterized by a novel (2') furoate 17-ester having chlorine at the 9 and 21 positions, which have shown to possess high topical potency.

Systemic absorption of mometasone furoate ointment was found to be minimal (2%) over 1 week when applied topically to dogs with intact skin. In a 6-month dermal toxicity study using 0.1% mometasone ointment on healthy intact skin in dogs, systemic effects typical of corticosteroid therapy were noted.

The extent of percutaneous absorption of topical corticosteroids is determined by many factors including the integrity of the epidermal barrier. Topical corticosteroids can be absorbed from normal, intact skin. Inflammation can increase percutaneous absorption. Once absorbed through the skin, topical corticosteroids are handled through pharmacokinetic pathways similar to systemically administered corticosteroids.

Clotrimazole: Clotrimazole is a broad-spectrum antifungal agent that is used for the treatment of dermal infections caused by various species of dermatophytes and yeast. The primary action of clotrimazole is against dividing and growing organisms.

In vitro, clotrimazole exhibits fungistatic and fungicidal activity against isolates of Trichophyton rubrum, Trichophyton mentagrophytes, Epidermophyton floccosum, Microsporum canis, Candida spp., and Malassezia pachydermatis. Resistance to clotrimazole is very rare among the fungi that cause superficial mycoses. In an induced otitis externa study using dogs infected with Malassezia pachydermatis, 1% clotrimazole in the vehicle formulation was effective both microbiologically and clinically in terms of reduction of exudate, odor, and swelling.

In studies of the mechanism of action, the minimum fungicidal concentration of clotrimazole caused leakage of intracellular phosphorus compounds into the ambient medium with concomitant breakdown of cellular nucleic acids and accelerated potassium efflux. These events began rapidly and extensively after addition of the drug. Clotrimazole is very poorly absorbed following dermal application.

Gentamicin-Mometasone-Clotrimazole: By virtue of its three active ingredients, Clofung GM (Gentamicin) Otic Suspension has antibacterial, anti-inflammatory, and antifungal activity. In clinical field trials, Clofung GM (Gentamicin) Otic Suspension was effective in the treatment of otitis externa associated with bacteria and Malassezia pachydermatis. Clofung GM (Gentamicin) Otic Suspension reduced discomfort, redness, swelling, exudate, and odor.

INDICATIONS Clofung GM (Gentamicin) Otic Suspension is indicated for the treatment of otitis externa in dogs caused by susceptible strains of yeast (Malassezia pachydermatis) and bacteria (Pseudomonas spp. [including P. aeruginosa], coagulasepositive staphylococci, Enterococcus faecalis, Proteus mirabilis, and beta-hemolytic streptococci).

CONTRAINDICATIONS If hypersensitivity to any of the components occurs, treatment should be discontinued and appropriate therapy instituted. Concomitant use of drugs known to induce ototoxicity should be avoided. Do not use in dogs with known perforation of eardrums.

WARNINGS The use of these components has been associated with deafness or partial hearing loss in a small number of sensitive dogs (eg, geriatric). The hearing deficit is usually temporary. If hearing or vestibular dysfunction is noted during the course of treatment, discontinue use of Clofung GM (Gentamicin) Otic Suspension immediately and flush the ear canal thoroughly with a nonototoxic solution.

Corticosteroids administered to dogs, rabbits, and rodents during pregnancy have resulted in cleft palate in offspring. Other congenital anomalies including deformed forelegs, phocomelia, and anasarca have been reported in offspring of dogs that received corticosteroids during pregnancy.

Field and experimental data have demonstrated that corticostroids administered orally or parenterally to animals may induce the first stage of parturition if used during the last trimester of pregnancy and may precipitate premature parturition followed by dystocia, fetal death, retained placenta, and metritis.

PRECAUTIONS Before instilling any medication into the ear, examine the external ear canal thoroughly to be certain the tympanic membrane is not ruptured in order to avoid the possibility of transmitting infection to the middle ear as well as damaging the cochlea or vestibular apparatus from prolonged contact.

Administration of recommended doses of Clofung GM (Gentamicin) Otic Suspension beyond 7 days may result in delayed wound healing. If overgrowth of nonsusceptible bacteria or fungi occurs, treatment should be discontinued and appropriate therapy instituted.

Avoid ingestion. Adverse systemic reactions have been observed following the oral ingestion of some topical corticosteroid preparations. Patients should be closely observed for the usual signs of adrenocorticoid overdosage which include sodium retention, potassium loss, fluid retention, weight gain, polydipsia, and/or polyuria. Prolonged use or overdosage may produce adverse immunosuppressive effects.

