FDA label 22f8a043-7434-448f-9ce0-ee8ec866379e

WARNING: ASTHMA-RELATED DEATH Long-acting beta 2 -adrenergic agonists (LABA), such as formoterol the active ingredient in FORADIL AEROLIZER, increase the risk of asthma-related death. Data from a large placebo controlled US study that compared the safety of another LABA ( 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 [ see Warnings and Precautions (5.1) ]. 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. Because of this risk, use of FORADIL AEROLIZER for the treatment of asthma without a concomitant long-term asthma control medication, such as an inhaled corticosteroid, is contraindicated. Use FORADIL AEROLIZER only as additional therapy for patients with asthma who are currently taking but are inadequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue FORADIL AEROLIZER) 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 FORADIL AEROLIZER for patients whose asthma is adequately controlled on low or medium dose inhaled corticosteroids. Pediatric and Adolescent Patients Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. For pediatric and adolescent patients with asthma who require addition of a LABA to an inhaled corticosteroid, a fixed-dose combination product containing both an inhaled corticosteroid and LABA should ordinarily be considered to ensure adherence with both drugs. In cases where use of a separate long-term asthma control medication (e.g., inhaled corticosteroid) and LABA is clinically indicated, appropriate steps must be taken to ensure adherence with both treatment components. If adherence cannot be assured, a fixed-dose combination product containing both an inhaled corticosteroid and LABA is recommended. WARNING: ASTHMA-RELATED DEATH See full prescribing information for complete boxed warning Long-acting beta 2 -adrenergic agonists (LABA), such as formoterol the active ingredient in FORADIL, increase the risk of asthma-related death. A large placebo-controlled study with another LABA (salmeterol) showed an increase in asthma-related deaths in patients receiving salmeterol. This finding with salmeterol is considered a class effect of LABA, including formoterol. ( 5.1 ) Prescribe FORADIL AEROLIZER only as additional therapy for patients with asthma who are currently taking but are inadequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue FORADIL AEROLIZER) 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 FORADIL AEROLIZER for patients whose asthma is adequately controlled on low- or medium-dose inhaled corticosteroids. ( 1.1 , 5.1 ). Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. ( 5.1 )

5 WARNINGS AND PRECAUTIONS Asthma-related deaths and asthma-related hospitalizations: LABA increase the risk. Prescribe for asthma only as concomitant therapy with a long-term control medication such as an inhaled corticosteroid. ( 5.1 ) Deterioration of asthma and acute episodes: Do not initiate during acutely deteriorating asthma. Do not use to treat acute symptoms. ( 5.2 ) Corticosteroids: Not a substitute for corticosteroids. Corticosteroids should not be stopped or reduced when FORADIL AEROLIZER is initiated. ( 5.3 ) Use with additional long-acting beta 2 -agonist: Do not use in combination because of risk of overdose. ( 5.4 ) Paradoxical bronchospasm: Discontinue FORADIL AEROLIZER and institute alternative therapy if paradoxical bronchospasm occurs. ( 5.5 ) Patients with cardiovascular or central nervous system disorders: Use with caution because of beta-adrenergic stimulation. ( 5.6 ) Coexisting conditions: Use with caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, ketoacidosis, aneurysm, and pheochromocytoma. ( 5.8 ) Metabolic effects: Be alert to hypokalemia and hyperglycemia. ( 5.9 ) 5.1 Asthma-Related Death Long-acting beta 2 -adrenergic agonists, such as formoterol, the active ingredient in FORADIL AEROLIZER, 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. Because of this risk, use of FORADIL AEROLIZER for the treatment of asthma without concomitant use of a long-term asthma control medication, such as an inhaled corticosteroid, is contraindicated. