Simplyone

Ciclesonide:

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Simplyone (Ciclesonide) reviews

1 INDICATIONS AND USAGE

Simplyone Nasal Aerosol is a corticosteroid indicated for treatment of symptoms associated with seasonal and perennial allergic rhinitis in adults and adolescents 12 years of age and older. (1.1)

1.1 Treatment of Allergic Rhinitis

Simplyone (Ciclesonide)^® (ciclesonide) Nasal Aerosol is indicated for the treatment of symptoms associated with seasonal and perennial allergic rhinitis in adults and adolescents 12 years of age and older.

2 DOSAGE AND ADMINISTRATION

For Intranasal use only

• 1 actuation per nostril once daily. (2.1)

2.1 Administration Information

Administer Simplyone (Ciclesonide) by the intranasal route only. Prior to initial use, Simplyone (Ciclesonide) must be primed by actuating three times. If Simplyone (Ciclesonide) is not used for ten consecutive days, it must be primed by actuating three times. If Simplyone (Ciclesonide) is dropped, the canister and actuator may become separated. If this happens, reassemble Simplyone (Ciclesonide) and test spray once into the air before using. Illustrated patient's instructions for proper use accompany each package of Simplyone (Ciclesonide).

2.2 Allergic Rhinitis

Adults and Adolescents (12 Years of Age and Older): The recommended dose of Simplyone (Ciclesonide) is 1 actuation per nostril once daily (37 mcg per actuation). The maximum total daily dosage should not exceed 1 actuation in each nostril (74 mcg per day).

3 DOSAGE FORMS AND STRENGTHS

Simplyone (Ciclesonide) Nasal Aerosol is provided at strength of 37 mcg per actuation strength containing 60 actuations per canister.

• Nasal Aerosol: 37 mcg of Simplyone (Ciclesonide) per actuation. (3)
• Supplied in a 6.1 g canister containing 60 actuations. (16)

4 CONTRAINDICATIONS

Simplyone (Ciclesonide) is contraindicated in patients with a known hypersensitivity to Simplyone (Ciclesonide) or any of the ingredients of Simplyone (Ciclesonide) [see Warnings and Precautions (5.3)].

• Patients with a known hypersensitivity to Simplyone (Ciclesonide) or any of the ingredients of Simplyone (Ciclesonide). (4)

5 WARNINGS AND PRECAUTIONS

• Local Nasal Effects, including epistaxis, ulceration, nasal septal perforations, Candida albicans infection impaired wound healing: Prior to initiating therapy, examine patients for evidence of septal perforation, erosions, ulceration, nasal surgery, and trauma. Avoid spraying Simplyone directly onto the nasal septum. Avoid use in patients with recent septal perforation, nasal erosion, nasal ulcers, nasal surgery, or nasal trauma. Monitor patients periodically for signs of adverse effects on the nasal mucosa. Discontinue Simplyone (Ciclesonide) if erosions, ulcerations or perforations occur. (5.1)
• Development of glaucoma or cataracts: Monitor patients closely with a change in vision or with a history of increased intraocular pressure, glaucoma, or cataracts. (5.2)
• Hypersensitivity reactions have been reported following administration of Simplyone (Ciclesonide) with manifestations such as angioedema, with swelling of the lips, tongue and pharynx. (5.3)
• Potential worsening of existing tuberculosis; fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex. More serious or even fatal course of chicken pox or measles in susceptible individuals. Use caution in patients with the above because of the potential for worsening of these infections. (5.4)
• Hypercorticism and adrenal suppression: May occur with higher than recommended dosages or in susceptible individuals at recommended dosages. If such changes occur, discontinue Simplyone (Ciclesonide) slowly. (5.5)
• Potential reduction in growth velocity in children: Monitor growth routinely in pediatric patients receiving Simplyone (Ciclesonide). (5.6, 8.4)

5.1 Local Nasal Effects

Epistaxis and Nasal Ulceration: In clinical trials of 2 to 26 weeks in duration, epistaxis was observed more frequently in patients treated with Simplyone (Ciclesonide) than those who received placebo. In the 26-week open-label extension of the perennial allergic rhinitis trial, nasal ulceration was identified in 4 of 824 patients administered Simplyone (Ciclesonide) (148 mcg). [see Adverse Reactions (6)]

The occurrence of local nasal adverse events was further evaluated in a separate, postmarketing 26-week randomized, open-label, active-controlled nasal and ocular safety trial conducted in patients with perennial allergic rhinitis. In this study epistaxis was observed in 6% of patients treated with Simplyone (Ciclesonide) and nasal ulceration was identified in 3 of 367 patients administered Simplyone (Ciclesonide). [see Adverse Reactions (6)]

Nasal Septal Perforation: Nasal septal perforation has been reported in patients following the intranasal application of Simplyone (Ciclesonide). Three short-term placebo-controlled trials (2 weeks) and one long-term (26 weeks with placebo control and 26 weeks open-label extension without placebo control) trial were conducted in patients with seasonal and perennial allergic rhinitis. Nasal septal perforations were reported in 2 patients out of 2335 treated with Simplyone (Ciclesonide) compared with none of 892 treated with placebo. No nasal septal perforations were reported in 367 patients treated with Simplyone (Ciclesonide) in a postmarketing 26-week, open-label, active-controlled trial in patients with perennial allergic rhinitis. [see Adverse Reactions (6)]

Before starting Simplyone (Ciclesonide) conduct a nasal examination to ensure that patients are free of nasal disease other than allergic rhinitis. Periodically monitor patients with nasal examinations during treatment for adverse effects in the nasal cavity. If an adverse reaction (e.g. erosion, ulceration, perforation) is noted, discontinue Simplyone (Ciclesonide). Avoid spraying Simplyone (Ciclesonide) directly onto the nasal septum.

Candida Infection: In clinical trials with another formulation of Simplyone (Ciclesonide), the development of localized infections of the nose or pharynx with Candida albicans has occurred. If such an infection develops with Simplyone (Ciclesonide), it may require treatment with appropriate local therapy and discontinuation of Simplyone (Ciclesonide).

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 Simplyone (Ciclesonide) until healing has occurred.

5.2 Glaucoma and Cataracts

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

5.3 Hypersensitivity

Simplyone is contraindicated in patients with a known hypersensitivity to Simplyone (Ciclesonide) or any of the ingredients of Simplyone (Ciclesonide). Cases of hypersensitivity reactions following administration of Simplyone (Ciclesonide) with manifestations such as angioedema, with swelling of the lips, tongue and pharynx, have been reported.

5.4 Immunosuppression

Patients who are using drugs that suppress the immune system are more susceptible to infections than healthy individuals. Chicken pox 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 or prior corticosteroid treatment to the risk is also not known. If a patient is exposed to chicken pox, 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 develops, treatment with antiviral agents may be considered.

Corticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infections of the respiratory tract; or in patients with 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 Suppression

Hypercorticism and adrenal suppression may occur when intranasal corticosteroids, such as Simplyone, are used at higher than recommended dosages or in susceptible individuals at recommended dosages. If such changes occur, the dosage of Simplyone (Ciclesonide) should be discontinued slowly, consistent with accepted procedures for discontinuing oral steroid 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 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 those 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. Monitor the growth routinely (e.g., via stadiometry) in pediatric patients receiving Simplyone (Ciclesonide). [see Pediatric Use (8.4)]

6 ADVERSE REACTIONS

Systemic and local corticosteroid use may result in the following:

• Epistaxis, ulcerations, nasal septal perforations, Candida albicans infection, impaired wound healing [see Warnings and Precautions ]
• Glaucoma and cataracts [see Warnings and Precautions (5.2)]
• Immunosuppression [see Warnings and Precautions (5.4)]
• Hypothalamic-pituitary-adrenal (HPA) axis effects, including growth reduction [see Warnings and Precautions (5.5, 5.6), Use in Specific Populations (8.4)]

The most common adverse reactions (≥2% incidence) included nasal discomfort, headache and epistaxis. (6)

To report SUSPECTED ADVERSE REACTIONS, contact Sunovion Pharmaceuticals Inc. at 1-877-737-7226 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience

The safety data described below for adults and adolescents 12 years of age and older are based on 4 clinical trials evaluating doses of Simplyone (Ciclesonide) nasal aerosol from 74 to 282 mcg. Three of the clinical trials were 2 to 6 weeks in duration and one trial was 26 weeks in duration with an additional 26-week open-label extension. Data from the first 6 weeks of the 26-week trial were pooled with data from the three 2-week trials. Short-term data (2 to 6 weeks) included 3001 patients with seasonal and perennial allergic rhinitis, of these, 884 received ZETONNA 74 mcg once daily and 892 received placebo. The short-term data included 1098 (36.6%) males, 1903 (63.4%) females, 2587 (86.2%) Caucasians, 320 (10.7%) Blacks, 49 (1.6%) Asians, and 45 (1.5%) patients classified as Other. The 26-week trial was conducted in 1110 patients with perennial allergic rhinitis [394 (35.5%) males and 716 (64.5%) females, ages 12 to 78 years old] treated with Simplyone (Ciclesonide) 74 mcg, 148 mcg or placebo once daily. Of these patients, 298 were treated with 74 mcg Simplyone (Ciclesonide), 505 with 148 mcg, and 307 with placebo. The racial distribution in this trial included 922 (83.1%) Caucasians, 146 (13.2%) Blacks, 18 (1.6%) Asians, and 24 (2.2%) patients classified as Other. The 26-week open-label extension included 824 patients [295 (35.8%) males and 529 (64.2%) females, ages 12 to 79 years old] given Simplyone (Ciclesonide) 148 mcg once daily. The racial distribution in the open-label extension included 690 (83.7%) Caucasians, 104 (12.6%) Blacks, 15 (1.8%) Asians, and 15 (1.8%) patients classified as Other.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Short-Term (2-6 weeks) Trials:

In three short-term trials and the first 6 weeks of one long-term trial, conducted in the US, 884 patients with a history of seasonal or perennial allergic rhinitis were treated with Simplyone (Ciclesonide) 74 mcg daily. Adverse reactions did not differ appreciably based on age, gender, or race. The table below displays reactions that occurred with an incidence of at least 2.0% and more frequently with Simplyone (Ciclesonide) 74 mcg than with placebo in seasonal or perennial allergic rhinitis clinical trials of 2 to 6 weeks duration.

When considering the data from higher doses evaluated in the short-term trials, epistaxis demonstrated a dose response. In addition, two patients treated with Simplyone (Ciclesonide) 74 mcg experienced nasal septal perforations in the short-term trials compared to no patients treated with placebo.

Approximately 1.2% of patients treated with Simplyone (Ciclesonide) 74 mcg in clinical trials discontinued because of adverse reactions; this rate was similar for patients treated with placebo. Discontinuations due to local adverse reactions were similar in Simplyone (Ciclesonide) 74 mcg treated patients (0.8%) compared to placebo treated patients (0.8%). Local adverse reactions leading to discontinuation that occurred only in Simplyone (Ciclesonide) treated patients included ear infection, nasal discomfort, nasal dryness, nasal mucosal/septum disorders, pharyngitis, streptococcal pharyngitis, sinus headache, and tonsillitis.

Long-Term (26-Week Double-Blind and 26-Week Open-Label) Safety Trial:

In one 26-week double-blind, placebo-controlled safety trial that included 1110 adult and adolescent patients with perennial allergic rhinitis, additional adverse reactions, with an incidence of at least 2%, that occurred more frequently with Simplyone (Ciclesonide) than with placebo were upper respiratory tract infection, urinary tract infection, oropharyngeal pain, nasal mucosal/septum disorders, viral upper respiratory tract infection, cough, influenza, bronchitis, streptococcal pharyngitis, muscle strain, and nausea. Nasal discomfort (5.7%) and epistaxis

(11.4%) were also more frequent in the 26-week safety trial compared to clinical trials 2 to 6 weeks in duration. Nasal mucosal/septum disorders and cough demonstrated a dose response.

Discontinuations due to adverse reactions were higher in Simplyone (Ciclesonide) treated patients compared to placebo treated patients and demonstrated a dose response. Local adverse reactions leading to discontinuation were also higher in Simplyone (Ciclesonide) 74 mcg treated patients (1.7%) compared to placebo treated patients (0.7%). The only local adverse reaction leading to discontinuation that occurred in Simplyone (Ciclesonide) treated patients and was not observed in the 2- to 6-week trials was upper respiratory tract infection.

A total of 824 patients with perennial allergic rhinitis who completed the 26-week double-blind trial enrolled into an open-label extension and received Simplyone (Ciclesonide) 148 mcg for 26 weeks. Additional adverse reactions, observed with an incidence of at least 2% were sinusitis, nasopharyngitis, and back pain.

A total of 4 nasal septal ulcerations were also reported in the 26-week open-label extension.

There were no reports of nasal septal perforations in the long-term safety trial.

Long-Term (6-Month Open-Label) Nasal Safety Trial:

Nasal and ocular safety was evaluated in one 26-week, postmarketing, randomized, open-label, active-controlled trial, in adult and adolescent patients 12-74 years of age with a history of perennial allergic rhinitis. A total of 737 patients were treated with Simplyone (Ciclesonide) 74 mcg or Simplyone (Ciclesonide) nasal spray 200 mcg once daily. The combined incidence of nasal mucosal or septum disorders, including erosions and ulcerations, was 3 (0.8%) for Simplyone (Ciclesonide) 74 mcg and 4 (1.1%) for Simplyone (Ciclesonide) nasal spray 200 mcg treated patients. There were no nasal septal perforations reported with either treatment. Ocular findings, including the development or worsening of lens opacities, increase in intraocular pressure, and worsening visual acuity, were also evaluated over the 26-week treatment period. The occurrence of ocular safety events was similar for the Simplyone (Ciclesonide) 74 mcg and Simplyone (Ciclesonide) nasal spray 200 mcg treatment groups.

6.2 Post-marketing Experience

The following adverse reactions have been identified during post-approval use of other formulations of Simplyone (Ciclesonide), ALVESCO^® Inhalation Aerosol and OMNARIS^® Nasal Spray. 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.

ALVESCO^® Inhalation Aerosol: immediate or delayed hypersensitivity reactions such as angioedema with swelling of the lips, tongue, and pharynx.

OMNARIS^® Nasal Spray: nasal congestion, nasal ulcer, and dizziness. Localized infections of the nose or mouth with Candida albicans have also occurred with OMNARIS^® Nasal Spray.

7 DRUG INTERACTIONS

In vitro studies and clinical pharmacology studies suggested that des-ciclesonide has no potential for metabolic drug interactions or protein binding-based drug interactions [see Clinical Pharmacology (12.3)]. In a drug interaction study, co-administration of orally inhaled Simplyone (Ciclesonide) and oral ketoconazole, a potent inhibitor of cytochrome P450 3A4, increased the exposure (AUC) of des-ciclesonide by approximately 3.6-fold at steady state, while levels of Simplyone (Ciclesonide) remained unchanged. Erythromycin, a moderate inhibitor of cytochrome P450 3A4, had no effect on the pharmacokinetics of either des-ciclesonide or erythromycin following oral inhalation of Simplyone (Ciclesonide) [see Clinical Pharmacology (12.3)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Teratogenic Effects: Pregnancy Category C.

There are no adequate and well-controlled trials in pregnant women. Simplyone 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.

Oral administration of Simplyone (Ciclesonide) in rats at approximately 120 times the maximum recommended human daily intranasal dose (MRHDID) in adults (on a mcg/m² basis at a maternal dose of 900 mcg/kg/day) produced no teratogenicity or other fetal effects. However, subcutaneous administration of Simplyone (Ciclesonide) in rabbits at similar to MRHDID (on a mcg/m² basis at a maternal dose of 5 mcg/kg/day) produced fetal toxicity. This included fetal loss, reduced fetal weight, cleft palate, skeletal abnormalities including incomplete ossifications, and skin effects. No toxicity was observed at ¼ of the MRHDID in adults (on a mcg/m² basis at a maternal dose of 1 mcg/kg/day).

Nonteratogenic 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 if Simplyone (Ciclesonide) is excreted in human milk. However, other corticosteroids are excreted in human milk. In a study with lactating rats, minimal but detectable levels of radiolabeled Simplyone (Ciclesonide) were recovered in milk. Caution should be used when Simplyone (Ciclesonide) is administered to nursing women.

