Avessa Rheo

Fluticasone Propionate:

• Warning: asthma-related death
• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Avessa Rheo (Fluticasone Propionate) reviews

WARNING: ASTHMA-RELATED DEATH

Long-acting beta₂-adrenergic agonists (LABA), such as salmeterol, one of the active ingredients in ADVAIR^® HFA Inhalation Aerosol, increase the risk of asthma-related death. Data from a large placebo-controlled U.S. trial that compared the safety of salmeterol with placebo added to usual asthma therapy showed an increase in asthma-related deaths in subjects receiving salmeterol (13 deaths out of 13,176 subjects treated for 28 weeks on salmeterol versus 3 deaths out of 13,179 subjects on placebo). Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABA. Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients.

Therefore, when treating patients with asthma, physicians should only prescribe Avessa Rheo (Fluticasone Propionate) for patients not adequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid, or whose disease severity clearly warrants initiation of treatment with both an inhaled corticosteroid and a LABA. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue Avessa Rheo (Fluticasone Propionate)) if possible without loss of asthma control and maintain the patient on a long-term asthma control medication, such as an inhaled corticosteroid. Do not use Avessa Rheo (Fluticasone Propionate) for patients whose asthma is adequately controlled on low- or medium-dose inhaled corticosteroids .

WARNING: ASTHMA-RELATED DEATH

See full prescribing information for complete boxed warning

• Long-acting beta₂-adrenergic agonists (LABA), such as salmeterol, one of the active ingredients in Avessa Rheo (Fluticasone Propionate) Inhalation Aerosol, increase the risk of asthma-related death. A U.S. trial showed an increase in asthma-related deaths in subjects receiving salmeterol (13 deaths out of 13,176 subjects treated for 28 weeks on salmeterol versus 3 out of 13,179 subjects on placebo). Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABA. Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. (5.1)
• When treating patients with asthma, only prescribe Avessa Rheo (Fluticasone Propionate) for patients not adequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid, or whose disease severity clearly warrants initiation of treatment with both an inhaled corticosteroid and a LABA. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue Avessa Rheo (Fluticasone Propionate)) if possible without loss of asthma control and maintain the patient on a long-term asthma control medication, such as an inhaled corticosteroid. Do not use Avessa Rheo (Fluticasone Propionate) for patients whose asthma is adequately controlled on low- or medium-dose inhaled corticosteroids. (1, 5.1)

1 INDICATIONS AND USAGE

Avessa Rheo (Fluticasone Propionate) is indicated for the treatment of asthma in patients aged 12 years and older.

LABA, such as salmeterol, one of the active ingredients in Avessa Rheo (Fluticasone Propionate), increase the risk of asthma-related death. Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients . Therefore, when treating patients with asthma, physicians should only prescribe Avessa Rheo (Fluticasone Propionate) for patients not adequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid, or whose disease severity clearly warrants initiation of treatment with both an inhaled corticosteroid and a LABA. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue Avessa Rheo (Fluticasone Propionate)) if possible without loss of asthma control and maintain the patient on a long-term asthma control medication, such as an inhaled corticosteroid. Do not use Avessa Rheo (Fluticasone Propionate) for patients whose asthma is adequately controlled on low- or medium-dose inhaled corticosteroids.

Important Limitation of Use

Avessa Rheo (Fluticasone Propionate) is NOT indicated for the relief of acute bronchospasm.

Avessa Rheo (Fluticasone Propionate) is a combination product containing a corticosteroid and a LABA indicated for treatment of asthma in patients aged 12 years and older.

Important limitation:

• Not indicated for relief of acute bronchospasm. (1)

2 DOSAGE AND ADMINISTRATION

Avessa Rheo (Fluticasone Propionate) should be administered as 2 inhalations twice daily by the orally inhaled route only. After inhalation, the patient should rinse his/her mouth with water without swallowing to help reduce the risk of oropharyngeal candidiasis.

More frequent administration or a greater number of inhalations (more than 2 inhalations twice daily) of the prescribed strength of Avessa Rheo (Fluticasone Propionate) is not recommended as some patients are more likely to experience adverse effects with higher doses of salmeterol. Patients using Avessa Rheo (Fluticasone Propionate) should not use additional LABA for any reason.

