Data from Two Phase III Studies of Merck's Investigational Asthma Drug Presented at American Academy of Allergy, Asthma & Immunology (AAAAI) Annual Meeting

NEW ORLEANS--(BUSINESS WIRE)--Mar 2, 2010 - Data from two Phase III studies of Merck's investigational fixed-dose combinations of mometasone furoate and formoterol fumarate (MF/F) were presented by researchers today in two poster presentations at the American Academy of Allergy, Asthma & Immunology (AAAAI) annual meeting.


 

A New Drug Application (NDA) for MF/F is currently under review by the U.S. Food and Drug Administration (FDA). Merck has also submitted a Marketing Authorization Application (MAA) for MF/F to the European Medicines Evaluation Agency (EMEA). MF/F combines the active ingredient of an inhaled corticosteroid, ASMANEX® TWISTHALER® (mometasone furoate inhalation powder), with the active ingredient of a long-acting beta2-agonist, FORADIL® AEROLIZER® (formoterol fumarate inhalation powder), administered via a single metered-dose inhaler.


 

"Asthma is a common and complex disease. Results from these studies help us to better understand the potential role of MF/F in asthma management,” said Eli Meltzer, M.D., co-director of the Allergy & Asthma Medical Group and Research Center in San Diego, California and study investigator.


 

The first randomized, multicenter, double-blind, placebo-controlled study assessed the efficacy and safety of MF/F 100/10mcg administered via a metered dose inhaler (MDI) twice daily in patients 12 years of age and older with persistent asthma previously treated with low dose inhaled corticosteroids with or without a long-acting beta2-agonist. Patients were assigned to a two-to-three week open-label, run-in period with mometasone furoate MDI 100mcg twice daily prior to study randomization. A total of 746 patients were then randomized to 26 weeks of double-blind, twice daily treatment with: MF/F (100/10mcg), mometasone furoate MDI (100mcg), formoterol MDI (10mcg) or placebo.


 

The co-primary endpoints of the study were the comparison of MF/F versus formoterol in time-to-first severe asthma exacerbation over 26 weeks and the comparison of MF/F versus mometasone furoate in the week 12 area under the concentration-time curve (AUC) over baseline for forced expiratory volume in one second (FEV1), measured from 0 to 12 hours. In this study, a severe asthma exacerbation was defined as a meaningful reduction in lung function or an occurrence of any clinical deterioration of asthma resulting in emergency treatment, hospitalization, or treatment with additional asthma medication that was excluded from the clinical studies (such as an oral or systemic steroid).


 

Compared with formoterol, MF/F 100/10mcg twice daily increased time-to-first severe exacerbation and decreased the proportion of patients experiencing severe exacerbations over the course of the study; 16.5 percent of patients treated with MF/F 100/10mcg twice daily experienced severe exacerbations versus 44.7 percent of formoterol-treated patients (p<0.001).


 

Compared with mometasone furoate, patients receiving MF/F 100/10mcg twice daily showed improvements in lung function. Results showed the mean FEV1 AUC (0-12h) over baseline at week 12 was 4.00 liter-hours in patients receiving MF/F 100/10mcg twice daily compared with 2.53 liter-hours in patients receiving mometasone furoate 100mcg twice daily (p=0.001).


 

The most common treatment emergent adverse events occurring in the MF/F 100/10mcg twice daily group were nasopharyngitis (9.3 percent), headache (6.6 percent) upper respiratory tract infection (5.5 percent), pharyngolaryngeal pain (3.8 percent), and pharyngitis (2.7 percent).


 

The second study presented was a randomized, multicenter, double-blind, placebo-controlled clinical trial that assessed the safety and efficacy of MF/F 200/10mcg administered via MDI twice daily in patients 12 years of age and older with persistent asthma previously treated with medium dose inhaled corticosteroids with or without a long-acting beta2 agonist. Patients were assigned to a two-to-three week open-label, run-in period with mometasone furoate MDI 200mcg twice daily prior to study randomization. A total of 781 patients were then randomized to 26 weeks of double-blind, twice daily treatment with: MF/F (200/10mcg), mometasone furoate MDI (200mcg), formoterol MDI (10mcg) or placebo.


 

The co-primary endpoints of the study were the comparison of MF/F versus formoterol in time-to-first severe asthma exacerbation over 26 weeks and the comparison of MF/F versus mometasone furoate in the week 12 area under the concentration-time curve (AUC) over baseline for forced expiratory volume in one second (FEV1), measured from 0 to 12 hours. In this study, a severe asthma exacerbation was defined as a meaningful reduction in lung function or an occurrence of any clinical deterioration of asthma resulting in emergency treatment, hospitalization, or treatment with additional asthma medication that was excluded from the clinical studies (such as an oral or systemic steroid).