8.4 Pediatric Use

The safety and effectiveness for seasonal and perennial allergic rhinitis in children 12 years of age and older have been established. The safety and efficacy of Simplyone for treatment of the symptoms of seasonal and perennial allergic rhinitis in patients 11 years of age and younger have not been established.

The safety and efficacy of Simplyone (Ciclesonide) in pediatric patients 6-11 years of age were evaluated in two randomized, double blind, parallel placebo-controlled clinical trials in 1693 pediatric patients with allergic rhinitis. Of the two trials, one was 2 weeks in duration and evaluated the efficacy of two doses of Simplyone (Ciclesonide) (37 mcg and 74 mcg once daily) in 847 patients with seasonal allergic rhinitis. The second clinical trial was 12 weeks in duration and evaluated the efficacy of two doses of Simplyone (Ciclesonide) (37 mcg and 74 mcg once daily) in 846 patients with perennial allergic rhinitis. The trials were similar in design to the trials conducted in adolescents and adults. The primary efficacy endpoint was the difference from placebo in the change from baseline of the average morning and evening reflective total nasal symptom scores (rTNSS) averaged over 2 weeks of treatment in the seasonal allergic rhinitis trial and over the first 6 weeks of treatment in the perennial allergic rhinitis trial. In the 2-week trial in patients with seasonal allergic rhinitis, treatment with Simplyone (Ciclesonide) at either dose failed to demonstrate efficacy. In the 12-week trial in patients with perennial allergic rhinitis, Simplyone (Ciclesonide) 37 mcg and 74 mcg once daily both demonstrated significant improvement in rTNSS compared to placebo with treatment differences of 0.59 (95% CI: 0.23, 0.95) and 0.47 (95% CI: 0.11, 0.83), respectively. The safety profile observed in children 6 to 11 years of age with seasonal or perennial allergic rhinitis was similar to the adverse reactions observed in the clinical trial population of patients 12 year of age and older [see Adverse Reactions (6.1)].

The effect of Simplyone (Ciclesonide) on the HPA axis was evaluated in one placebo-controlled clinical study of 6 weeks in duration in children 6 to11 years of age with perennial allergic rhinitis [see Clinical Pharmacology (12.2)].

Studies in children under 6 years of age have not been conducted.

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 this 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 Simplyone (Ciclesonide), should be monitored routinely (e.g., via stadiometry). A 52-week, multi-center, double-blind, randomized, placebo-controlled parallel-group trial was conducted to assess the effect of orally inhaled Simplyone (Ciclesonide) (ALVESCO^® Inhalation Aerosol) on growth rate in 609 pediatric patients with mild persistent asthma, aged 5 to 8.5 years. Treatment groups included orally inhaled Simplyone (Ciclesonide) 40 mcg or 160 mcg or placebo given once daily. Growth was measured by stadiometer height during the baseline, treatment and follow-up periods. The primary comparison was the difference in growth rates between Simplyone (Ciclesonide) 40 and 160 mcg and placebo groups. Conclusions cannot be drawn from this trial because compliance could not be assured. Simplyone (Ciclesonide) blood levels were also not measured during the one-year treatment period. There was no difference in efficacy measures between the placebo and the orally inhaled Simplyone (Ciclesonide) (ALVESCO^® Inhalation Aerosol) groups.

The potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the availability of safe and effective noncorticosteroid treatment alternatives. To minimize the systemic effects of intranasal corticosteroids, each patient should be titrated to the lowest dose that effectively controls his/her symptoms.

The potential for Simplyone (Ciclesonide) to cause growth suppression in susceptible patients or when given at higher than recommended dosages cannot be ruled out.

8.5 Geriatric Use

Clinical trials of Simplyone (Ciclesonide) did not include sufficient numbers of patients age 65 and over to determine whether they responded differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious 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 or symptoms of hypercorticism [see Warnings and Precautions (5.5)]. There are no data on the effects of acute or chronic overdosage with Simplyone (Ciclesonide).

11 DESCRIPTION

The active component of Simplyone (Ciclesonide) is Simplyone (Ciclesonide), a non-halogenated glucocorticoid having the chemical name pregna -1,4-diene-3,20-dione, 16,17-[[R-cyclohexylmethylene]bis(oxy)]-11-hydroxy-21-(2-methyl-1-oxopropoxy)-,(11ß,16α)-. Simplyone (Ciclesonide) is delivered as the R-epimer. The empirical formula is C₃₂H₄₄O₇ and its molecular weight is 540.7. Its structural formula is as follows:

Priming Your Simplyone (Ciclesonide) Nasal Aerosol For Use

• Remove Simplyone (Ciclesonide) Nasal Aerosol from its package.
• Before you use Simplyone (Ciclesonide) Nasal Aerosol for the first time or if you have not used your medicine for 10 days in a row, you will need to prime your Simplyone (Ciclesonide) Nasal Aerosol.
• Open the purple plastic dust cap by gently squeezing both sides and pulling the cap away from the nasal actuator. Hold the nasal actuator upright. (See Figure B )

• Spray 3 times into the air away from the face, by pressing down fully on the top of the canister three times (See Figure C ). Make sure the canister returns to its original position after each spray.

Using Your Simplyone (Ciclesonide) Nasal Aerosol

Step 1. Open the purple plastic dust cap.

Step 2. Hold the nasal actuator upright, with the nose piece pointing upwards, between your thumb and forefinger (and middle finger) (See Figure D ).

Step 3. Tilt your head back slightly and insert the end of the nose piece into 1 nostril, pointing it slightly toward the outside nostril wall away from the nasal septum (the wall between the 2 nostrils), while holding your other nostril closed with 1 finger (See Figure E ). Do not get any spray in your eyes or directly on your nasal septum.

Step 4. Press down on the canister to release 1 spray and at the same time breathe in gently through the nostril. Hold your breath for a few seconds then breathe out slowly through your mouth.

Step 5. Remove the nose piece from your nostril. Make sure the canister has returned to its original position and repeat steps 2-4 for the second spray in your other nostril.

Step 6. Replace the protective purple dust cap on the nasal actuator.

Step 7. Avoid blowing your nose for the next 15 minutes.

Cleaning Your Nasal Actuator

The outside of the nose piece should be cleaned weekly, by wiping with a clean, dry tissue or cloth (see Figure F ).

Do not wash or put any part of the Simplyone (Ciclesonide) Nasal Aerosol canister or actuator in water.

How to Tell if Your Simplyone (Ciclesonide) Nasal Aerosol Is Empty

• Each canister of Simplyone (Ciclesonide) Nasal Aerosol contains enough medicine for you to spray medicine 60 times (or 30 times for sample size product). This does not count the first 3 priming sprays.
• The actuator of your Simplyone (Ciclesonide) Nasal Aerosol is fitted with a dose indicator which shows you how much medicine is left after each use. The dose indicator will display the number of sprays remaining in groups of 5 or 10 actuations.
• The display window will begin showing a green color. As you continue to use the medicine, the window will show a yellow color. A yellow color in the window means that you need to replace your medicine soon. When the medicine is almost empty, the window will show a red color.
• When the window shows red and you see the dose indicator read zero, “0” (see Figure G ), you should throw away the canister and nasal actuator.

• Do not throw your Simplyone (Ciclesonide) Nasal Aerosol canister in the fire or an incinerator.
• Do not use your Simplyone (Ciclesonide) Nasal Aerosol after zero is shown in the window of the dose indicator even though it may look like there is medicine left in the canister. You may not get the right amount of medicine.
• Talk with your healthcare provider before your supply of Simplyone (Ciclesonide) Nasal Aerosol runs out to see if you should get a refill of your medicine.

What to Do if You Drop Your Simplyone (Ciclesonide) Nasal Aerosol

• If you drop your Simplyone (Ciclesonide) Nasal Aerosol, the canister may become separated from the actuator. If this happens, insert the canister into the actuator as shown in Figure H , test spray once into the air away from your face, then use as described above.

• If the Simplyone (Ciclesonide) Nasal Aerosol is dropped, the dose counter may not work. It is recommended to keep track of the number of sprays taken from your Simplyone (Ciclesonide) Nasal Aerosol based on your records.

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

SUNOVION

Manufactured for:

Sunovion Pharmaceuticals Inc.

Marlborough, MA 01752 USA

Made in the United Kingdom

© 2014 Sunovion Pharmaceuticals Inc. All rights reserved.