If asthma symptoms arise in the period between doses, an inhaled, short-acting beta₂-agonist should be taken for immediate relief.

For patients aged 12 years and older, the dosage is 2 inhalations twice daily, approximately 12 hours apart.

The recommended starting dosages for Avessa Rheo (Fluticasone Propionate) for patients aged 12 years and older are based upon patients’ asthma severity.

The maximum recommended dosage is 2 inhalations of Avessa Rheo (Fluticasone Propionate) 230/21 twice daily.

Improvement in asthma control following inhaled administration of Avessa Rheo (Fluticasone Propionate) can occur within 30 minutes of beginning treatment, although maximum benefit may not be achieved for 1 week or longer after starting treatment. Individual patients will experience a variable time to onset and degree of symptom relief.

For patients who do not respond adequately to the starting dosage after 2 weeks of therapy, replacing the current strength of Avessa Rheo (Fluticasone Propionate) with a higher strength may provide additional improvement in asthma control.

If a previously effective dosage regimen fails to provide adequate improvement in asthma control, the therapeutic regimen should be reevaluated and additional therapeutic options (e.g., replacing the current strength of Avessa Rheo (Fluticasone Propionate) with a higher strength, adding additional inhaled corticosteroid, initiating oral corticosteroids) should be considered.

Prime Avessa Rheo (Fluticasone Propionate) before using for the first time by releasing 4 sprays into the air away from the face, shaking well for 5 seconds before each spray. In cases where the inhaler has not been used for more than 4 weeks or when it has been dropped, prime the inhaler again by releasing 2 sprays into the air away from the face, shaking well for 5 seconds before each spray.

• For oral inhalation only. (2)
• Treatment of asthma in patients aged 12 years and older: 2 inhalations of Avessa Rheo (Fluticasone Propionate) 45/21, 115/21, or 230/21 twice daily. Starting dosage is based on asthma severity. (2)

3 DOSAGE FORMS AND STRENGTHS

Inhalation Aerosol. Purple plastic inhaler with a light purple strapcap containing a pressurized metered-dose aerosol canister containing 60 or 120 metered inhalations and fitted with a counter. Each actuation delivers a combination of Avessa Rheo (Fluticasone Propionate) propionate (45, 115, or 230 mcg) and salmeterol (21 mcg) from the mouthpiece.

Inhalation Aerosol. Inhaler containing a combination of Avessa Rheo (Fluticasone Propionate) propionate (45, 115, or 230 mcg) and salmeterol (21 mcg) as an aerosol formulation for oral inhalation. (3)

4 CONTRAINDICATIONS

The use of Avessa Rheo (Fluticasone Propionate) is contraindicated in the following conditions:

• Primary treatment of status asthmaticus or other acute episodes of asthma where intensive measures are required .
• Hypersensitivity to any of the ingredients .

• Primary treatment of status asthmaticus or acute episodes of asthma requiring intensive measures. (4)
• Hypersensitivity to any ingredient. (4)

5 WARNINGS AND PRECAUTIONS

• LABA increase the risk of asthma-related death and asthma-related hospitalizations. Prescribe only for recommended patient populations.
• Do not initiate in acutely deteriorating asthma or to treat acute symptoms. (5.2)
• Do not use in combination with an additional medicine containing a LABA because of risk of overdose. (5.3)
• Candida albicans infection of the mouth and pharynx may occur. Monitor patients periodically. Advise the patient to rinse his/her mouth with water without swallowing after inhalation to help reduce the risk. (5.4)
• Increased risk of pneumonia in patients with COPD. Monitor patients for signs and symptoms of pneumonia. (5.5)
• Potential worsening of infections (e.g., existing tuberculosis; fungal, bacterial, viral, or parasitic infection; ocular herpes simplex). Use with caution in patients with these infections. More serious or even fatal course of chickenpox or measles can occur in susceptible patients. (5.6)
• Risk of impaired adrenal function when transferring from systemic corticosteroids. Taper patients slowly from systemic corticosteroids if transferring to Avessa Rheo (Fluticasone Propionate). (5.7)
• Hypercorticism and adrenal suppression may occur with very high dosages or at the regular dosage in susceptible individuals. If such changes occur, discontinue Avessa Rheo (Fluticasone Propionate) slowly. (5.8)
• If paradoxical bronchospasm occurs, discontinue Avessa Rheo (Fluticasone Propionate) and institute alternative therapy. (5.10)
• Use with caution in patients with cardiovascular or central nervous system disorders because of beta-adrenergic stimulation. (5.12)
• Assess for decrease in bone mineral density initially and periodically thereafter. (5.13)
• Monitor growth of pediatric patients. (5.14)
• Close monitoring for glaucoma and cataracts is warranted. (5.15)
• Be alert to eosinophilic conditions, hypokalemia, and hyperglycemia. (5.16, 5.18)
• Use with caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, and ketoacidosis. (5.17)