 

Compared with formoterol, MF/F 200/10mcg twice daily increased time-to-first severe exacerbation and decreased the proportion of patients experiencing severe exacerbations over the course of the study; 30 percent of patients treated with MF/F 200/10mcg twice daily experienced severe exacerbations versus 54 percent of formoterol-treated patients (p<0.001).


 

Compared with mometasone furoate, patients receiving MF/F 200/10mcg twice daily showed improvements in lung function. Results showed the mean FEV1 AUC (0-12h) over baseline at week 12 was 3.11 liter-hours in patients receiving MF/F 200/10mcg twice daily compared with 1.30 liter-hours in patients receiving mometasone furoate 200mcg twice daily (p<0.001).


 

The most common treatment emergent adverse reactions occurring in the MF/F 200/10mcg twice daily group were nasopharyngitis (6.3 percent), upper respiratory tract infection (5.8 percent), headache (4.7 percent), pharyngitis (4.2 percent), pharyngolaryngeal pain (3.1 percent), pyrexia (3.1 percent), viral infection (3.1 percent), bronchitis (2.6 percent), influenza (2.6 percent), rhinitis (2.6 percent), and sinusitis (2.6 percent).


 

Results from these studies, as well as six additional abstracts from the MF/F clinical development program, are being presented at an AAAAI poster session from 9:45-10:45 am CST Tuesday, March 2, 2010.


 

About ASMANEX® TWISTHALER®


 

ASMANEX® TWISTHALER® (mometasone furoate inhalation powder) is indicated for the maintenance treatment of asthma in patients four years of age and older. ASMANEX TWISTHALER will not relieve sudden asthma symptoms and is not for children under the age of four.


 

ASMANEX TWISTHALER is available in two dose strengths, 110 mcg for children between 4 and 11 years old, and 220 mcg for patients 12 and older.


 

Important Safety Information about ASMANEX® TWISTHALER®


 

ASMANEX TWISTHALER is not a rescue inhaler and should not be used to treat sudden asthma symptoms. Use a rescue inhaler to relieve sudden asthma symptoms. ASMANEX should not be used to treat acute asthma episodes (including status asthmaticus) where extra measures are required.


 

ASMANEX is not for patients who have a hypersensitivity (including allergic reactions) to mometasone or any of the ingredients in ASMANEX. There have been cases of hypersensitivity, allergic reactions, facial swelling, hives and throat tightness reported. Patients who use inhaled steroid medicines for asthma may develop a fungal infection of the mouth and throat. Rinse your mouth after using ASMANEX.


 

It is possible that hypercorticism (an excess level of steroids in your body) or adrenal insufficiency (your adrenal gland cannot produce enough steroids) may appear in a small number of patients, particularly when ASMANEX is administered at higher than recommended doses over prolonged periods of time. If such effects occur, consult your health care provider as the dosage of ASMANEX should be reduced slowly.


 

If you or your child took steroids by mouth and are having them decreased or are being switched to ASMANEX, you should be followed closely by your health care provider and the oral steroids should be reduced slowly. Deaths due to adrenal insufficiency have occurred during and after switching from oral steroids to inhaled steroids. Tell your health care provider right away about any symptoms such as feeling tired or exhausted, weakness, nausea, vomiting, or symptoms of low blood pressure (such as dizziness or faintness). If you or your child is under stress, such as with surgery, after surgery, or trauma, you may need steroids by mouth again.


 

Avoid coming in contact with measles, chicken pox virus, tuberculosis, or any other infections before or while using ASMANEX. Contact your health care provider immediately if you or your child have been exposed.


 

Patients who use inhaled steroids, including ASMANEX, for a long time may have an increased risk of decreased bone mass, which can affect bone strength. Patients who are at increased risk of decreased bone mass should be monitored.


 

Inhaled steroids, including ASMANEX, may cause a reduction in growth velocity when administered to pediatric patients. The long-term effect on final adult height is unknown. Health care providers should closely follow the growth of children and adolescents taking corticosteroids by any route, and reduce each patient's dose to the lowest dose that effectively controls his/her symptoms.


 

ASMANEX may increase the risk of some eye problems such as cataracts, glaucoma, and increased intraocular pressure. Patients with a change in vision or a history of eye problems should be monitored by their health care provider.


 

Use ASMANEX as directed by your health care provider, since its ability to work in your lungs depends on regular use. Maximum benefit may take 1 to 2 weeks or longer. If your asthma symptoms do not improve, or get worse, contact your health care provider.