For customer service, call 1-888-394-7377

901641R01

620392213

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

PACKAGE LABEL - PRINCIPAL DISPLAY PANEL - carton – 37 mcg 60-count

NDC 63402-737-60

Net Contents: 6.1 g

Simplyone (Ciclesonide)

(ciclesonide) Nasal Aerosol

37 mcg per actuation

For Intranasal Use Only.

Simplyone (Ciclesonide) Nasal Aerosol Canister

Should Be Used with Simplyone (Ciclesonide)

Nasal Aerosol Actuator Only.

60 Metered Actuations

Rx ONLY

Sunovion

PACKAGE LABEL - PRINCIPAL DISPLAY PANEL – canister - 37 mcg 60-count

NDC 63402-737-60

Net Contents: 6.1 g

Simplyone (Ciclesonide)

(ciclesonide) Nasal Aerosol

37 mcg per actuation

For Intranasal Use Only.

Use with Simplyone (Ciclesonide) Nasal Aerosol

Actuator Only.

60 Metered Actuations

Rx ONLY

Sunovion

PACKAGE LABEL - PRINCIPAL DISPLAY PANEL – actuator - 37 mcg 60-count

Simplyone (Ciclesonide)

(ciclesonide) Nasal Aerosol

37 mcg per actuation

For Intranasal Use Only.

Use with Simplyone (Ciclesonide)

Nasal Aerosol Canister Only.

60 Metered Actuations

Formoterol Fumarate:

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• How supplied/storage and handling
• Patient counseling information
• Medication guide
• Simplyone (Formoterol Fumarate) reviews

WARNING: ASTHMA-RELATED DEATH

Long-acting beta₂-adrenergic agonists (LABA) increase the risk of asthma-related death. Data from a large placebo-controlled US study that compared the safety of another long-acting beta₂-adrenergic agonist (salmeterol) or placebo added to usual asthma therapy showed an increase in asthma-related deaths in patients receiving salmeterol. This finding with salmeterol is considered a class effect of LABA, including formoterol, the active ingredient in Simplyone (Formoterol Fumarate) Inhalation Solution. The safety and efficacy of Simplyone (Formoterol Fumarate) in patients with asthma have not been established. All LABA, including Simplyone (Formoterol Fumarate), are contraindicated in patients with asthma without use of a long-term asthma control medication .

WARNING: ASTHMA-RELATED DEATH

See full prescribing information for complete boxed warning.

• Long-acting beta₂-adrenergic agonists (LABA) increase the risk of asthma-related death. (5.1)
• A placebo-controlled study with another long-acting beta₂-adrenergic agonist (salmeterol) showed an increase in asthma-related deaths in patients receiving salmeterol. (5.1)
• The finding of an increased risk of asthma-related death with salmeterol is considered a class effect of LABA, including formoterol, the active ingredient in Simplyone (Formoterol Fumarate). The safety and efficacy of Simplyone (Formoterol Fumarate) in patients with asthma have not been established. All LABA, including Simplyone (Formoterol Fumarate), are contraindicated in patients with asthma without use of a long-term asthma control medication. (4, 5.1)

1 INDICATIONS AND USAGE

Simplyone Inhalation Solution is a long-acting beta₂-adrenergic agonist (beta₂-agonist) indicated for:

• Long-term, twice daily (morning and evening) administration in the maintenance treatment of bronchoconstriction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema. (1.1)

Important limitations of use:

• Simplyone (Formoterol Fumarate) Inhalation Solution is not indicated to treat acute deteriorations of chronic obstructive pulmonary disease. (1.2, 5.2)
• Simplyone (Formoterol Fumarate) Inhalation Solution is not indicated to treat asthma. (1.2)

1.1 Maintenance Treatment of COPD

Simplyone (Formoterol Fumarate) (formoterol fumarate) Inhalation Solution is indicated for the long-term, twice daily (morning and evening) administration in the maintenance treatment of bronchoconstriction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema.

1.2 Important Limitations of Use

Simplyone (Formoterol Fumarate) Inhalation Solution is not indicated to treat acute deteriorations of chronic obstructive pulmonary disease .

Simplyone (Formoterol Fumarate) Inhalation Solution is not indicated to treat asthma. The safety and effectiveness of Simplyone (Formoterol Fumarate) Inhalation Solution in asthma have not been established.

2 DOSAGE AND ADMINISTRATION

The recommended dose of Simplyone (Formoterol Fumarate) (formoterol fumarate) Inhalation Solution is one 20 mcg unit-dose vial administered twice daily (morning and evening) by nebulization. A total daily dose greater than 40 mcg is not recommended.

Simplyone (Formoterol Fumarate) Inhalation Solution should be administered by the orally inhaled route via a standard jet nebulizer connected to an air compressor. The safety and efficacy of Simplyone (Formoterol Fumarate) Inhalation Solution have been established in clinical trials when administered using the PARI-LC Plus^® nebulizer (with a facemask or mouthpiece) and the PRONEB^® Ultra compressor. The safety and efficacy of Simplyone (Formoterol Fumarate) Inhalation Solution delivered from non-compressor based nebulizer systems have not been established.

Simplyone (Formoterol Fumarate) Inhalation Solution should always be stored in the foil pouch, and only removed IMMEDIATELY BEFORE USE. Contents of any partially used container should be discarded.

If the recommended maintenance treatment regimen fails to provide the usual response, medical advice should be sought immediately, as this is often a sign of destabilization of COPD. Under these circumstances, the therapeutic regimen should be re-evaluated and additional therapeutic options should be considered.

The drug compatibility (physical and chemical), efficacy, and safety of Simplyone (Formoterol Fumarate) Inhalation Solution when mixed with other drugs in a nebulizer have not been established.

For oral inhalation only.

• One 20 mcg/2 mL vial every 12 hours (2)
• For use with a standard jet nebulizer (with a facemask or mouthpiece) connected to an air compressor (2)

3 DOSAGE FORMS AND STRENGTHS

Simplyone (Formoterol Fumarate) (formoterol fumarate) Inhalation Solution is supplied as a sterile solution for nebulization in low-density polyethylene unit-dose vials. Each vial contains Simplyone (Formoterol Fumarate) dihydrate, USP equivalent to 20 mcg/2 mL of Simplyone (Formoterol Fumarate).

Inhalation Solution (unit dose vial for nebulization); 20 mcg/2 mL solution (3)

4 CONTRAINDICATIONS

All LABA, including Simplyone (Formoterol Fumarate), are contraindicated in patients with asthma without use of a long-term asthma control medication. .

• All LABA, including Simplyone (Formoterol Fumarate), are contraindicated in patients with asthma without use of a long-term asthma control medication. (4)

5 WARNINGS AND PRECAUTIONS

• Do not initiate Simplyone Inhalation Solution in acutely deteriorating patients. (5.2)
• Do not use for relief of acute symptoms. Concomitant short-acting beta₂-agonists can be used as needed for acute relief. (5.2)
• Do not exceed the recommended dose. Excessive use of Simplyone (Formoterol Fumarate) Inhalation Solution, or use in conjunction with other medications containing long-acting beta₂-agonists, can result in clinically significant cardiovascular effects, and may be fatal. (5.3, 5.5)
• Life-threatening paradoxical bronchospasm can occur. Discontinue Simplyone (Formoterol Fumarate) Inhalation Solution immediately. (5.4)
• Use with caution in patients with cardiovascular or convulsive disorders, thyrotoxicosis, or with sensitivity to sympathomimetic drugs. (5.6, 5.7)

5.1 Asthma-Related Deaths

Data from a large placebo-controlled study in asthma patients showed that long-acting beta₂-adrenergic agonists may increase the risk of asthma-related death. Data are not available to determine whether the rate of death in patients with COPD is increased by long-acting beta₂-adrenergic agonists.

A 28-week, placebo-controlled US study comparing the safety of salmeterol with placebo, each added to usual asthma therapy, showed an increase in asthma-related deaths in patients receiving salmeterol (13/13,176 in patients treated with salmeterol vs. 3/13,179 in patients treated with placebo; RR 4.37, 95% CI 1.25, 15.34). The increased risk of asthma-related death is considered a class effect of the long-acting beta₂-adrenergic agonists, including Simplyone (Formoterol Fumarate) Inhalation Solution. No study adequate to determine whether the rate of asthma related death is increased in patients treated with Simplyone (Formoterol Fumarate) Inhalation Solution has been conducted. The safety and efficacy of Simplyone (Formoterol Fumarate) in patients with asthma have not been established. All LABA, including Simplyone (Formoterol Fumarate), are contraindicated in patients with asthma without use of a long-term asthma control medication. .