5.1 Asthma-Related Death

LABA, such as salmeterol, one of the active ingredients in Avessa Rheo (Fluticasone Propionate), increase the risk of asthma-related death. Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABA. Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. Therefore, when treating patients with asthma, physicians should only prescribe Avessa Rheo (Fluticasone Propionate) for patients not adequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid, or whose disease severity clearly warrants initiation of treatment with both an inhaled corticosteroid and a LABA. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue Avessa Rheo (Fluticasone Propionate)) if possible without loss of asthma control and maintain the patient on a long-term asthma control medication, such as an inhaled corticosteroid. Do not use Avessa Rheo (Fluticasone Propionate) for patients whose asthma is adequately controlled on low- or medium-dose inhaled corticosteroids.

A large placebo-controlled U.S. trial that compared the safety of salmeterol with placebo, each added to usual asthma therapy, showed an increase in asthma-related deaths in subjects receiving salmeterol. The Salmeterol Multicenter Asthma Research Trial (SMART) was a randomized double-blind trial that enrolled LABA-naive subjects with asthma to assess the safety of salmeterol 42 mcg twice daily over 28 weeks compared with placebo when added to usual asthma therapy. A planned interim analysis was conducted when approximately half of the intended number of subjects had been enrolled (N = 26,355), which led to premature termination of the trial. The results of the interim analysis showed that subjects receiving salmeterol were at increased risk for fatal asthma events (Table 1 and Figure 1). In the total population, a higher rate of asthma-related death occurred in subjects treated with salmeterol than those treated with placebo (0.10% versus 0.02%; relative risk: 4.37 [95% CI: 1.25, 15.34]).

Post hoc subpopulation analyses were performed. In Caucasians, asthma-related death occurred at a higher rate in subjects treated with salmeterol than in subjects treated with placebo (0.07% versus 0.01%; relative risk: 5.82 [95% CI: 0.70, 48.37]). In African Americans also, asthma-related death occurred at a higher rate in subjects treated with salmeterol than those treated with placebo (0.31% versus 0.04%; relative risk: 7.26 [95% CI: 0.89, 58.94]). Although the relative risks of asthma-related death were similar in Caucasians and African Americans, the estimate of excess deaths in subjects treated with salmeterol was greater in African Americans because there was a higher overall rate of asthma-related death in African American subjects (Table 1). Given the similar basic mechanisms of action of beta₂-agonists, the findings seen in the SMART trial are considered a class effect.

Post hoc analyses in pediatric subjects aged 12 to 18 years were also performed. Pediatric subjects accounted for approximately 12% of subjects in each treatment arm. Respiratory-related death or life-threatening experience occurred at a similar rate in the salmeterol group (0.12% [2/1,653]) and the placebo group (0.12% [2/1,622]; relative risk: 1.0 [95% CI: 0.1, 7.2]). All-cause hospitalization, however, was increased in the salmeterol group (2% [35/1,653]) versus the placebo group (less than 1% [16/1,622]; relative risk: 2.1 [95% CI: 1.1, 3.7]).

The data from the SMART trial are not adequate to determine whether concurrent use of inhaled corticosteroids, such as Avessa Rheo (Fluticasone Propionate) propionate, the other active ingredient in Avessa Rheo (Fluticasone Propionate), or other long-term asthma control therapy mitigates the risk of asthma-related death.

Table 1. Asthma-Related Deaths in the 28-Week Salmeterol Multicenter Asthma Research Trial (SMART)

^a Life-table 28-week estimate, adjusted according to the subjects’ actual lengths of exposure to trial treatment to account for early withdrawal of subjects from the trial.