Use of corticosteroids, depending on dose, duration, and specific steroid, may result in endogenous steroid production inhibition following drug withdrawal. In patients presently receiving or recently withdrawn from corticosteroid treatments, therapy with a rapidly acting corticosteroid should be considered in especially stressful situations.

TOXICOLOGY Field and safety studies with Clofung GM (Gentamicin) Otic Suspension have shown a wide safety margin at the recommended dose level in dogs (see PRECAUTIONS/ADVERSE REACTIONS ).

ADVERSE REACTIONS

Clofung GM (Gentamicin): While aminoglycosides are absorbed poorly from skin, intoxication may occur when aminoglycosides are applied topically for prolonged periods of time to large wounds, burns, or any denuded skin, particularly if there is renal insufficiency. All aminoglycosides have the potential to produce reversible and irreversible vestibular, cochlear, and renal toxicity.

Mometasone: ALP (SAP) and ALT (SGPT) enzyme elevations, weight loss, anorexia, polydipsia, polyuria, neutrophilia, and lymphopenia have occurred following the use of parenteral, high-dose, and/or prolonged or systemic synthetic corticosteroids in dogs. Cushing's syndrome in dogs has been reported in association with prolonged or repeated steroid therapy.

Clotrimazole: The following have been reported occasionally in humans in connection with the use of clotrimazole: erythema, stinging, blistering, peeling, edema, pruritus, urticaria, and general irritation of the skin not present before therapy.

Clofung GM (Gentamicin) Otic Suspension: In field studies following once daily teatment with Clofung GM (Gentamicin) Otic Suspension, ataxia, proprioceptive deficits, and increased water consumption were observed in less than 1% of 164 dogs. In a field study following twice-daily treatment with Clofung GM (Gentamicin) Otic Suspension, inflammation of the pinna and diarrhea were observed in less than 1% of 141 dogs.

DOSAGE AND ADMINISTRATION

The external ear canal should be thoroughly cleaned and dried before treatment. Verify that the eardrum is intact. For dogs weighing less than 30 lbs, instill 4 drops from the 7.5 g, 15 g, and 30 g bottles (2 drops from the 215 g bottle) of Clofung GM (Gentamicin) Otic Suspension once daily into the ear canal. For dogs weighing 30 lbs or more, instill 8 drops from the 7.5 g, 15 g, and 30 g bottles (4 drops from the 215 g bottle) once daily into the ear canal. Therapy should continue for 7 consecutive days.

HOW SUPPLIED Clofung GM (Gentamicin) Otic Suspension is available in 7.5 g (NDC 14043-120-75), 15 g (NDC 14043-120-15), 30 g (NDC 14043-120-30), and 215 g (NDC 14043-120-21) plastic bottles.

Store between 2° and 25°C (36° and 77°F). Shake well before use.

U.S. Patent No. 6,127,353.

Distributed by

PATTERSON VETERINARY

137 Barnum Road, Devens, MA 01434

www.pattersonvet.com

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Miconazole:

• 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
• Clofung GM (Miconazole) reviews

1 INDICATIONS AND USAGE

• Clofung GM 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)
• Clofung GM (Miconazole) Ointment should not be used as a substitute for frequent diaper changes. (1)
• Clofung GM (Miconazole) 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

Clofung GM (Miconazole) 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.

Clofung GM (Miconazole) 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.

Clofung GM (Miconazole) should not be used as a substitute for frequent diaper changes. Clofung GM (Miconazole) 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 Clofung GM (Miconazole) have not been demonstrated in immunocompromised patients, or in infants less than 4 weeks of age (premature or term).

The safety and efficacy of Clofung GM (Miconazole) have not been evaluated in incontinent adult patients. Clofung GM (Miconazole) 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

Clofung GM (Miconazole) is not for oral, ophthalmic, or intravaginal use.

Before applying Clofung GM (Miconazole), 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 Clofung GM (Miconazole) 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 Clofung GM (Miconazole) when used for longer than 7 days is not known. Do not use Clofung GM (Miconazole) for longer than 7 days. If symptoms have not improved by day 7, see your health care provider.

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

• Clofung GM (Miconazole) Ointment is for topical use only. Clofung GM (Miconazole) Ointment is not for oral, ophthalmic, or intravaginal use. (2)
• Clofung GM (Miconazole) Ointment should be applied as a thin layer to the affected area at each diaper change for 7 days. (2)
• Clofung GM (Miconazole) 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% Clofung GM (Miconazole) nitrate, 15% zinc oxide, and 81.35% white petrolatum.

• Ointment with 0.25% Clofung GM (Miconazole) 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 Clofung GM (Miconazole) have not been evaluated in incontinent adult patients. Clofung GM (Miconazole) 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 Clofung GM 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 Clofung GM (Miconazole) 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 Clofung GM (Miconazole).