Clinical studies with Simplyone (Formoterol Fumarate) administered as a dry powder inhaler suggested a higher incidence of serious asthma exacerbations in patients who received formoterol than in those who received placebo. The sizes of these studies were not adequate to precisely quantify the differences in serious asthma exacerbation rates between treatment groups.

5.2 Deterioration of Disease and Acute Episodes

Simplyone Inhalation Solution should not be initiated in patients with acutely deteriorating COPD, which may be a life-threatening condition. Simplyone (Formoterol Fumarate) Inhalation Solution has not been studied in patients with acutely deteriorating COPD. The use of Simplyone (Formoterol Fumarate) Inhalation Solution in this setting is inappropriate.

Simplyone (Formoterol Fumarate) Inhalation Solution should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. Simplyone (Formoterol Fumarate) Inhalation Solution has not been studied in the relief of acute symptoms and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled short-acting beta₂-agonist.

When beginning Simplyone (Formoterol Fumarate) Inhalation Solution, patients who have been taking inhaled, short-acting beta₂-agonists on a regular basis (e.g., four times a day) should be instructed to discontinue the regular use of these drugs and use them only for symptomatic relief of acute respiratory symptoms. When prescribing Simplyone (Formoterol Fumarate) Inhalation Solution, the healthcare provider should also prescribe an inhaled, short-acting beta₂-agonist and instruct the patient how it should be used. Increasing inhaled beta₂-agonist use is a signal of deteriorating disease for which prompt medical attention is indicated. COPD may deteriorate acutely over a period of hours or chronically over several days or longer. If Simplyone (Formoterol Fumarate) Inhalation Solution no longer controls the symptoms of bronchoconstriction, or the patient’s inhaled, short-acting beta₂-agonist becomes less effective or the patient needs more inhalation of short-acting beta₂-agonist than usual, these may be markers of deterioration of disease. In this setting, a re-evaluation of the patient and the COPD treatment regimen should be undertaken at once. Increasing the daily dosage of Simplyone (Formoterol Fumarate) Inhalation Solution beyond the recommended 20 mcg twice daily dose is not appropriate in this situation.

5.3 Excessive Use and Use with Other Long-Acting Beta₂-Agonists

As with other inhaled beta₂-adrenergic drugs, Simplyone (Formoterol Fumarate) Inhalation Solution should not be used more often, at higher doses than recommended, or in conjunction with other medications containing long-acting beta₂-agonists, as an overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs.

5.4 Paradoxical Bronchospasm

As with other inhaled beta₂-agonists, Simplyone Inhalation Solution can produce paradoxical bronchospasm that may be life-threatening. If paradoxical bronchospasm occurs, Simplyone (Formoterol Fumarate) Inhalation Solution should be discontinued immediately and alternative therapy instituted.

5.5 Cardiovascular Effects

Simplyone (Formoterol Fumarate) Inhalation Solution, like other beta₂-agonists, can produce a clinically significant cardiovascular effect in some patients as measured by increases in pulse rate, systolic and/or diastolic blood pressure, and/or symptoms. If such effects occur, Simplyone (Formoterol Fumarate) Inhalation Solution may need to be discontinued. In addition, beta-agonists have been reported to produce ECG changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression. The clinical significance of these findings is unknown. Therefore, Simplyone (Formoterol Fumarate) Inhalation Solution, like other sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

5.6 Coexisting Conditions

Simplyone Inhalation Solution, like other sympathomimetic amines, should be used with caution in patients with convulsive disorders or thyrotoxicosis, and in patients who are unusually responsive to sympathomimetic amines. Doses of the related beta₂-agonist albuterol, when administered intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis.

5.7 Hypokalemia and Hyperglycemia

Beta-agonist medications may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects . The decrease in serum potassium is usually transient, not requiring supplementation. Beta-agonist medications may produce transient hyperglycemia in some patients.

Clinically significant changes in serum potassium and blood glucose were infrequent during clinical studies with long-term administration of Simplyone (Formoterol Fumarate) Inhalation Solution at the recommended dose.

5.8 Immediate Hypersensitivity Reactions

Immediate hypersensitivity reactions may occur after administration of Simplyone (Formoterol Fumarate) Inhalation Solution, as demonstrated by cases of anaphylactic reactions, urticaria, angioedema, rash, and bronchospasm.

6 ADVERSE REACTIONS

Long acting beta₂-adrenergic agonists such as formoterol increase the risk of asthma-related death .

Most common adverse reactions (>2% and more common than placebo) are diarrhea, nausea, nasopharyngitis, dry mouth, vomiting, dizziness, and insomnia (6.2)

To report SUSPECTED ADVERSE REACTIONS, contact Mylan Specialty L.P. at 1-800-429-7751 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Beta₂-Agonist Adverse Reaction Profile

Adverse reactions to Simplyone (Formoterol Fumarate) Inhalation Solution are expected to be similar in nature to other beta₂-adrenergic receptor agonists including: angina, hypertension or hypotension, tachycardia, arrhythmias, nervousness, headache, tremor, dry mouth, muscle cramps, palpitations, nausea, dizziness, fatigue, malaise, insomnia, hypokalemia, hyperglycemia, and metabolic acidosis.

6.2 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adults with COPD

The data described below reflect exposure to Simplyone Inhalation Solution 20 mcg twice daily by oral inhalation in 586 patients, including 232 exposed for 6 months and 155 exposed for at least 1 year. Simplyone (Formoterol Fumarate) Inhalation Solution was studied in a 12-week, placebo- and active-controlled trial (123 subjects treated with Simplyone (Formoterol Fumarate) Inhalation Solution) and a 52-week, active-controlled trial (463 subjects treated with Simplyone (Formoterol Fumarate) Inhalation Solution). Patients were mostly Caucasians (88%) between 40-90 years old (mean, 64 years old) and had COPD, with a mean FEV₁ of 1.33 L. Patients with significant concurrent cardiac and other medical diseases were excluded from the trials.

Table 1 shows adverse reactions from the 12-week, double-blind, placebo-controlled trial where the frequency was greater than or equal to 2% in the Simplyone (Formoterol Fumarate) Inhalation Solution group and where the rate in the Simplyone (Formoterol Fumarate) Inhalation Solution group exceeded the rate in the placebo group. In this trial, the frequency of patients experiencing cardiovascular adverse events was 4.1% for Simplyone (Formoterol Fumarate) Inhalation Solution and 4.4% for placebo. There were no frequently occurring specific cardiovascular adverse events for Simplyone (Formoterol Fumarate) Inhalation Solution (frequency greater than or equal to 1% and greater than placebo). The rate of COPD exacerbations was 4.1% for Simplyone (Formoterol Fumarate) Inhalation Solution and 7.9% for placebo.

Patients treated with Simplyone (Formoterol Fumarate) Inhalation Solution 20 mcg twice daily in the 52-week open-label trial did not experience an increase in specific clinically significant adverse events above the number expected based on the medical condition and age of the patients.

6.3 Postmarketing Experience

The following adverse reactions have been reported during post-approval use of Simplyone (Formoterol Fumarate) Inhalation Solution. 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.

Anaphylactic reactions, urticaria, angioedema (presenting as face, lip, tongue, eye, pharyngeal, or mouth edema), rash, and bronchospasm

7 DRUG INTERACTIONS

• Other adrenergic drugs may potentiate effect. Use with caution.
• Xanthine derivatives, steroids, diuretics, or non-potassium sparing diuretics may potentiate hypokalemia or ECG changes. Use with caution. (5.7, 7.2, 7.3)
• MAO inhibitors, tricyclic antidepressants and drugs that prolong QTc interval may potentiate effect on the cardiovascular system. Use with extreme caution. (7.4)
• Beta-blockers may decrease effectiveness. Use with caution and only when medically necessary. (7.5)

7.1 Adrenergic Drugs

If additional adrenergic drugs are to be administered by any route, they should be used with caution because the sympathetic effects of formoterol may be potentiated .