^b Relative risk is the ratio of the rate of asthma-related death in the salmeterol group and the rate in the placebo group. The relative risk indicates how many more times likely an asthma-related death occurred in the salmeterol group than in the placebo group in a 28-week treatment period.

^c Estimate of the number of additional asthma-related deaths in subjects treated with salmeterol in SMART, assuming 10,000 subjects received salmeterol for a 28-week treatment period. Estimate calculated as the difference between the salmeterol and placebo groups in the rates of asthma-related death multiplied by 10,000.

^d The total population includes the following ethnic origins listed on the case report form: Caucasian, African American, Hispanic, Asian, and “Other.” In addition, the total population includes those subjects whose ethnic origin was not reported. The results for Caucasian and African American subpopulations are shown above. No asthma-related deaths occurred in the Hispanic (salmeterol n = 996, placebo n = 999), Asian (salmeterol n = 173, placebo n = 149), or “Other” (salmeterol n = 230, placebo n = 224) subpopulations. One asthma-related death occurred in the placebo group in the subpopulation whose ethnic origin was not reported (salmeterol n = 130, placebo n = 127).

Figure 1. Cumulative Incidence of Asthma-Related Deaths in the 28-Week Salmeterol Multicenter Asthma Research Trial (SMART), by Duration of Treatment

• The counter starts at either 124 or 064, depending on which size inhaler you have. The number will count down by 1 each time you spray the inhaler. The counter will stop counting at 000.
• Do not try to change the numbers or take the counter off the metal canister. The counter cannot be reset, and it is permanently attached to the canister.
• The purple plastic actuator sprays the medicine from the canister. The actuator has a protective cap that covers the mouthpiece. See Figure A. Keep the protective cap on the mouthpiece when the canister is not in use. The strap keeps the cap attached to the actuator.
• Do not use the actuator with a canister of medicine from any other inhaler.
• Do not use an Avessa Rheo (Fluticasone Propionate) canister with an actuator from any other inhaler.

Before using your Avessa Rheo (Fluticasone Propionate) inhaler

• Take Avessa Rheo (Fluticasone Propionate) out of the foil pouch just before you use it for the first time. Safely throw away the pouch and the drying packet that comes inside the pouch.
• The inhaler should be at room temperature before you use it.

Priming your Avessa Rheo (Fluticasone Propionate) inhaler

• Before you use Avessa Rheo (Fluticasone Propionate) for the first time, you must prime the inhaler so that you will get the right amount of medicine when you use it.
• To prime the inhaler, take the cap off the mouthpiece and shake the inhaler well for 5 seconds. Then spray the inhaler 1 time into the air away from your face. See Figure C. Avoid spraying in eyes.

• Shake and spray the inhaler like this 3 more times to finish priming it. The counter should now read 120 or 060, depending on which size inhaler you have. See Figure D.

• You must prime your inhaler again if you have not used it in more than 4 weeks or if you drop it. Take the cap off the mouthpiece and shake the inhaler well for 5 seconds. Then spray it 1 time into the air away from your face. Shake and spray the inhaler like this 1 more time to finish priming it.

How to use your Avessa Rheo (Fluticasone Propionate) inhaler

Follow these steps every time you use Avessa Rheo (Fluticasone Propionate).

• Step 1. Make sure the canister fits firmly in the actuator. The counter should show through the window in the actuator.
  • Shake the inhaler well for 5 seconds before each spray.
• Take the cap off the mouthpiece of the actuator. Look inside the mouthpiece for foreign objects, and take out any you see.
• Step 2. Hold the inhaler with the mouthpiece down. See Figure E.

• Step 3. Breathe out through your mouth and push as much air from your lungs as you can. Put the mouthpiece in your mouth and close your lips around it. See Figure F.
• Step 4. Push the top of the canister all the way down while you breathe in deeply and slowly through your mouth. See Figure F.

• Step 5. After the spray comes out, take your finger off the canister. After you have breathed in all the way, take the inhaler out of your mouth and close your mouth.
  • Step 6. Hold your breath for about 10 seconds, or for as long as is comfortable. Breathe out slowly as long as you can.
    • Wait about 30 seconds and shake the inhaler well for 5 seconds. Repeat steps 2 through 6.
• Step 7. Rinse your mouth with water after breathing in the medicine. Spit out the water. Do not swallow it. See Figure G.