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue FORADIL AEROLIZER) 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 FORADIL AEROLIZER for patients whose asthma is adequately controlled on low or medium dose inhaled corticosteroids. Pediatric and Adolescent Patients Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. For pediatric and adolescent patients with asthma who require addition of a LABA to an inhaled corticosteroid, a fixed-dose combination product containing both an inhaled corticosteroid and LABA should ordinarily be considered to ensure adherence with both drugs. In cases where use of a separate long-term asthma control medication (e.g., inhaled corticosteroid) and LABA is clinically indicated, appropriate steps must be taken to ensure adherence with both treatment components. If adherence cannot be assured, a fixed-dose combination product containing both an inhaled corticosteroid and LABA is recommended. 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 formoterol. No study adequate to determine whether the rate of asthma-related death is increased with FORADIL AEROLIZER has been conducted. Clinical studies with FORADIL AEROLIZER suggested a higher incidence of serious asthma exacerbations in patients who received FORADIL AEROLIZER than in those who received placebo [ see Adverse Reactions (6.2, 6.3) ]. The sizes of these studies were not adequate to precisely quantify the differences in serious asthma exacerbation rates between treatment groups. The studies described above enrolled patients with asthma. No studies have been conducted that were adequate to determine whether the rate of death in patients with COPD is increased by long-acting beta 2 -adrenergic agonists. 5.2 Deterioration of Disease and Acute Episodes FORADIL AEROLIZER should not be initiated in patients with significantly worsening, acutely deteriorating, or potentially life-threatening episodes of asthma or COPD. The use of FORADIL AEROLIZER in this setting is not appropriate [ see Indications and Usage (1.1, 1.3) ]. Asthma may deteriorate acutely over a period of hours or chronically over several days or longer. It is important to watch for signs of worsening asthma, such as increasing use of inhaled, short-acting beta 2 -adrenergic agonists or a significant decrease in peak expiratory flow (PEF) or lung function. Such findings require immediate evaluation. Patients should be advised to seek immediate attention should their condition deteriorate. Increasing the daily dosage of FORADIL AEROLIZER beyond the recommended dose in this situation is not appropriate. FORADIL AEROLIZER should not be used more frequently than twice daily (morning and evening) at the recommended dose. FORADIL AEROLIZER should not be used to treat acute symptoms. FORADIL AEROLIZER has not been studied in the relief of acute symptoms and extra doses should not be used for that purpose. When prescribing FORADIL AEROLIZER, the physician should also provide the patient with an inhaled, short-acting beta 2 -agonist for treatment of symptoms that occur acutely, despite regular twice-daily (morning and evening) use of FORADIL AEROLIZER. Patients should also be cautioned that increasing inhaled beta 2 -agonist use is a signal of deteriorating asthma [ see Information for Patients (17) and the accompanying Medication Guide. ] When beginning treatment with FORADIL AEROLIZER, patients who have been taking inhaled, short-acting beta 2 -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 symptoms. 5.3 FORADIL AEROLIZER is not a substitute for corticosteroids There are no data demonstrating that FORADIL has any clinical anti-inflammatory effect and therefore it cannot be expected to take the place of corticosteroids. Corticosteroids should not be stopped or reduced at the time FORADIL AEROLIZER is initiated. Patients who already require oral or inhaled corticosteroids for treatment of asthma should be continued on this type of treatment even if they feel better as a result of initiating FORADIL AEROLIZER. Any change in corticosteroid dosage, in particular a reduction, should be made ONLY after clinical evaluation [ see Patient Counseling Information (17.2) ]. 5.4 Excessive Use and Use with Other Long-Acting Beta 2 -Agonists FORADIL AEROLIZER should not be used more often or at doses higher than recommended, or in conjunction with other medications containing LABA, as an overdose may result. Patients using FORADIL AEROLIZER should not use an additional LABA (e.g., salmeterol xinafoate, arformoterol tartrate) for any reason. Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs in patients with asthma. The exact cause of death is unknown, but cardiac arrest following an unexpected development of a severe acute asthmatic crisis and subsequent hypoxia is suspected. In addition, data from clinical trials with FORADIL AEROLIZER suggest that the use of doses higher than recommended is associated with an increased risk of serious asthma exacerbations [ see Adverse Reactions (6.2, 6.3) ]. 5.5 Paradoxical Bronchospasm As with other inhaled beta 2 -agonists, formoterol can produce paradoxical bronchospasm that may be life-threatening. If paradoxical bronchospasm occurs, FORADIL AEROLIZER should be discontinued immediately and alternative therapy instituted. 5.6 Cardiovascular and Central Nervous System Effects Excessive beta-adrenergic stimulation has been associated with seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats/min, arrhythmias, nervousness, headache, tremor, palpitation, nausea, dizziness, fatigue, malaise, and insomnia. Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs [ see Overdosage (10) ]. Formoterol fumarate, like other beta 2 -agonists, can produce a clinically significant cardiovascular effect in some patients as measured by increases in pulse rate, blood pressure, and/or symptoms. Although such effects are uncommon after administration of FORADIL AEROLIZER at recommended doses, if they occur, the drug 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, formoterol fumarate, like other sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension. 5.7 Immediate Hypersensitivity Reactions Immediate hypersensitivity reactions may occur after administration of FORADIL AEROLIZER, as demonstrated by cases of anaphylactic reactions, urticaria, angioedema, rash, and bronchospasm. FORADIL AEROLIZER contains lactose, which contains trace levels of milk proteins. Allergic reactions to products containing milk proteins may occur in patients with severe milk protein allergy. 5.8 Coexisting Conditions Formoterol fumarate, like other sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, hypertension, aneurysm, and pheochromocytoma; 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. 5.9 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. Clinically significant changes in blood glucose and/or serum potassium were infrequent during clinical studies with long-term administration of FORADIL AEROLIZER at the recommended dose. 5.10 Inappropriate Route of Administration FORADIL capsules should ONLY be used with the AEROLIZER Inhaler and SHOULD NOT be swallowed. FORADIL capsules should always be stored in the blister, and only removed IMMEDIATELY before use.

6 ADVERSE REACTIONS Long-acting beta 2 -adrenergic agonists (LABA), including formoterol, the active ingredient in FORADIL AEROLIZER, increase the risk of asthma-related death and may increase the risk of asthma-related hospitalizations in pediatric and adolescent patients. Clinical trials with FORADIL AEROLIZER suggested a higher incidence of serious asthma exacerbations in patients who received FORADIL AEROLIZER than in those who received placebo [ see Warnings and Precautions (5.1) ]. Adverse reactions common to LABA drugs include: angina, hypertension or hypotension, tachycardia, arrhythmias, nervousness, headache, tremor, dry mouth, palpitation, muscle cramps, nausea, dizziness, fatigue, malaise, hypokalemia, hyperglycemia, metabolic acidosis, and insomnia. 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 clinical trials. Most common adverse reactions (incidence ≥1% and more common than placebo) are: Asthma: viral infection, bronchitis, chest infection, dyspnea, chest pain, tremor, dizziness, insomnia, tonsillitis, rash, dysphonia, and serious asthma exacerbation. ( 6.1 , 6.3 ) COPD: Upper respiratory tract infection, back pain, pharyngitis, chest pain, sinusitis, fever, leg cramps, muscle cramps, anxiety, pruritus, increased sputum, and dry mouth. ( 6.2 ) To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp & Dohme Corporation, a subsidiary of Merck & Co., Inc. at 1-877-888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. Number and Frequency of Adverse Experiences in Patients 5 Years of Age and Older from Multiple-Dose Controlled Clinical Trials Number and Frequency of Adverse Experiences in Adult COPD Patients Treated in Multiple-Dose Controlled Clinical Trials 6.1 Asthma Of the 5824 patients in multiple-dose controlled clinical trials, 1985 were treated with FORADIL AEROLIZER at the recommended dose of 12 mcg twice daily. The following table