 

The most common side effects with ASMANEX in patients 4-11 years old include fever, allergic rhinitis, abdominal pain, vomiting, urinary tract infection, and bruise. The most common side effects with ASMANEX in patients ‰¥ 12 years old include headache, allergic rhinitis, sore throat, and upper respiratory infection.


 

About FORADIL® AEROLIZER®


 

FORADIL® AEROLIZER® is for the maintenance treatment of asthma in those five years and older when taken on a long-term, twice-daily basis. FORADIL AEROLIZER should only be used as additional therapy for patients not adequately controlled on other asthma controller medications.


 

FORADIL AEROLIZER is not indicated for patients whose asthma can be managed by occasional use of fast-acting rescue inhalers.


 

FORADIL AEROLIZER is also for the acute prevention of exercise-induced bronchospasm (EIB) in those five years of age and older when administered on an occasional, as-needed basis at least 15 minutes before exercise.


 

FORADIL AEROLIZER is 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.


 

Important Safety Information about FORADIL® AEROLIZER®


 

FORADIL belongs to a class of medications known as long-acting beta2-adrenergic agonists or LABAs. In patients with asthma, LABAs may increase the chance of asthma related death. Therefore, FORADIL should only be used as additional therapy for patients not adequately controlled on other asthma controller medications.


 

In asthma clinical trials, the most common adverse events reported with FORADIL AEROLIZER were viral infection, bronchitis and chest infection. In COPD clinical trials, the most common adverse events reported with FORADIL AEROLIZER were upper respiratory infection, back pain and sore throat.


 

FORADIL capsules should only be inhaled orally using the AEROLIZER inhaler. The capsules should not be swallowed.


 

FORADIL AEROLIZER should not be used to treat acute symptoms. Acute symptoms should be treated with fast-acting rescue inhalers. Do not use more than one capsule twice daily. FORADIL AEROLIZER should be used with caution in patients with cardiovascular disorders. FORADIL AEROLIZER is not a substitute for inhaled or oral corticosteroids and, in the treatment of asthma, they should not be stopped or reduced at the time FORADIL AEROLIZER is initiated.


 

FDA's Communication Regarding Long-Acting Beta2-Agonists, including FORADIL AEROLIZER


 

The U.S. Food and Drug Administration (FDA) issued a communication on February 18, 2010 regarding guidance for long-acting beta2-agonists (LABAs) and LABA-containing medicines, including FORADIL AEROLIZER, in the maintenance treatment of asthma. FDA has determined that the benefits of LABAs in improving asthma symptoms outweigh the potential risks when used appropriately with an asthma controller medication in patients who need the addition of LABAs. FDA has requested updates to the prescribing information, including a requirement that LABAs only be used concomitantly with other controller medications in the treatment of asthma. The FDA communication is available at http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm200776.htm.


 

About Asthma


 

Asthma is a chronic lung disease characterized by inflammation of the air passages, resulting in the temporary narrowing of the airways that transport air from the nose and mouth to the lungs.1 Asthma symptoms can be triggered by allergens or irritants and can include difficulty breathing, wheezing, coughing, shortness of breath and tightness in the chest.1 With more than 22 million people living with asthma in the United States2, it is one of the most common and costly chronic diseases.1 Annually, this disease leads to almost two million asthma-related emergency room visits and more than 4,000 asthma-related deaths in the United States.1 There is no cure for asthma, but asthma can be managed with proper treatment.1


 

About Merck


 

Today's Merck is working to help the world be well. Through our medicines, vaccines, biologic therapies, and consumer and animal products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to healthcare through far-reaching programs that donate and deliver our products to the people who need them. For more information, visit www.merck.com


 

Forward-Looking Statement


 

This news release includes “forward-looking statements” within the meaning of the safe harbor provisions of the United States Private Securities Litigation Reform Act of 1995. Such statements may include, but are not limited to, statements about the benefits of the merger between Merck and Schering-Plough, including future financial and operating results, the combined company's plans, objectives, expectations and intentions and other statements that are not historical facts. Such statements are based upon the current beliefs and expectations of Merck's management and are subject to significant risks and uncertainties. Actual results may differ from those set forth in the forward-looking statements.


 

The following factors, among others, could cause actual results to differ from those set forth in the forward-looking statements: the possibility that the expected synergies from the merger of Merck and Schering-Plough will not be realized, or will not be realized within the expected time period, due to, among other things, the impact of pharmaceutical industry regulation and pending legislation that could affect the pharmaceutical industry; the risk that the businesses will not be integrated successfully; disruption from the merger making it more difficult to maintain business and operational relationships; Merck's ability to accurately predict future market conditions; dependence on the effectiveness of Merck's patents and other protections for innovative products; the risk of new and changing regulation and health policies in the U.S. and internationally and the exposure to litigation and/or regulatory actions.