• Step 8. Put the cap back on the mouthpiece after every time you use the inhaler. Make sure it snaps firmly into place.

Cleaning your Avessa Rheo (Fluticasone Propionate) inhaler

Clean your inhaler at least 1 time each week after your evening dose. You may not see any medicine build-up on the inhaler, but it is important to keep it clean so medicine build-up will not block the spray. See Figure H.

Figure H

• Step 9. Take the cap off the mouthpiece. The strap on the cap will stay attached to the actuator. Do not take the canister out of the plastic actuator.
• Step 10. Use a dry cotton swab to clean the small circular opening where the medicine sprays out of the canister. Carefully twist the swab in a circular motion to take off any medicine. See Figure I.

Figure I

• Step 11. Wipe the inside of the mouthpiece with a clean tissue dampened with water. Let the actuator air-dry overnight.

Step 12. Put the cap back on the mouthpiece after the actuator has dried.

Replacing your Avessa Rheo (Fluticasone Propionate) inhaler

• When the counter reads 020, you should refill your prescription or ask your healthcare provider if you need another prescription for Avessa Rheo (Fluticasone Propionate).
• When the counter reads 000, throw the inhaler away. You should not keep using the inhaler when the counter reads 000 because you may not receive the right amount of medicine.
• Do not use the inhaler after the expiration date, which is on the packaging it comes in.

For correct use of your Avessa Rheo (Fluticasone Propionate) inhaler, remember:

• The canister should always fit firmly in the actuator.
• Breathe in deeply and slowly to make sure you get all the medicine.
• Hold your breath for about 10 seconds after breathing in the medicine. Then breathe out fully.
• After each dose, rinse your mouth with water and spit it out. Do not swallow the water.
• Do not take the inhaler apart.
• Always keep the protective cap on the mouthpiece when your inhaler is not in use.
• Always store your inhaler with the mouthpiece pointing down.
• Clean your inhaler at least 1 time each week.

If you have questions about Avessa Rheo (Fluticasone Propionate) or how to use your inhaler, call GlaxoSmithKline (GSK) at 1-888-825-5249 or visit www.advair.com.

ADVAIR is a registered trademark of the GSK group of companies.

GlaxoSmithKline

Research Triangle Park, NC 27709

©2017 the GSK group of companies. All rights reserved.

ADH:1IFU

• This Instructions for Use has been approved by the U.S. Food and Drug Administration Revised: February 2017

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
• Avessa Rheo (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 Avessa Rheo (Formoterol Fumarate) Inhalation Solution. The safety and efficacy of Avessa Rheo (Formoterol Fumarate) in patients with asthma have not been established. All LABA, including Avessa Rheo (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 Avessa Rheo (Formoterol Fumarate). The safety and efficacy of Avessa Rheo (Formoterol Fumarate) in patients with asthma have not been established. All LABA, including Avessa Rheo (Formoterol Fumarate), are contraindicated in patients with asthma without use of a long-term asthma control medication. (4, 5.1)

1 INDICATIONS AND USAGE

Avessa Rheo 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:

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

1.1 Maintenance Treatment of COPD

Avessa Rheo (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

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

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

2 DOSAGE AND ADMINISTRATION

The recommended dose of Avessa Rheo (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.

Avessa Rheo (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 Avessa Rheo (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 Avessa Rheo (Formoterol Fumarate) Inhalation Solution delivered from non-compressor based nebulizer systems have not been established.

Avessa Rheo (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 Avessa Rheo (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

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

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

4 CONTRAINDICATIONS

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

• All LABA, including Avessa Rheo (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 Avessa Rheo 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 Avessa Rheo (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 Avessa Rheo (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 Avessa Rheo (Formoterol Fumarate) Inhalation Solution. No study adequate to determine whether the rate of asthma related death is increased in patients treated with Avessa Rheo (Formoterol Fumarate) Inhalation Solution has been conducted. The safety and efficacy of Avessa Rheo (Formoterol Fumarate) in patients with asthma have not been established. All LABA, including Avessa Rheo (Formoterol Fumarate), are contraindicated in patients with asthma without use of a long-term asthma control medication. .