shows treatment-emergent adverse reactions where the frequency was greater than or equal to 1% in the FORADIL twice daily group and where the rates in the FORADIL group exceeded placebo. Three treatment-emergent adverse reactions showed dose ordering among tested doses of 6, 12, and 24 mcg administered twice daily; tremor, dizziness and dysphonia. Number and Frequency of Treatment-Emergent Adverse Reactions in Patients 5 Years of Age and Older from Multiple-Dose Controlled Clinical Trials In patients 5-12 years of age, the numbers and percent of patients who reported treatment-emergent adverse reactions were comparable in the 12 mcg twice daily and placebo groups. In general, the pattern of the treatment-emergent adverse reactions observed in children differed from the usual pattern seen in adults. Treatment-emergent adverse reactions that were more frequent in the formoterol group than in the placebo group reflected infection/inflammation (viral infection, rhinitis, tonsillitis, gastroenteritis) or abdominal complaints (abdominal pain, nausea, dyspepsia). Serious Asthma Exacerbations in Adolescents and Adults 12 Years of Age and Older In two 12-week controlled trials with combined enrollment of 1095 patients 12 years of age and older, FORADIL AEROLIZER 12 mcg twice daily was compared to FORADIL AEROLIZER 24 mcg twice daily, albuterol 180 mcg four times daily, and placebo. Serious asthma exacerbations (acute worsening of asthma resulting in hospitalization) occurred more commonly with FORADIL AEROLIZER 24 mcg twice daily than with the recommended dose of FORADIL AEROLIZER 12 mcg twice daily, albuterol, or placebo. The results are shown in the following table. Number and Frequency of Serious Asthma Exacerbations in Patients 12 Years of Age and Older from Two 12-Week Controlled Clinical Trials Foradil 12 mcg twice daily Foradil 24 mcg twice daily Albuterol 180 mcg four times daily Placebo Trial #1 Serious asthma exacerbations 0/136 (0) 4/135 (3.0%) 1 2/134 (1.5%) 0/136 (0) Trial #2 Serious asthma exacerbations 1/139 (0.7%) 5/136 (3.7%) 2 0/138 (0) 2/141 (1.4%) 1 patient required intubation 2 patients had respiratory arrest; 1 of the patients died In a 16-week, randomized, multi-center, double-blind, parallel-group trial, patients who received either 24 mcg twice daily or 12 mcg twice daily doses of FORADIL AEROLIZER experienced more serious asthma exacerbations than patients who received placebo [ see Clinical Trials (14.1) ]. The results are shown in the following table. Number and Frequency of Serious Asthma Exacerbations in Patients 12 Years of Age and Older from a 16-Week Trial Foradil 12 mcg twice daily Foradil 24 mcg twice daily Placebo Serious asthma exacerbations 3/527 (0.6%) 2/527 (0.4%) 1/514 (0.2%) Serious Asthma Exacerbations in Children 5-11 Years of Age The safety of FORADIL AEROLIZER 12 mcg twice daily compared to FORADIL AEROLIZER 24 mcg twice daily and placebo was investigated in one large, multicenter, randomized, double-blind, 52-week clinical trial in 518 children with asthma (ages 5-12 years) in need of daily bronchodilators and anti-inflammatory treatment. More children who received FORADIL AEROLIZER 24 mcg twice daily than children who received FORADIL AEROLIZER 12 mcg twice daily or placebo experienced serious asthma exacerbations, as shown in the next table. Number and Frequency of Serious Asthma Exacerbations in Patients 5-12 Years of Age from a 52-Week Trial Foradil 12 mcg twice daily Foradil 24 mcg twice daily Placebo Serious asthma exacerbations 8/171 (4.7%) 11/171 (6.4%) 0/176 (0) 6.2 COPD Of the 1634 patients in two pivotal multiple-dose Chronic Obstructive Pulmonary Disease (COPD) controlled trials, 405 were treated with FORADIL AEROLIZER 12 mcg twice daily. Treatment-emergent adverse reactions reported were similar to those seen in asthmatic patients, but with a higher incidence of COPD-related events in both placebo and formoterol treated patients. The following table shows treatment-emergent adverse reactions where the frequency was greater than or equal to 1% in the FORADIL AEROLIZER group and where the rates in the FORADIL AEROLIZER group exceeded placebo. The two clinical trials included doses of 12 mcg and 24 mcg, administered twice daily. Seven treatment-emergent adverse reactions showed dose ordering among tested doses of 12 and 24 mcg administered twice daily; pharyngitis, fever, muscle cramps, increased sputum, dysphonia, myalgia, and tremor. Number and Frequency of Treatment-Emergent Adverse Reactions in Adult COPD Patients Treated in Multiple-Dose Controlled Clinical Trials Overall, the frequency of all cardiovascular treatment-emergent adverse reactions in the two pivotal studies was 6.4% for FORADIL AEROLIZER 12 mcg twice daily, and 6.0% for placebo. There were no frequently-occurring specific cardiovascular treatment-emergent adverse reactions for FORADIL AEROLIZER (frequency greater than or equal to 1% and greater than placebo). 