 

Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in Merck's 2009 Annual Report on Form 10-K and the company's other filings with the Securities and Exchange Commission (SEC) available at the SEC's Internet site (www.sec.gov).


 

# # #


 

Prescribing Information and the Medication Guide for FORADIL® AEROLIZER® are attached and are also available at www.merck.com.


 

Prescribing information for ASMANEX® TWISTHALER® is attached and is also available at www.merck.com.


 

1“Asthma Facts and Figures.” Asthma and Allergy Foundation of America, 2005. Available at: http://www.aafa.org/display.cfm?id=8&sub=42.


 

2“What is asthma?” National Heart Lung and Blood Institute. National Institutes of Health, September 2008. Available at http://www.nhlbi.nih.gov/health/dci/Diseases/Asthma/Asthma_WhatIs.html.


 


HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use ASMANEX TWISTHALER safely and effectively. See full prescribing information for ASMANEX TWISTHALER.



ASMANEX TWISTHALER 110 mcg, 220 mcg (mometasone furoate inhalation powder)

Initial U.S. Approval: 1987

 


 
---------------------------- --------------------------

 


 

----------------------------INDICATIONS AND USAGE---------------------------


 

ASMANEX TWISTHALER is a corticosteroid indicated for:


 

 


 


  • Maintenance treatment of asthma as prophylactic therapy in patients 4 years of age and older. (1.1)
     


 

ASMANEX TWISTHALER is NOT indicated for the relief of acute bronchospasm (1.1, 5.2) or in children less than 4 years of age (1.1, 8.4).


 

----------------------DOSAGE AND ADMINISTRATION-----------------------


 

 


 


  • FOR ORAL INHALATION ONLY. (2)
     
  • Instruct patients to inhale rapidly and deeply and to rinse mouth after inhalation. (2)
     


 

 
Recommended Dosages for ASMANEX TWISTHALER Treatment
Previous Therapy     Recommended

Starting Dose

 


 
    Highest

Recommended Daily

Dose

 


 
Patients ‰¥12 years who received

bronchodilators alone

 


 
    220 mcg once

daily in the

evening*

 


 
    440 mcg**
Patients ‰¥12 years who received

inhaled corticosteroids

 


 
    220 mcg once

daily in the

evening*

 


 
    440 mcg**
Patients ‰¥12 years who received

oral corticosteroids 

 


 
    440 mcg twice

daily

 


 
    880 mcg
Children 4 – 11 years of age¡     110 mcg once

daily in the

evening*

 


 
    110 mcg*
* **   ¡ Please refer to section 2.1 for full dosage recommendations and details.

 


 


 

---------------------DOSAGE FORMS AND STRENGTHS----------------------


 

 


 


  • 220 mcg TWISTHALER: delivers 200 mcg mometasone furoate per actuation. (3)
     
  • 110 mcg TWISTHALER: delivers 100 mcg mometasone furoate per actuation. (3)
     


 

--------------------------CONTRAINDICATIONS--------------------------


 

 


 


  • Patients with status asthmaticus or other acute episodes of asthma where intensive measures are required. (4.1)
     
  • Patients with a known hypersensitivity to mometasone or any of the ingredients in ASMANEX TWISTHALER. (4.2)
     


 

----------------------WARNINGS AND PRECAUTIONS-----------------------


 

 


 


  • Candida albicans infection of the mouth and pharynx. Monitor patients periodically for signs of adverse effects in the mouth and pharynx.

    Advise patients to rinse mouth after inhalation. (5.1)
     
  • Potential worsening of existing tuberculosis, fungal, bacterial, viral, or parasitic infection, or ocular herpes simplex. More serious or even fatal course of chickenpox or measles in susceptible patients. Use caution in patients with the above because of the potential for worsening of these infections. (5.3)
     
  • Risk of impaired adrenal function when transferring from oral steroids to inhaled corticosteroids. Taper patients slowly from systemic corticosteroids if transferring to ASMANEX TWISTHALER. (5.4)
     
  • Hypercorticism, suppression of hypothalamic-pituitary-adrenal (HPA) function with very high dosages or at the regular dosage in susceptible individuals. If such changes occur discontinue ASMANEX TWISTHALER slowly. (5.5)
     
  • Reduction in bone mineral density with long-term administration. Monitor patients with major risk factors for decreased bone mineral content. (5.6)
     