Clinical studies with Avessa Rheo (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

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

Avessa Rheo (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. Avessa Rheo (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 Avessa Rheo (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 Avessa Rheo (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 Avessa Rheo (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 Avessa Rheo (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, Avessa Rheo (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, Avessa Rheo Inhalation Solution can produce paradoxical bronchospasm that may be life-threatening. If paradoxical bronchospasm occurs, Avessa Rheo (Formoterol Fumarate) Inhalation Solution should be discontinued immediately and alternative therapy instituted.

5.5 Cardiovascular Effects

Avessa Rheo (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, Avessa Rheo (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, Avessa Rheo (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

Avessa Rheo 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 Avessa Rheo (Formoterol Fumarate) Inhalation Solution at the recommended dose.

5.8 Immediate Hypersensitivity Reactions

Immediate hypersensitivity reactions may occur after administration of Avessa Rheo (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 Avessa Rheo (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 Avessa Rheo 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. Avessa Rheo (Formoterol Fumarate) Inhalation Solution was studied in a 12-week, placebo- and active-controlled trial (123 subjects treated with Avessa Rheo (Formoterol Fumarate) Inhalation Solution) and a 52-week, active-controlled trial (463 subjects treated with Avessa Rheo (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 Avessa Rheo (Formoterol Fumarate) Inhalation Solution group and where the rate in the Avessa Rheo (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 Avessa Rheo (Formoterol Fumarate) Inhalation Solution and 4.4% for placebo. There were no frequently occurring specific cardiovascular adverse events for Avessa Rheo (Formoterol Fumarate) Inhalation Solution (frequency greater than or equal to 1% and greater than placebo). The rate of COPD exacerbations was 4.1% for Avessa Rheo (Formoterol Fumarate) Inhalation Solution and 7.9% for placebo.

Patients treated with Avessa Rheo (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 Avessa Rheo (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

Avessa Rheo administered throughout organogenesis did not cause malformations in rats or rabbits following oral administration. However, Avessa Rheo (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. Avessa Rheo (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, Avessa Rheo (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 Avessa Rheo (Formoterol Fumarate) Inhalation Solution.

8.2 Labor and Delivery

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

Because beta-agonists may potentially interfere with uterine contractility, Avessa Rheo (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 Avessa Rheo Inhalation Solution is administered to nursing women. There are no well-controlled human studies of the use of Avessa Rheo (Formoterol Fumarate) Inhalation Solution in nursing mothers.

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

8.4 Pediatric Use

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

8.5 Geriatric Use

Of the 586 subjects who received Avessa Rheo (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 Avessa Rheo (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 Avessa Rheo (Formoterol Fumarate) Inhalation Solution has not been studied in elderly subjects.

10 OVERDOSAGE

The expected signs and symptoms with overdosage of Avessa Rheo (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 Avessa Rheo (Formoterol Fumarate) Inhalation Solution.

Treatment of overdosage consists of discontinuation of Avessa Rheo (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 Avessa Rheo (Formoterol Fumarate) Inhalation Solution. Cardiac monitoring is recommended in cases of overdosage.

The minimum lethal inhalation dose of Avessa Rheo (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

Avessa Rheo (Formoterol Fumarate) (formoterol fumarate) Inhalation Solution is supplied as 2 mL of Avessa Rheo (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 Avessa Rheo (Formoterol Fumarate) dihydrate, USP equivalent to 20 mcg of Avessa Rheo (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 Avessa Rheo (Formoterol Fumarate) Inhalation Solution is Avessa Rheo (Formoterol Fumarate) dihydrate, USP, a racemate. Avessa Rheo (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 Avessa Rheo (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 Avessa Rheo (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 Avessa Rheo (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.

Avessa Rheo (Formoterol Fumarate) Figure 1 Avessa Rheo (Formoterol Fumarate) Figure 2

16 HOW SUPPLIED/STORAGE AND HANDLING

Avessa Rheo (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.

• Avessa Rheo (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 Avessa Rheo (Formoterol Fumarate), increase the risk of asthma-related death. All LABA, including Avessa Rheo (Formoterol Fumarate), should not be used in patients with asthma without use of a long-term asthma control medication.