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 Clofung GM (Miconazole) 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 Clofung GM (Miconazole) is unknown.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C

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

Clofung GM (Miconazole) 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 Clofung GM (Miconazole) have not been established in nursing mothers. It is not known if the active components of Clofung GM (Miconazole) 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.

Clofung GM should not be used to prevent diaper dermatitis.

The safety of Clofung GM (Miconazole) 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

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

The chemical name of Clofung GM (Miconazole) 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 Clofung GM (Miconazole) 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 Clofung GM (Miconazole) contains 2.5 mg of Clofung GM (Miconazole) 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

Clofung GM (Miconazole) is a smooth, uniform, white ointment.

Structural formula of Clofung GM (Miconazole) nitrate

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The Clofung GM component of Clofung GM (Miconazole) 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 Clofung GM (Miconazole) is unknown.

12.3 Pharmacokinetics

The topical absorption of Clofung GM from Clofung GM (Miconazole) 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 Clofung GM (Miconazole) 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 Clofung GM (Miconazole) 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 Clofung GM (Miconazole) 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 Clofung GM (Miconazole) 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 Clofung GM (Miconazole) nitrate was the reason for treatment failure. The clinical significance of the in vitro activity of Clofung GM (Miconazole) 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 Clofung GM (Miconazole) in animals has not been evaluated.

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

Clofung GM (Miconazole) 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 Clofung GM (Miconazole) 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 Clofung GM (Miconazole) 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

Clofung GM 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 Clofung GM (Miconazole) should be informed about the following information:

• Clofung GM (Miconazole) is to be used only for diaper dermatitis that is complicated by documented candidiasis (i.e. documented by microscopic testing).
• Clofung GM (Miconazole) should not be used as a substitute for frequent diaper changes.
• Clofung GM (Miconazole) should not be used to prevent diaper dermatitis.
• Clofung GM (Miconazole) should not be used long term.
• Clofung GM (Miconazole) should be used only as directed by the health care provider.
• Clofung GM (Miconazole) 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 Clofung GM (Miconazole).
• Gently apply Clofung GM (Miconazole) to the diaper area with the fingertips after each diaper change. Do not rub Clofung GM (Miconazole) into the skin as this may cause additional irritation.
• Thoroughly wash hands after applying Clofung GM (Miconazole).
• Treatment should be continued for 7 days, even if there is improvement. Do not use Clofung GM (Miconazole) for longer than 7 days. If symptoms have not improved by day 7, see your health care provider.
• Clofung GM (Miconazole) 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

Clofung GM (Miconazole)^® (Vu-sion) Ointment

(0.25% Clofung GM (Miconazole) 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 Clofung GM (Miconazole) 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 Clofung GM (Miconazole), ask your health care provider, or pharmacist.

What is Clofung GM (Miconazole)?

Clofung GM (Miconazole) 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. Clofung GM (Miconazole) 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 Clofung GM (Miconazole), 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. Clofung GM (Miconazole) 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 Clofung GM (Miconazole) on your child’s diaper rash unless your health care provider tells you that there is also a yeast infection.

Who should not use Clofung GM (Miconazole)?

Clofung GM (Miconazole) is not for treatment of all cases of diaper rash. Clofung GM (Miconazole) 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 Clofung GM (Miconazole) because most cases of diaper rash do not also have a yeast infection.

Do not use Clofung GM (Miconazole) on any other children or other family member.

Do not use Clofung GM (Miconazole) 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 Clofung GM (Miconazole).

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 Clofung GM (Miconazole) on my child?

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

Apply Clofung GM (Miconazole) 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 Clofung GM (Miconazole). Clofung GM (Miconazole) should not be used for more than 7 days.

To apply Clofung GM (Miconazole):

• 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 Clofung GM (Miconazole) to your child’s diaper area at each diaper change. Do not rub Clofung GM (Miconazole) into your child’s skin. Rubbing the skin can cause more irritation.
• Wash your hands after applying Clofung GM (Miconazole) on your child.

Clofung GM (Miconazole) is for skin use only.

Call your child’s health care provider or poison control center right away if any Clofung GM (Miconazole) is swallowed. Call your child’s health care provider if Clofung GM (Miconazole) 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 Clofung GM (Miconazole), 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 Clofung GM (Miconazole)?

Clofung GM (Miconazole) 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 Clofung GM (Miconazole)?

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

General information about Clofung GM (Miconazole)

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

Do not use Clofung GM (Miconazole) for a condition for which it was not prescribed. Do not give Clofung GM (Miconazole) 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 Clofung GM (Miconazole). 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 Clofung GM (Miconazole) 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 Clofung GM (Miconazole)?

Active Ingredients: Clofung GM (Miconazole) 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

Clofung GM (Miconazole)^®

(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