  • Suppression of growth in children. Monitor growth routinely in pediatric patients receiving ASMANEX TWISTHALER. (5.7)
     
  • Development of glaucoma, increased intraocular pressure and posterior subcapsular cataracts. Monitor patients with a change in vision or with a history of increased intraocular pressure, glaucoma, and/or cataracts closely. (5.8)
     


 

------------------------------ADVERSE REACTIONS-------------------------------


 


The most common adverse reactions (incidence ‰¥5%) are headache, allergic rhinitis, pharyngitis, upper respiratory tract infection, sinusitis, oral candidiasis, dysmenorrhea, musculoskeletal pain, back pain, and dyspepsia. (6.1)

 


 
 
To report SUSPECTED ADVERSE REACTIONS, contact Schering-Plough at 1-800-526-4099 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

 


 
 
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.
 
Revised: November 2008
 

 


 

FULL PRESCRIBING INFORMATION: CONTENTS*


 

1 INDICATIONS AND USAGE


 

1.1 Treatment of Asthma


 

2 DOSAGE AND ADMINISTRATION


 

2.1 Recommended Dosages in Patients 4 Years of Age and Older


 

3 DOSAGE FORMS AND STRENGTHS


 

4 CONTRAINDICATIONS


 

4.1 Status Asthmaticus


 

4.2 Hypersensitivity


 

5 WARNINGS AND PRECAUTIONS


 

5.1 Local Effects


 

5.2 Acute Asthma Episodes


 

5.3 Immunosuppression


 

5.4 Transferring Patients from Systemic Corticosteroid Therapy


 

5.5 Hypercorticism and Adrenal Suppression


 

5.6 Reduction in Bone Mineral Density


 

5.7 Effect on Growth


 

5.8 Glaucoma and Cataracts


 

5.9 Bronchospasm


 

6 ADVERSE REACTIONS


 

6.1 Clinical Studies Experience


 

7 DRUG INTERACTIONS


 

7.1 Inhibitors of Cytochrome P450 3A4


 

8 USE IN SPECIFIC POPULATIONS


 

8.1 Pregnancy


 

8.3 Nursing Mothers


 

8.4 Pediatric Use


 

8.5 Geriatric Use


 

8.6 Hepatic Impairment


 

10 OVERDOSAGE


 

11 DESCRIPTION


 

12 CLINICAL PHARMACOLOGY


 

12.1 Mechanism of Action


 

12.2 Pharmacodynamics


 

12.3 Pharmacokinetics


 

13 NONCLINICAL TOXICOLOGY


 

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility


 

13.2 Animal Toxicology and/or Pharmacology


 

14 CLINICAL STUDIES


 

14.1 Asthma


 

16 HOW SUPPLIED/STORAGE AND HANDLING


 

17 PATIENT COUNSELING INFORMATION


 


*Sections or subsections omitted from the full prescribing information are not listed.          
 

FULL PRESCRIBING INFORMATION


 

1 INDICATIONS AND USAGE


 

1.1 Treatment of Asthma


 

ASMANEX® TWISTHALER® is indicated for the maintenance treatment of asthma as prophylactic therapy in patients 4 years of age and older.


 

Important Limitations of Use


 

ASMANEX TWISTHALER is NOT indicated for the relief of acute bronchospasm.


 

ASMANEX TWISTHALER is NOT indicated in children less than 4 years of age.


 

2 DOSAGE AND ADMINISTRATION


 

Administer ASMANEX TWISTHALER by the orally inhaled route only. Instruct patients to inhale rapidly and deeply. Advise patients to rinse the mouth after inhalation. Individual patients will experience a variable time to onset and degree of symptom relief. Maximum benefit may not be achieved for 1 to 2 weeks or longer after initiation of treatment. After asthma stability has been achieved, it is desirable to titrate to the lowest effective dosage to reduce the possibility of side effects. For patients ‰¥12 years of age who do not respond adequately to the starting dose after 2 weeks of therapy, higher doses may provide additional asthma control. The safety and efficacy of ASMANEX TWISTHALER when administered in excess of recommended doses have not been established.


 

2.1 Recommended Dosages in Patients 4 Years of Age and Older


 

The recommended starting doses and highest recommended daily dose for ASMANEX TWISTHALER treatment based on prior asthma therapy are provided in Table 1.