6.3 Postmarketing Experience The following adverse reactions have been identified during post approval use of FORADIL. 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. In extensive worldwide marketing experience with FORADIL, serious exacerbations of asthma, including some that have been fatal, have been reported. While most of these cases have been in patients with severe or acutely deteriorating asthma [ see Warnings and Precautions (5.1, 5.2) ], a few have occurred in patients with less severe asthma. It is not possible to determine from these individual case reports whether FORADIL AEROLIZER contributed to the events. Immune system disorders: rare reports of anaphylactic reactions, including severe hypotension and angioedema Metabolism and nutrition disorders: Hypokalemia, hyperglycemia Respiratory, thoracic and mediastinal disorders: Cough Skin and subcutaneous tissue disorders: Rash Cardiac disorders: Angina pectoris, cardiac arrhythmias, e.g., atrial fibrillation, ventricular extrasystoles, tachyarrhythmia Investigations: Electrocardiogram QT prolonged, blood pressure increased (including hypertension)

<table> <caption>Number and Frequency of Serious Asthma Exacerbations in Patients 12 Years of Age and Older from Two 12-Week Controlled Clinical Trials</caption> <col width="131"/> <col width="131"/> <col width="131"/> <col width="146"/> <col width="116"/> <tbody> <tr> <td styleCode="Toprule "/> <td styleCode="Toprule "> <content styleCode="bold">Foradil 12 mcg twice daily</content> </td> <td styleCode="Toprule "> <content styleCode="bold">Foradil 24 mcg twice daily</content> </td> <td styleCode="Toprule "> <content styleCode="bold">Albuterol 180 mcg four times daily</content> </td> <td styleCode="Toprule "> <content styleCode="bold">Placebo</content> </td> </tr> <tr> <td styleCode="Toprule " colspan="5"> <content styleCode="bold">Trial #1</content> </td> </tr> <tr> <td> <content styleCode="bold">Serious asthma exacerbations</content> </td> <td>0/136 (0)</td> <td>4/135 (3.0%)¹ </td> <td>2/134 (1.5%)</td> <td>0/136 (0)</td> </tr> <tr> <td styleCode="Toprule " colspan="5"> <content styleCode="bold">Trial #2</content> </td> </tr> <tr> <td> <content styleCode="bold">Serious asthma exacerbations</content> </td> <td>1/139 (0.7%)</td> <td>5/136 (3.7%)² </td> <td>0/138 (0)</td> <td>2/141 (1.4%)</td> </tr> <tr> <td styleCode="Toprule " colspan="5"> ¹ patient required intubation ² patients had respiratory arrest; 1 of the patients died</td> </tr> </tbody> </table>

<table> <caption>Number and Frequency of Serious Asthma Exacerbations in Patients 12 Years of Age and Older from a 16-Week Trial</caption> <col width="155"/> <col width="170"/> <col width="162"/> <col width="168"/> <tbody> <tr> <td styleCode="Toprule "/> <td styleCode="Toprule "> <content styleCode="bold">Foradil 12 mcg twice daily</content> </td> <td styleCode="Toprule "> <content styleCode="bold">Foradil 24 mcg twice daily</content> </td> <td styleCode="Toprule "> <content styleCode="bold">Placebo</content> </td> </tr> <tr> <td styleCode="Toprule "> <content styleCode="bold">Serious asthma exacerbations</content> </td> <td styleCode="Toprule ">3/527 (0.6%)</td> <td styleCode="Toprule ">2/527 (0.4%)</td> <td styleCode="Toprule ">1/514 (0.2%)</td> </tr> </tbody> </table>

<table> <caption>Number and Frequency of Serious Asthma Exacerbations in Patients 5-12 Years of Age from a 52-Week Trial</caption> <col width="155"/> <col width="170"/> <col width="162"/> <col width="168"/> <tbody> <tr> <td/> <td> <content styleCode="bold">Foradil 12 mcg twice daily</content> </td> <td> <content styleCode="bold">Foradil 24 mcg twice daily</content> </td> <td> <content styleCode="bold">Placebo</content> </td> </tr> <tr> <td> <content styleCode="bold">Serious asthma exacerbations</content> </td> <td>8/171 (4.7%)</td> <td>11/171 (6.4%)</td> <td>0/176 (0)</td> </tr> </tbody> </table>