7.2 Xanthine Derivatives, Steroids, or Diuretics

Concomitant treatment with xanthine derivatives, steroids, or diuretics may potentiate any hypokalemic effect of adrenergic agonists .

7.3 Non-potassium Sparing Diuretics

The ECG changes and/or hypokalemia that may result from the administration of non-potassium sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is not known, caution is advised in the co-administration of beta-agonists with non-potassium sparing diuretics.

7.4 MAO Inhibitors, Tricyclic Antidepressants, QTc Prolonging Drugs

Formoterol, as with other beta₂-agonists, should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors, tricyclic antidepressants, or drugs known to prolong the QTc interval because the effect of adrenergic agonists on the cardiovascular system may be potentiated by these agents. Drugs that are known to prolong the QTc interval have an increased risk of ventricular arrhythmias.

7.5 Beta-blockers

Beta-adrenergic receptor antagonists (beta-blockers) and formoterol may inhibit the effect of each other when administered concurrently. Beta-blockers not only block the therapeutic effects of beta-agonists, but may produce severe bronchospasm in COPD patients. Therefore, patients with COPD should not normally be treated with beta-blockers. However, under certain circumstances, e.g., as prophylaxis after myocardial infarction, there may be no acceptable alternatives to the use of beta-blockers in patients with COPD. In this setting, cardioselective beta-blockers could be considered, although they should be administered with caution.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Teratogenic Effects: Pregnancy Category C

Simplyone administered throughout organogenesis did not cause malformations in rats or rabbits following oral administration. However, Simplyone (Formoterol Fumarate) was found to be teratogenic in rats and rabbits in other testing laboratories. When given to rats throughout organogenesis, oral doses of 0.2 mg/kg (approximately 40 times the maximum recommended daily inhalation dose in humans on a mg/m² basis) and above delayed ossification of the fetus, and doses of 6 mg/kg (approximately 1200 times the maximum recommended daily inhalation dose in humans on a mg/m² basis) and above decreased fetal weight. Simplyone (Formoterol Fumarate) has been shown to cause stillbirth and neonatal mortality at oral doses of 6 mg/kg and above in rats receiving the drug during the late stage of pregnancy. These effects, however, were not produced at a dose of 0.2 mg/kg. Because there are no adequate and well-controlled studies in pregnant women, Simplyone (Formoterol Fumarate) Inhalation Solution should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Women should be advised to contact their physician if they become pregnant while taking Simplyone (Formoterol Fumarate) Inhalation Solution.

8.2 Labor and Delivery

There are no adequate and well-controlled human studies that have investigated the effects of Simplyone (Formoterol Fumarate) Inhalation Solution during labor and delivery.

Because beta-agonists may potentially interfere with uterine contractility, Simplyone (Formoterol Fumarate) Inhalation Solution should be used during labor only if the potential benefit justifies the potential risk.

8.3 Nursing Mothers

In reproductive studies in rats, formoterol was excreted in the milk. It is not known whether formoterol is excreted in human milk, but because many drugs are excreted in human milk, caution should be exercised if Simplyone Inhalation Solution is administered to nursing women. There are no well-controlled human studies of the use of Simplyone (Formoterol Fumarate) Inhalation Solution in nursing mothers.

Women should be advised to contact their physician if they are nursing while taking Simplyone (Formoterol Fumarate) Inhalation Solution.

8.4 Pediatric Use

Simplyone (Formoterol Fumarate) Inhalation Solution is not indicated for use in children. The safety and effectiveness of Simplyone (Formoterol Fumarate) Inhalation Solution in pediatric patients have not been established. The pharmacokinetics of Simplyone (Formoterol Fumarate) has not been studied in pediatric patients.

8.5 Geriatric Use

Of the 586 subjects who received Simplyone (Formoterol Fumarate) Inhalation Solution in clinical studies, 284 were 65 years and over, while 89 were 75 years and over. Of the 123 subjects who received Simplyone (Formoterol Fumarate) Inhalation Solution in the 12-week safety and efficacy trial, 48 (39%) were 65 years of age or older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger adult patients, but greater sensitivity of some older individuals cannot be ruled out.

The pharmacokinetics of Simplyone (Formoterol Fumarate) Inhalation Solution has not been studied in elderly subjects.

10 OVERDOSAGE

The expected signs and symptoms with overdosage of Simplyone (Formoterol Fumarate) Inhalation Solution are those of excessive beta-adrenergic stimulation and/or occurrence or exaggeration of any of the signs and symptoms listed under ADVERSE REACTIONS. Signs and symptoms may include angina, hypertension or hypotension, tachycardia with rates up to 200 beats/min, arrhythmias, nervousness, headache, tremor, seizures, muscle cramps, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, insomnia, hyperglycemia, hypokalemia, and metabolic acidosis. As with all inhaled sympathomimetic medications, cardiac arrest and even death may be associated with an overdose of Simplyone (Formoterol Fumarate) Inhalation Solution.

Treatment of overdosage consists of discontinuation of Simplyone (Formoterol Fumarate) Inhalation Solution together with institution of appropriate symptomatic and/or supportive therapy. The judicious use of a cardioselective beta-receptor blocker may be considered, bearing in mind that such medication can produce bronchospasm. There is insufficient evidence to determine if dialysis is beneficial for overdosage of Simplyone (Formoterol Fumarate) Inhalation Solution. Cardiac monitoring is recommended in cases of overdosage.

The minimum lethal inhalation dose of Simplyone (Formoterol Fumarate) in rats is 156 mg/kg (approximately 32,000 times the maximum recommended daily inhalation dose in humans on a mg/m² basis). The median lethal oral doses in Chinese hamsters, rats, and mice provide even higher multiples of the maximum recommended daily inhalation dose in humans.

For additional information about overdose treatment, call a poison control center (1-800-222-1222).

11 DESCRIPTION

Simplyone (Formoterol Fumarate) (formoterol fumarate) Inhalation Solution is supplied as 2 mL of Simplyone (Formoterol Fumarate) inhalation solution packaged in a 2.5 mL single-use low-density polyethylene vial and overwrapped in a foil pouch. Each vial contains 2 mL of a clear, colorless solution composed of Simplyone (Formoterol Fumarate) dihydrate, USP equivalent to 20 mcg of Simplyone (Formoterol Fumarate) in an isotonic, sterile aqueous solution containing sodium chloride, pH adjusted to 5.0 with citric acid and sodium citrate.

The active component of Simplyone (Formoterol Fumarate) Inhalation Solution is Simplyone (Formoterol Fumarate) dihydrate, USP, a racemate. Simplyone (Formoterol Fumarate) dihydrate is a beta₂-adrenergic bronchodilator. Its chemical name is (±)-2-hydroxy-5-[(1RS)-1-hydroxy-2-[[(1RS)-2-(4-methoxyphenyl)-1-methylethyl]-amino]ethyl]formanilide fumarate dihydrate; its structural formula is:

Figure 2 Mean* FEV1 at Endpoint after 12 Weeks of Treatment

• * Figures show least-squares means adjusted for baseline FEV₁

Patients treated with Simplyone (Formoterol Fumarate) Inhalation Solution used less rescue albuterol during the trial compared to patients treated with placebo.

Examination of age (≥ 65 or younger) and gender subgroups did not identify differences in response to Simplyone (Formoterol Fumarate) Inhalation Solution. There were too few non-Caucasian subjects to assess differences in populations defined by race adequately.

In the 12 week study, 78% of subjects achieved a 15% increase from baseline FEV₁ following the first dose of Simplyone (Formoterol Fumarate) Inhalation Solution 20 mcg. In these subjects, the median time to onset of bronchodilation, defined as 15% increase in FEV₁, was 11.7 minutes. When defined as an increase in FEV₁ of 12% and 200 mL, the time to onset of bronchodilation was 13.1 minutes after dosing. The median time to peak bronchodilator effect was 2 hours after dosing.

Simplyone (Formoterol Fumarate) Figure 1 Simplyone (Formoterol Fumarate) Figure 2

16 HOW SUPPLIED/STORAGE AND HANDLING

Simplyone (Formoterol Fumarate) (formoterol fumarate) Inhalation Solution is supplied as a 2 mL sterile solution for nebulization in 2.5 mL low-density polyethylene unit dose vials. Each vial is overwrapped in a foil pouch and supplied in cartons as listed below.