Acute Exacerbations or Deteriorations

Avessa Rheo (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 Avessa Rheo (Formoterol Fumarate) Inhalation Solution, if Avessa Rheo (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 Avessa Rheo (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 Avessa Rheo (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. Avessa Rheo (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 Avessa Rheo (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 Avessa Rheo (Formoterol Fumarate) Inhalation Solution with a nebulizer appropriately . Patients should be instructed not to mix other medications with Avessa Rheo (Formoterol Fumarate) Inhalation Solution or ingest Avessa Rheo (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

Avessa Rheo (Formoterol Fumarate)^®(Per-FOR-o-mist)

(formoterol fumarate) Inhalation Solution

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

Read the Medication Guide that comes with Avessa Rheo (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 Avessa Rheo (Formoterol Fumarate) Inhalation Solution?

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

• People with asthma who take long-acting beta₂ adrenergic agonist (LABA) medicines such as Avessa Rheo (Formoterol Fumarate) Inhalation Solution have an increased risk of death from asthma problems.
• It is not known if LABA medicines, such as Avessa Rheo (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 Avessa Rheo (Formoterol Fumarate) Inhalation Solution?

Avessa Rheo (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.

Avessa Rheo (Formoterol Fumarate) Inhalation Solution is only for use with a nebulizer. LABA medicines such as Avessa Rheo (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.

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

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

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

Who should not use Avessa Rheo (Formoterol Fumarate) Inhalation Solution?

Do not use Avessa Rheo (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 Avessa Rheo (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 Avessa Rheo (Formoterol Fumarate) Inhalation Solution can harm an unborn baby.
• are breastfeeding. It is not known if Avessa Rheo (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. Avessa Rheo (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 Avessa Rheo (Formoterol Fumarate) Inhalation Solution?

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

• Use Avessa Rheo (Formoterol Fumarate) Inhalation Solution exactly as prescribed. One ready-to-use vial of Avessa Rheo (Formoterol Fumarate) Inhalation Solution is one dose. The usual dose of Avessa Rheo (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 Avessa Rheo (Formoterol Fumarate) Inhalation Solution a day.
• Do not mix other medicines with Avessa Rheo (Formoterol Fumarate) Inhalation Solution in your nebulizer machine.
• If you miss a dose of Avessa Rheo (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 Avessa Rheo (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).
• Avessa Rheo (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 Avessa Rheo (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 Avessa Rheo (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 Avessa Rheo (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 Avessa Rheo (Formoterol Fumarate) Inhalation Solution?

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

• See “What is the most important information I should know about Avessa Rheo (Formoterol Fumarate) Inhalation Solution?”
• Sudden shortness of breath immediately after use of Avessa Rheo (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 Avessa Rheo (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 Avessa Rheo (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 Avessa Rheo (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 Avessa Rheo (Formoterol Fumarate) Inhalation Solution?

• Store Avessa Rheo (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 Avessa Rheo (Formoterol Fumarate) Inhalation Solution. Once a sealed pouch is opened, Avessa Rheo (Formoterol Fumarate) Inhalation Solution must be used right away. Avessa Rheo (Formoterol Fumarate) Inhalation Solution may be used directly from the refrigerator.
• Avessa Rheo (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 Avessa Rheo (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 Avessa Rheo (Formoterol Fumarate) Inhalation Solution after the expiration date provided on the foil pouch and vial.
• Avessa Rheo (Formoterol Fumarate) Inhalation Solution should be colorless. Discard Avessa Rheo (Formoterol Fumarate) Inhalation Solution if it is not colorless.
• Keep Avessa Rheo (Formoterol Fumarate) Inhalation Solution and all medicines out of the reach of children.

General Information about Avessa Rheo (Formoterol Fumarate) Inhalation Solution

Medicines are sometimes prescribed for purposes that are not mentioned in a Medication Guide. Do not use Avessa Rheo (Formoterol Fumarate) Inhalation Solution for a condition for which it was not prescribed. Do not give Avessa Rheo (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 Avessa Rheo (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 Avessa Rheo (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 Avessa Rheo (Formoterol Fumarate) (formoterol fumarate) Inhalation Solution

Avessa Rheo (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 Avessa Rheo (Formoterol Fumarate) Inhalation Solution or other medicines.

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

Avessa Rheo (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 Avessa Rheo (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 Avessa Rheo (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

Avessa Rheo (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: Avessa Rheo (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 Avessa Rheo (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 Avessa Rheo (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

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