 


 
TABLE 1: Recommended Dosages for ASMANEX TWISTHALER Treatment
Previous Therapy     Recommended

Starting Dose

 


 
    Highest Recommended

Daily Dose

 


 
Patients ‰¥12 years who received bronchodilators alone     220 mcg once daily in the evening*     440 mcg**
Patients ‰¥12 years who received inhaled corticosteroids     220 mcg once daily in the evening*     440 mcg**
Patients ‰¥12 years who received oral corticosteroids      440 mcg twice daily     880 mcg
Children 4 – 11 years of age¡     110 mcg once daily in the evening*     110 mcg*
* When administered once daily, ASMANEX TWISTHALER should be taken only in the evening. ** The 440 mcg daily dose may be administered in divided doses of 220 mcg twice daily or as 440 mcg once daily.

 


 
  For Patients Currently Receiving Chronic Oral Corticosteroid Therapy: Prednisone should be reduced no faster than 2.5 mg/day on a weekly basis, beginning after at least 1 week of ASMANEX TWISTHALER therapy. Monitor patients carefully for signs of asthma instability, including serial objective measures of airflow, and for signs of adrenal insufficiency during steroid taper and following discontinuation of oral corticosteroid therapy [see Warnings and Precautions (5.4)]. ¡Recommended pediatric dosage is 110 mcg once daily in the evening regardless of prior therapy.

3 DOSAGE FORMS AND STRENGTHS


 

ASMANEX TWISTHALER is a dry powder for inhalation that is available in two strengths.


 

ASMANEX TWISTHALER 220 mcg delivers 200 mcg mometasone furoate per actuation from the mouthpiece.


 

ASMANEX TWISTHALER 110 mcg delivers 100 mcg mometasone furoate per actuation from the mouthpiece.


 

4 CONTRAINDICATIONS


 

4.1 Status Asthmaticus


 

ASMANEX TWISTHALER therapy is contraindicated in the primary treatment of status asthmaticus or other acute episodes of asthma where intensive measures are required.


 

4.2 Hypersensitivity


 

ASMANEX TWISTHALER is contraindicated in patients with known hypersensitivity to mometasone or any of the ingredients in ASMANEX TWISTHALER. In the clinical trials and postmarketing experience with ASMANEX TWISTHALER, cases of allergic reaction, facial edema, urticaria, hypersensitivity, and throat tightness have been reported.


 

5 WARNINGS AND PRECAUTIONS


 

5.1 Local Effects


 

In clinical trials, the development of localized infections of the mouth and pharynx with Candida albicans occurred in 195 of 3007 patients treated with ASMANEX TWISTHALER. If oropharyngeal candidiasis develops, it should be treated with appropriate local or systemic (i.e., oral) antifungal therapy while remaining on treatment with ASMANEX TWISTHALER therapy, but at times therapy with the ASMANEX TWISTHALER may need to be interrupted. Advise patients to rinse the mouth after inhalation of ASMANEX TWISTHALER.


 

5.2 Acute Asthma Episodes


 

ASMANEX TWISTHALER is not a bronchodilator and is not indicated for rapid relief of bronchospasm or other acute episodes of asthma. Instruct patients to contact their physician immediately if episodes of asthma that are not responsive to bronchodilators occur during the course of treatment with ASMANEX TWISTHALER. During such episodes, patients may require therapy with oral corticosteroids.


 

5.3 Immunosuppression


 

Persons who are using drugs that suppress the immune system are more susceptible to infections than healthy individuals. Chickenpox and measles, for example, can have a more serious or even fatal course in susceptible children or adults using corticosteroids. In such children or adults who have not had these diseases or who are not properly immunized, particular care should be taken to avoid exposure. How the dose, route, and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information.) If chickenpox develops, treatment with antiviral agents may be considered.


 

Inhaled corticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infection of the respiratory tract, untreated systemic fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex.


 

5.4 Transferring Patients from Systemic Corticosteroid Therapy


 

Particular care is needed for patients who are transferred from systemically active corticosteroids to ASMANEX TWISTHALER because deaths due to adrenal insufficiency have occurred in asthmatic patients during and after transfer from systemic corticosteroids to less systemically available inhaled corticosteroids. After withdrawal from systemic corticosteroids, a number of months are required for recovery of hypothalamic-pituitary-adrenal (HPA) function.


 

Patients who have been previously maintained on 20 mg or more per day of prednisone (or its equivalent) may be most susceptible, particularly when their systemic corticosteroids have been almost completely withdrawn. During this period of HPA suppression, patients may exhibit signs and symptoms of adrenal insufficiency when exposed to trauma, surgery, or infection (particularly gastroenteritis) or other conditions associated with severe electrolyte loss. Although ASMANEX TWISTHALER may improve control of asthma symptoms during


 

these episodes, in recommended doses it supplies less than normal physiological amounts of corticosteroid systemically and does NOT provide the mineralocorticoid activity necessary for coping with these emergencies.