Carton of 30 individually wrapped unit dose vials, NDC 49502-605-30

Carton of 60 individually wrapped unit dose vials, NDC 49502-605-61

Storage and Handling:

Prior to dispensing to the patient: Store in a refrigerator, 2°C to 8°C (36°F to 46°F)

After dispensing to the patient: Store at 2°C to 25°C (36°F to 77°F) for up to 3 months. Protect pouch from heat.

• Simplyone (Formoterol Fumarate) Inhalation Solution should only be administered via a standard jet nebulizer connected to an air compressor with an adequate airflow and equipped with a facemask or mouthpiece.
• Vial should always be stored in the foil pouch, and only removed IMMEDIATELY before use.
• Do not take by mouth.
• Contents of any partially used container should be discarded.
• Discard the container and top after use.
• Keep out of the reach of children

17 PATIENT COUNSELING INFORMATION

Asthma-Related Death

Patients should be informed that long acting beta agonist, such as Simplyone (Formoterol Fumarate), increase the risk of asthma-related death. All LABA, including Simplyone (Formoterol Fumarate), should not be used in patients with asthma without use of a long-term asthma control medication.

Acute Exacerbations or Deteriorations

Simplyone (Formoterol Fumarate) Inhalation Solution is not indicated for relief of acute symptoms, and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled, short-acting beta₂-agonist (the healthcare provider should provide the patient with such medication and instruct the patient in how it should be used). Patients should be instructed to seek medical attention if their symptoms worsen despite recommended doses of Simplyone (Formoterol Fumarate) Inhalation Solution, if Simplyone (Formoterol Fumarate) Inhalation Solution treatment becomes less effective, or if they need more inhalations of a short-acting beta₂-agonist than usual.

Appropriate Dosing

Patients should not stop using Simplyone (Formoterol Fumarate) Inhalation Solution unless told to do so by a healthcare provider because symptoms may get worse. Patients should not inhale more than the prescribed number of vials at any one time. The daily dosage of Simplyone (Formoterol Fumarate) Inhalation Solution should not exceed one vial twice daily (40 mcg total daily dose). Excessive use of sympathomimetics may cause significant cardiovascular effects, and may be fatal.

Concomitant Therapy

Patients who have been taking inhaled, short-acting beta₂-agonists (e.g., albuterol) on a regular basis should be instructed to discontinue the regular use of these products and use them only for symptomatic relief of acute symptoms. Simplyone (Formoterol Fumarate) Inhalation Solution should not be used in conjunction with other inhaled medications containing long-acting beta₂-agonists. Patients should be warned not to stop or change the dose of other concomitant COPD therapy without medical advice, even if symptoms improve after initiating treatment with Simplyone (Formoterol Fumarate) Inhalation Solution.

Common Adverse Reactions with Beta₂-agonists

Patients should be informed that treatment with beta₂-agonists may lead to adverse reactions that include palpitations, chest pain, rapid heart rate, increased or decreased blood pressure, headache, tremor, nervousness, dry mouth, muscle cramps, nausea, dizziness, fatigue, malaise, low blood potassium, high blood sugar, high blood acid, or trouble sleeping .

Instructions for Administration

It is important that patients understand how to use Simplyone (Formoterol Fumarate) Inhalation Solution with a nebulizer appropriately . Patients should be instructed not to mix other medications with Simplyone (Formoterol Fumarate) Inhalation Solution or ingest Simplyone (Formoterol Fumarate) Inhalation Solution. Patients should throw the plastic dispensing container away immediately after use. Due to their small size, the container and top pose a danger of choking to young children.

FDA-Approved Medication Guide

See the accompanying Medication Guide.

Manufactured for:

Mylan Specialty L.P.

Morgantown, WV 26505

Manufactured by:

The Ritedose Corporation

Columbia, SC 29203

U.S. Pat. No. 6,667,344

U.S. Pat. No. 6,814,953

A3-031-00

MEDICATION GUIDE

Simplyone (Formoterol Fumarate)^®(Per-FOR-o-mist)

(formoterol fumarate) Inhalation Solution

Simplyone (Formoterol Fumarate) Inhalation Solution is only for use with a nebulizer.

Read the Medication Guide that comes with Simplyone (Formoterol Fumarate) Inhalation Solution before you start using it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or treatment.

What is the most important information I should know about Simplyone (Formoterol Fumarate) Inhalation Solution?

Simplyone (Formoterol Fumarate) Inhalation Solution can cause serious side effects including:

• People with asthma who take long-acting beta₂ adrenergic agonist (LABA) medicines such as Simplyone (Formoterol Fumarate) Inhalation Solution have an increased risk of death from asthma problems.
• It is not known if LABA medicines, such as Simplyone (Formoterol Fumarate) Inhalation Solution, increase the risk of death in people with chronic obstructive pulmonary disease (COPD).
• Get emergency medical care if:
  • breathing problems worsen quickly
  • you use your rescue inhaler medicine, but it does not relieve your breathing problems

What is Simplyone (Formoterol Fumarate) Inhalation Solution?

Simplyone (Formoterol Fumarate) Inhalation Solution is used long term, 2 times a day (morning and evening), in controlling symptoms of chronic obstructive pulmonary disease (COPD) in adults with COPD.

Simplyone (Formoterol Fumarate) Inhalation Solution is only for use with a nebulizer. LABA medicines such as Simplyone (Formoterol Fumarate) Inhalation Solution help the muscles around the airways in your lungs stay relaxed to prevent symptoms, such as wheezing, cough, chest tightness, and shortness of breath.

Simplyone (Formoterol Fumarate) Inhalation Solution is not for use to treat sudden symptoms of COPD.

Simplyone (Formoterol Fumarate) Inhalation Solution should not be used in children. It is not known if Simplyone (Formoterol Fumarate) Inhalation Solution is safe and effective in children.

It is not known if Simplyone (Formoterol Fumarate) Inhalation Solution is safe and effective in people with asthma.

Who should not use Simplyone (Formoterol Fumarate) Inhalation Solution?

Do not use Simplyone (Formoterol Fumarate) Inhalation Solution if you have asthma without using a long-term asthma control medicine.

What should I tell my healthcare provider before using Simplyone (Formoterol Fumarate) Inhalation Solution?

Tell your healthcare provider about all of your health conditions, including if you:

• have heart problems
• have high blood pressure
• have diabetes
• have seizures
• have thyroid problems
• have liver problems
• are pregnant or planning to become pregnant. It is not known if Simplyone (Formoterol Fumarate) Inhalation Solution can harm an unborn baby.
• are breastfeeding. It is not known if Simplyone (Formoterol Fumarate) Inhalation Solution passes into breast milk and if it can harm your baby.

Tell your healthcare provider about all the medicines you take including prescription and non-prescription medicines, vitamins and herbal supplements. Simplyone (Formoterol Fumarate) Inhalation Solution and certain other medicines may interact with each other. This may cause serious side effects.

Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist each time you get a new medicine.

How should I use Simplyone (Formoterol Fumarate) Inhalation Solution?

Read the step-by-step instructions for using Simplyone (Formoterol Fumarate) Inhalation Solution at the end of this Medication Guide.

• Use Simplyone (Formoterol Fumarate) Inhalation Solution exactly as prescribed. One ready-to-use vial of Simplyone (Formoterol Fumarate) Inhalation Solution is one dose. The usual dose of Simplyone (Formoterol Fumarate) Inhalation Solution is one ready-to-use vial, twice a day (morning and evening) breathed in through your nebulizer machine. The 2 doses should be about 12 hours apart. Do not use more than 2 vials of Simplyone (Formoterol Fumarate) Inhalation Solution a day.
• Do not mix other medicines with Simplyone (Formoterol Fumarate) Inhalation Solution in your nebulizer machine.
• If you miss a dose of Simplyone (Formoterol Fumarate) Inhalation Solution, just skip that dose. Take your next dose at your usual time. Do not take 2 doses at one time.
• While you are using Simplyone (Formoterol Fumarate) Inhalation Solution 2 times each day:
  • do not use other medicines that contain a long-acting beta₂-agonist (LABA) for any reason.
  • do not use your short-acting beta₂-agonist medicine on a regular basis (four times a day).
• Simplyone (Formoterol Fumarate) Inhalation Solution does not relieve sudden symptoms of COPD. Always have a rescue inhaler medicine with you to treat sudden symptoms. If you do not have a rescue inhaler medicine, call your healthcare provider to have one prescribed for you.
• Do not stop using Simplyone (Formoterol Fumarate) Inhalation Solution or other medicines to control or treat your COPD unless told to do so by your healthcare provider because your symptoms might get worse. Your healthcare provider will change your medicines as needed.
• Do not use Simplyone (Formoterol Fumarate) Inhalation Solution:
  • more often than prescribed,
  • more medicine than prescribed for you, or
  • with other LABA medicines

Call your healthcare provider or get emergency medical care right away if:

• your breathing problems worsen with Simplyone (Formoterol Fumarate) Inhalation Solution
• you need to use your rescue inhaler medicine more often than usual
• your rescue inhaler medicine does not work as well for you at relieving symptoms

What are the possible side effects of Simplyone (Formoterol Fumarate) Inhalation Solution?

