Symbicort Forte Turbuhaler

Formoterol Fumarate Dihydrate:

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

1 INDICATIONS AND USAGE

Symbicort Forte Turbuhaler 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:

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

1.1 Maintenance Treatment of COPD

Symbicort Forte Turbuhaler (Formoterol Fumarate Dihydrate) (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

Symbicort Forte Turbuhaler (Formoterol Fumarate Dihydrate) Inhalation Solution is not indicated to treat acute deteriorations of chronic obstructive pulmonary disease .

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

2 DOSAGE AND ADMINISTRATION

The recommended dose of Symbicort Forte Turbuhaler (Formoterol Fumarate Dihydrate) (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.

Symbicort Forte Turbuhaler (Formoterol Fumarate Dihydrate) 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 Symbicort Forte Turbuhaler (Formoterol Fumarate Dihydrate) 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 Symbicort Forte Turbuhaler (Formoterol Fumarate Dihydrate) Inhalation Solution delivered from non-compressor based nebulizer systems have not been established.

Symbicort Forte Turbuhaler (Formoterol Fumarate Dihydrate) 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 Symbicort Forte Turbuhaler (Formoterol Fumarate Dihydrate) 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

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

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

4 CONTRAINDICATIONS

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

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

5 WARNINGS AND PRECAUTIONS

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

Clinical studies with 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

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

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

5.5 Cardiovascular Effects

Symbicort Forte Turbuhaler (Formoterol Fumarate Dihydrate) 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, Symbicort Forte Turbuhaler (Formoterol Fumarate Dihydrate) 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, Symbicort Forte Turbuhaler (Formoterol Fumarate Dihydrate) 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

Symbicort Forte Turbuhaler 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 Symbicort Forte Turbuhaler (Formoterol Fumarate Dihydrate) Inhalation Solution at the recommended dose.

5.8 Immediate Hypersensitivity Reactions

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

Patients treated with Symbicort Forte Turbuhaler (Formoterol Fumarate Dihydrate) 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 Symbicort Forte Turbuhaler (Formoterol Fumarate Dihydrate) 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

Formoterol fumarate administered throughout organogenesis did not cause malformations in rats or rabbits following oral administration. However, 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 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. 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, Symbicort Forte Turbuhaler (Formoterol Fumarate Dihydrate) 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 Symbicort Forte Turbuhaler (Formoterol Fumarate Dihydrate) Inhalation Solution.

8.2 Labor and Delivery

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

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

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

8.4 Pediatric Use

Symbicort Forte Turbuhaler (Formoterol Fumarate Dihydrate) Inhalation Solution is not indicated for use in children. The safety and effectiveness of Symbicort Forte Turbuhaler (Formoterol Fumarate Dihydrate) Inhalation Solution in pediatric patients have not been established. The pharmacokinetics of formoterol fumarate has not been studied in pediatric patients.

8.5 Geriatric Use

Of the 586 subjects who received Symbicort Forte Turbuhaler (Formoterol Fumarate Dihydrate) Inhalation Solution in clinical studies, 284 were 65 years and over, while 89 were 75 years and over. Of the 123 subjects who received Symbicort Forte Turbuhaler (Formoterol Fumarate Dihydrate) 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 Symbicort Forte Turbuhaler (Formoterol Fumarate Dihydrate) Inhalation Solution has not been studied in elderly subjects.

10 OVERDOSAGE

The expected signs and symptoms with overdosage of Symbicort Forte Turbuhaler (Formoterol Fumarate Dihydrate) 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 Symbicort Forte Turbuhaler (Formoterol Fumarate Dihydrate) Inhalation Solution.

Treatment of overdosage consists of discontinuation of Symbicort Forte Turbuhaler (Formoterol Fumarate Dihydrate) 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 Symbicort Forte Turbuhaler (Formoterol Fumarate Dihydrate) Inhalation Solution. Cardiac monitoring is recommended in cases of overdosage.