 

During periods of stress or severe asthma attack, patients who have been withdrawn from systemic corticosteroids should be instructed to resume oral corticosteroids (in large doses) immediately and to contact their physicians for further instruction. These patients should also be instructed to carry a medical identification card indicating that they may need supplementary systemic corticosteroids during periods of stress or severe asthma attack.


 

Patients requiring oral corticosteroids should be weaned slowly from systemic corticosteroid use after transferring to ASMANEX TWISTHALER. Prednisone reduction can be accomplished by reducing the daily prednisone dose by 2.5 mg on a weekly basis during treatment with ASMANEX TWISTHALER [see Dosage and Administration (2)]. Lung function (FEV1 or PEFR), beta-agonist use, and asthma symptoms should be carefully monitored during withdrawal of oral corticosteroids. In addition to monitoring asthma signs and symptoms, patients should be observed for signs and symptoms of adrenal insufficiency such as fatigue, lassitude, weakness, nausea and vomiting, and hypotension.


 

Transfer of patients from systemic corticosteroid therapy to ASMANEX TWISTHALER may unmask allergic conditions previously suppressed by the systemic corticosteroid therapy, e.g., rhinitis, conjunctivitis, eczema, arthritis, and eosinophilic conditions.


 

During withdrawal from oral corticosteroids, some patients may experience symptoms of systemically active corticosteroid withdrawal, e.g., joint and/or muscular pain, lassitude, and depression, despite maintenance or even improvement of respiratory function.


 

5.5 Hypercorticism and Adrenal Suppression


 

ASMANEX TWISTHALER will often help control asthma symptoms with less suppression of HPA function than therapeutically similar oral doses of prednisone. Since individual sensitivity to effects on cortisol production exists, physicians should consider this information when prescribing ASMANEX TWISTHALER. Particular care should be taken in observing patients postoperatively or during periods of stress for evidence of inadequate adrenal response. It is possible that systemic corticosteroid effects such as hypercorticism and adrenal suppression may appear in a small number of patients, particularly when ASMANEX TWISTHALER is administered at higher than recommended doses over prolonged periods of time. If such effects occur, the dosage of ASMANEX TWISTHALER should be reduced slowly, consistent with accepted procedures for reducing systemic corticosteroids and for management of asthma.


 

5.6 Reduction in Bone Mineral Density


 

Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing inhaled corticosteroids, including mometasone furoate. The clinical significance of small changes in BMD with regard to long-term outcomes is unknown. Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, or chronic use of drugs that can reduce bone mass (e.g., anticonvulsants and corticosteroids) should be monitored and treated with established standards of care.


 

In a 2-year double-blind study in 103 male and female asthma patients 18 to 50 years of age previously maintained on bronchodilator therapy (baseline FEV1 85%-88% predicted), treatment with ASMANEX TWISTHALER 220 mcg twice daily resulted in significant reductions in lumbar spine (LS) BMD at the end of the treatment period compared to placebo. The mean change from baseline to endpoint in the lumbar spine BMD was -0.015 (-1.43%) for the ASMANEX TWISTHALER group compared to 0.002 (0.25%) for the placebo group. In another 2-year double-blind study in 87 male and female asthma patients 18 to 50 years of age previously maintained on bronchodilator therapy (baseline FEV1 82%-83% predicted), treatment with ASMANEX TWISTHALER 440 mcg twice daily demonstrated no statistically significant changes in lumbar spine BMD at the end of the treatment period compared to placebo. The mean change from baseline to endpoint in the lumbar spine BMD was -0.018 (-1.57%) for the ASMANEX TWISTHALER group compared to -0.006 (-0.43%) for the placebo group.


 

5.7 Effect on Growth


 

Orally inhaled corticosteroids, including ASMANEX TWISTHALER, may cause a reduction in growth velocity when administered to pediatric patients. Monitor the growth of pediatric patients receiving ASMANEX TWISTHALER routinely (e.g., via stadiometry). To minimize the systemic effects of orally inhaled corticosteroids, including ASMANEX TWISTHALER, titrate each patient's dose to the lowest dosage that effectively controls his/her symptoms [see Use in Specific Populations (8.4)].


 

5.8 Glaucoma and Cataracts


 

In clinical trials glaucoma, increased intraocular pressure, and cataracts have been reported in 8 of 3007 patients following the administration of ASMANEX TWISTHALER. Close monitoring is warranted in patients with a change in vision or with a history of increased intraocular pressure, glaucoma, and/or cataracts.