Simplyone (Formoterol Fumarate) Inhalation Solution can cause serious side effects, including:

• See “What is the most important information I should know about Simplyone (Formoterol Fumarate) Inhalation Solution?”
• Sudden shortness of breath immediately after use of Simplyone (Formoterol Fumarate) Inhalation Solution.
• Serious allergic reactions including rash, hives, swelling of the face, mouth, and tongue, and breathing problems. Call your healthcare provider or get emergency medical care if you get any symptoms of a serious allergic reaction.
• chest pain
• increased or decreased blood pressure
• a fast and irregular heartbeat
• low blood potassium
• high blood sugar
• high blood acid

Common side effects of Simplyone (Formoterol Fumarate) Inhalation Solution include:

• headache
• tremor
• nervousness
• dry mouth
• muscle cramps
• nausea, vomiting
• diarrhea
• dizziness
• tiredness
• trouble sleeping
• If your COPD symptoms worsen over time do not increase your dose of Simplyone (Formoterol Fumarate) Inhalation Solution, instead call your healthcare provider.

Tell your healthcare provider if you get any side effect that bothers you or that does not go away.

These are not all the side effects with Simplyone (Formoterol Fumarate) Inhalation Solution. Ask your healthcare provider or pharmacist for more information.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store Simplyone (Formoterol Fumarate) Inhalation Solution?

• Store Simplyone (Formoterol Fumarate) Inhalation Solution in a refrigerator between 36° to 46°F (2^o to 8^oC) in the protective foil pouch. Protect from light and heat. Do not open a sealed pouch until you are ready to use a dose of Simplyone (Formoterol Fumarate) Inhalation Solution. Once a sealed pouch is opened, Simplyone (Formoterol Fumarate) Inhalation Solution must be used right away. Simplyone (Formoterol Fumarate) Inhalation Solution may be used directly from the refrigerator.
• Simplyone (Formoterol Fumarate) Inhalation Solution may also be stored at room temperature between 68ºF to 77ºF (20ºC to 25ºC) for up to 3 months (90 days). If stored at room temperature, discard Simplyone (Formoterol Fumarate) Inhalation Solution if it is not used after 3 months or if past the expiration date, whichever is sooner. Space is provided on the packaging to record dispense date and use by date.
• Do not use Simplyone (Formoterol Fumarate) Inhalation Solution after the expiration date provided on the foil pouch and vial.
• Simplyone (Formoterol Fumarate) Inhalation Solution should be colorless. Discard Simplyone (Formoterol Fumarate) Inhalation Solution if it is not colorless.
• Keep Simplyone (Formoterol Fumarate) Inhalation Solution and all medicines out of the reach of children.

General Information about Simplyone (Formoterol Fumarate) Inhalation Solution

Medicines are sometimes prescribed for purposes that are not mentioned in a Medication Guide. Do not use Simplyone (Formoterol Fumarate) Inhalation Solution for a condition for which it was not prescribed. Do not give Simplyone (Formoterol Fumarate) Inhalation Solution to other people, even if they have the same condition. It may harm them.

This Medication Guide summarizes the most important information about Simplyone (Formoterol Fumarate) Inhalation Solution. If you would like more information, talk with your health care provider. You can ask your health care provider or pharmacist for information about Simplyone (Formoterol Fumarate) Inhalation Solution that was written for healthcare professionals.

• For customer service, call 1-800-395-3376
• To report side effects, call 1-877-446-3679
• For medical information, call 1-800-429-7751

Instructions for Using Simplyone (Formoterol Fumarate) (formoterol fumarate) Inhalation Solution

Simplyone (Formoterol Fumarate) Inhalation Solution is used only in a standard jet nebulizer machine connected to an air compressor. Make sure you know how to use your nebulizer machine before you use it to breathe in Simplyone (Formoterol Fumarate) Inhalation Solution or other medicines.

Do not mix Simplyone (Formoterol Fumarate) Inhalation Solution with other medicines in your nebulizer machine.

Simplyone (Formoterol Fumarate) Inhalation Solution comes sealed in a foil pouch. Do not open a sealed pouch until you are ready to use a dose of Simplyone (Formoterol Fumarate) Inhalation Solution.

• Remove vial from the foil pouch.
• Twist the cap completely off the vial and squeeze all the medicine into the nebulizer medicine cup (reservoir) (Figure 1).
  

• Connect the nebulizer reservoir to the mouthpiece or facemask (Figure 2).
• Connect the nebulizer to the compressor.
• Sit in a comfortable, upright position. Place the mouthpiece in your mouth (Figure 3) or put on the facemask (Figure 4); and turn on the compressor.
• Breathe as calmly, deeply and evenly as possible through your mouth until no more mist is formed in the nebulizer reservoir. The average nebulization time is 9 minutes. At this point, the treatment is finished.
• Discard the Simplyone (Formoterol Fumarate) Inhalation Solution container and top after use.
• Clean the nebulizer.

Manufactured for:

Mylan Specialty L.P.

Morgantown, WV 26505

Manufactured by:

The Ritedose Corporation

Columbia, SC 29203

Revised MARCH 2013

This Medication Guide has been approved by the U.S. Food and Drug Administration

A3-031-00

Figure 1 Figure 2 Figures 3 and 4

PRINCIPAL DISPLAY PANEL - 20 mcg/2 mL vial

NDC 49502-605-61

Simplyone (Formoterol Fumarate)^®

(formoterol fumarate) INHALATION SOLUTION

20 mcg/2 mL vial

Medication Guide For Patients Enclosed

Sterile Unit Dose Vials - Individually Wrapped - For Oral Inhalation Only

CARTON CONTAINS: 60 individually wrapped 2 mL vials

EACH 2 mL VIAL CONTAINS: ACTIVE: Simplyone (Formoterol Fumarate), USP.

INACTIVES: Citric acid, sodium citrate, sodium chloride, and water.

STORAGE CONDITIONS:

PRIOR TO DISPENSING TO THE PATIENT: Store refrigerated, 2°C to 8°C (36°F to 46°F).

AFTER DISPENSING TO THE PATIENT: Store at 2°C to 25°C (36°F to 77°F) for up to 3 months.

Protect pouch from heat. VIAL SHOULD ALWAYS BE STORED IN THE FOIL POUCH, AND ONLY REMOVED IMMEDIATELY BEFORE USE.

Keep out of reach of children.

FOR THE HEALTHCARE PROVIDER: When Simplyone (Formoterol Fumarate)^® Inhalation Solution is dispensed to the patient, write an expiration date in the "Use by" box on the carton or dispensing container. The date should not exceed either 3 months from date dispensed or the expiration date on the product, whichever comes first. After dispensing to the patient, store at 2°C to 25°C (36°F to 77°F) for up to 3 months.

FOR THE PATIENT: Use Simplyone (Formoterol Fumarate)^® Inhalation Solution prior to the "Use by" date.

Rx Only

U.S. Pat. Nos. 6,667,344 and 6,814,953

Mylan Specialty L.P., Morgantown, WV 26505

Manufactured for:

Mylan Specialty L.P.

Morgantown, WV 26505

Manufactured by:

The Ritedose Corporation

Columbia, SC 29203

02-487-00

Simplyone (Formoterol Fumarate) Inhalation Solution 20 mcg/2 mL Carton