The minimum lethal inhalation dose of 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

Symbicort Forte Turbuhaler (Formoterol Fumarate Dihydrate) (formoterol fumarate) Inhalation Solution is supplied as 2 mL of 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 Symbicort Forte Turbuhaler (Formoterol Fumarate Dihydrate), USP equivalent to 20 mcg of 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 Symbicort Forte Turbuhaler (Formoterol Fumarate Dihydrate) Inhalation Solution is Symbicort Forte Turbuhaler (Formoterol Fumarate Dihydrate), USP, a racemate. Symbicort Forte Turbuhaler (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 Symbicort Forte Turbuhaler (Formoterol Fumarate Dihydrate) 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 Symbicort Forte Turbuhaler (Formoterol Fumarate Dihydrate) 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 Symbicort Forte Turbuhaler (Formoterol Fumarate Dihydrate) 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.

Symbicort Forte Turbuhaler (Formoterol Fumarate Dihydrate) Figure 1 Symbicort Forte Turbuhaler (Formoterol Fumarate Dihydrate) Figure 2

16 HOW SUPPLIED/STORAGE AND HANDLING

Symbicort Forte Turbuhaler (Formoterol Fumarate Dihydrate) (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.

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

Acute Exacerbations or Deteriorations

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

Symbicort Forte Turbuhaler (Formoterol Fumarate Dihydrate)^®(Per-FOR-o-mist)

(formoterol fumarate) Inhalation Solution

Symbicort Forte Turbuhaler (Formoterol Fumarate Dihydrate) Inhalation Solution is only for use with a nebulizer.

Read the Medication Guide that comes with Symbicort Forte Turbuhaler (Formoterol Fumarate Dihydrate) 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 Symbicort Forte Turbuhaler (Formoterol Fumarate Dihydrate) Inhalation Solution?

Symbicort Forte Turbuhaler (Formoterol Fumarate Dihydrate) Inhalation Solution can cause serious side effects including:

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

Symbicort Forte Turbuhaler (Formoterol Fumarate Dihydrate) 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.

Symbicort Forte Turbuhaler (Formoterol Fumarate Dihydrate) Inhalation Solution is only for use with a nebulizer. LABA medicines such as Symbicort Forte Turbuhaler (Formoterol Fumarate Dihydrate) 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.

Symbicort Forte Turbuhaler (Formoterol Fumarate Dihydrate) Inhalation Solution is not for use to treat sudden symptoms of COPD.

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

It is not known if Symbicort Forte Turbuhaler (Formoterol Fumarate Dihydrate) Inhalation Solution is safe and effective in people with asthma.

Who should not use Symbicort Forte Turbuhaler (Formoterol Fumarate Dihydrate) Inhalation Solution?

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

What should I tell my healthcare provider before using Symbicort Forte Turbuhaler (Formoterol Fumarate Dihydrate) 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 Symbicort Forte Turbuhaler (Formoterol Fumarate Dihydrate) Inhalation Solution can harm an unborn baby.
• are breastfeeding. It is not known if Symbicort Forte Turbuhaler (Formoterol Fumarate Dihydrate) 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. Symbicort Forte Turbuhaler (Formoterol Fumarate Dihydrate) 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 Symbicort Forte Turbuhaler (Formoterol Fumarate Dihydrate) Inhalation Solution?

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

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

Symbicort Forte Turbuhaler (Formoterol Fumarate Dihydrate) Inhalation Solution can cause serious side effects, including:

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

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

General Information about Symbicort Forte Turbuhaler (Formoterol Fumarate Dihydrate) Inhalation Solution

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

Symbicort Forte Turbuhaler (Formoterol Fumarate Dihydrate) 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 Symbicort Forte Turbuhaler (Formoterol Fumarate Dihydrate) Inhalation Solution or other medicines.

Do not mix Symbicort Forte Turbuhaler (Formoterol Fumarate Dihydrate) Inhalation Solution with other medicines in your nebulizer machine.

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

Symbicort Forte Turbuhaler (Formoterol Fumarate Dihydrate)^®

(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: 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 Symbicort Forte Turbuhaler (Formoterol Fumarate Dihydrate)^® 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 Symbicort Forte Turbuhaler (Formoterol Fumarate Dihydrate)^® 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

Symbicort Forte Turbuhaler (Formoterol Fumarate Dihydrate) Inhalation Solution 20 mcg/2 mL Carton