 

5.9 Bronchospasm


 

As with other inhaled asthma medications, bronchospasm may occur with an immediate increase in wheezing after dosing. If bronchospasm occurs following dosing with ASMANEX TWISTHALER, it should be treated immediately with a fast-acting inhaled bronchodilator.


 

Treatment with ASMANEX TWISTHALER should be discontinued and alternative therapy instituted.


 

6 ADVERSE REACTIONS


 

Systemic and local corticosteroid use may result in the following:


 

 


 


  • Candida albicans infection [see Warnings and Precautions (5.1)]
     
  • Immunosuppression [see Warnings and Precautions (5.3)]
     
  • Hypercorticism and adrenal suppression [see Warnings and Precautions (5.5)]
     
  • Growth effects [see Warnings and Precautions (5.7) and Use in Specific Populations (8.4)]
     
  • Glaucoma and cataracts [see Warnings and Precautions (5.8)]
     


 

6.1 Clinical Studies Experience


 

The safety data described below reflect exposure to ASMANEX TWISTHALER in 2380 patients with asthma exposed for 8 to 12 weeks and 627 patients with asthma exposed for 1 year in a total of 17 clinical trials.


 

In adult and adolescent patients 12 years of age and older, ASMANEX TWISTHALER was studied in 10 placebo-controlled clinical trials of 8 to 12 weeks duration with a total of 1750 patients receiving ASMANEX TWISTHALER. There were also 3 trials with a total of 475 patients receiving ASMANEX TWISTHALER for 1 year. In the 8- to 12-week clinical trials, the population was 12 to 83 years of age, 38% males and 62% females, and 83% Caucasian, 8% black, 6% Hispanic, and 3% other race/ethnicity. Patients received ASMANEX TWISTHALER 110 mcg twice daily (n=133), 220 mcg once daily in the morning (n=209), 220 mcg once daily in the evening (n=232), 220 mcg twice daily (n=433), 440 mcg once daily in the morning (n=419), 440 mcg once daily in the evening (n=250), or 440 mcg twice daily (n=74). In 3 long-term safety trials (two 9-month extensions of efficacy trials and one 52-week active-controlled safety trial), 475 patients with asthma (12 - 83 years of age, 44% males, 56% females, 87% Caucasian, 8% black, 4% Hispanic, and 1% other race/ethnicity) received various doses of ASMANEX TWISTHALER for 1 year.


 

In pediatric patients 4 to 11 years of age, ASMANEX TWISTHALER was studied in 3 placebo-controlled clinical trials of 12 weeks duration with a total of 630 patients receiving ASMANEX TWISTHALER and a 52-week, active-controlled safety trial with a total of 152 patients receiving ASMANEX TWISTHALER. In the 12-week clinical trials, the population was 4 to 11 years of age, 63% males and 37% females, and 67% Caucasian, 13% black, 17% Hispanic, and 3% other race/ethnicity. Patients received ASMANEX TWISTHALER 110 mcg once daily in the evening (n=98), 110 mcg once daily in the morning (n=181), 110 mcg twice daily (n=179), or 220 mcg once daily in the morning (n=172). In the long-term active-controlled safety trial (n=152), patients with asthma (4 to 11 years of age, 60% males and 40% females, 84% Caucasian, 11% Black, and 5% Hispanic) received ASMANEX TWISTHALER 110 mcg twice daily or 220 mcg once daily in the morning for 52 weeks.


 

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 and Adolescents 12 Years of Age and Older: The safety results of the 10 trials that were 8 to 12 weeks in duration were pooled because patients with asthma in these studies were previously maintained on bronchodilators and/or inhaled corticosteroids. The safety results of the one 12-week clinical trial in patients with asthma previously treated with oral corticosteroids are presented separately.


 

In the pooled 8- to 12-week clinical trials, adverse reactions were reported in 70% of patients treated with ASMANEX TWISTHALER (n=1750) compared to 65% of patients taking placebo (n=720). Table 2 displays the common adverse reactions (‰¥3% in any patient group receiving ASMANEX TWISTHALER) that occurred more frequently in patients treated with ASMANEX TWISTHALER compared to patients treated with placebo.


 


 
TABLE 2: Adverse Reactions with ‰¥3% Incidence in 10 Controlled Clinical Trials with ASMANEX TWISTHALER in Patients 12 Years of Age and Older Previously on Bronchodilators and/or Inhaled Corticosteroids
    (%) of Patients
  ASMANEX TWISTHALER   Placebo

(n=720)

 


 


 
Adverse Reaction

 


 
  220 mcg twice daily

(n=433)


 


 
  440 mcg once daily

(n=497)

Posted: March 2010

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