Foradil

Foradil is a prescription medicine used to treat breathing difficulties caused by asthma, exercise induced bronchospasm (EIB), and chronic obstructive pulmonary disease (COPD).

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

It is not known if Foradil crosses into human milk. Because many medications can cross into human milk and because of the possibility for serious adverse reactions in nursing infants with use of this medication, a choice should be made whether to stop nursing or stop the use of this medication. Your doctor and you will decide if the benefits outweigh the risk of using Foradil.

Do not use Foradil unless your healthcare provider has taught you and you understand everything. Ask your healthcare provider or pharmacist if you have any questions.

Foradil capsules are for use only in the Foradil Aerolizer device. Use only one capsule at a time. Do not take the capsules by mouth. Never place a capsule in the mouthpiece of the inhaler.

• Children should use Foradil with an adult’s help, as instructed by the child’s healthcare provider.
• Use Foradil exactly as prescribed. Do not use Foradil more often than prescribed.
• If you miss a dose of Foradil, just skip that dose. Take your next dose at your usual time. Never take 2 doses at one time.
• Do not use a spacer device.
• Do not breathe into the device.
• While you are using Foradil 2 times each day, do not use other medicines that contain a long-acting beta2-agonist (LABA) for any reason. Ask your healthcare provider or pharmacist for a list of these medicines. 
• Do not stop using Foradil or any of your asthma medicines unless told to do so by your healthcare provider because your symptoms might get worse. Your healthcare provider will change your medicines as needed.
• Foradil does not relieve sudden symptoms. Always have a rescue inhaler medicine with you to treat sudden symptoms. If you do not have an inhaled, short-acting bronchodilator, contact your healthcare provider to have one prescribed for you.

• Call your healthcare provider or get medical care right away if:
  • your breathing problems worsen with Foradil
  • 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
  • you need to use 4 or more inhalations of your rescue inhaler medicine for 2 or more days in a row
  • you use 1 whole canister of your rescue inhaler medicine in 8 weeks time
  • your peak flow meter results decrease. Your healthcare provider will tell you the numbers that are right for you.
  • you have asthma and your symptoms do not improve after using Foradil regularly for 1 week.

If you use too much Foradil, call your local Poison Control Center or seek emergency medical attention right away.

     Treatment of Asthma

Foradil AEROLIZER is indicated for the treatment of asthma and in the prevention of bronchospasm only as concomitant therapy with a long-term asthma control medication, such as an inhaled corticosteroid, in adults and children 5 years of age and older with reversible obstructive airways disease, including patients with symptoms of nocturnal asthma.

Long acting beta2-adrenergic agonists (LABA), such as formoterol, the active ingredient in Foradil AEROLIZER, increase the risk of asthma-related death. 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. 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 [see Contraindications (4) and Warnings and Precautions (5.1)].

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 used 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 [see Warnings and Precautions (5.1)].

Important Limitation of Use

Foradil AEROLIZER is NOT indicated for the relief of acute bronchospasm.

     Prevention of Exercise-Induced Bronchospasm

Foradil AEROLIZER is also indicated for the acute prevention of exercise-induced bronchospasm in adults and children 5 years of age and older, when administered on an occasional, as-needed basis. Use of Foradil AEROLIZER as a single agent for the prevention of exercise-induced bronchospasm may be clinically indicated in patients who do not have persistent asthma. In patients with persistent asthma, use of Foradil AEROLIZER for the prevention of exercise-induced bronchospasm may be clinically indicated, but the treatment of asthma should include a long-term asthma control medication, such as an inhaled corticosteroid.

     Maintenance Treatment of Chronic Obstructive Pulmonary Disease

Foradil AEROLIZER 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 including chronic bronchitis and emphysema.

Important Limitation of Use

Foradil AEROLIZER is NOT indicated for the relief of acute bronchospasm.

     Mechanism of Action

Formoterol fumarate is a long-acting beta2-adrenergic receptor agonist (beta2-agonist). Inhaled formoterol fumarate acts locally in the lung as a bronchodilator. In vitro studies have shown that formoterol has more than 200-fold greater agonist activity at beta2-receptors than at beta1-receptors. Although beta2-receptors are the predominant adrenergic receptors in bronchial smooth muscle and beta1-receptors are the predominant receptors in the heart, there are also beta2-receptors in the human heart comprising 10%-50% of the total beta-adrenergic receptors. The precise function of these receptors has not been established, but they raise the possibility that even highly selective beta2-agonists may have cardiac effects.

The pharmacologic effects of beta2-adrenoceptor agonist drugs, including formoterol, are at least in part attributable to stimulation of intracellular adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3', 5'-adenosine monophosphate (cyclic AMP). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells.

In vitro tests show that formoterol is an inhibitor of the release of mast cell mediators, such as histamine and leukotrienes, from the human lung. Formoterol also inhibits histamine-induced plasma albumin extravasation in anesthetized guinea pigs and inhibits allergen-induced eosinophil influx in dogs with airway hyper-responsiveness. The relevance of these in vitro and animal findings to humans is unknown.

     Pharmacodynamics

Systemic Safety and Pharmacokinetic/Pharmacodynamic Relationships

The major adverse effects of inhaled beta2-agonists occur as a result of excessive activation of the systemic beta-adrenergic receptors. The most common adverse effects in adults and adolescents include skeletal muscle tremor and cramps, insomnia, tachycardia, decreases in plasma potassium, and increases in plasma glucose.

Pharmacokinetic/pharmacodynamic (PK/PD) relationships between heart rate, ECG parameters, and serum potassium levels and the urinary excretion of formoterol were evaluated in 10 healthy male volunteers (25 to 45 years of age) following inhalation of single doses containing 12, 24, 48, or 96 mcg of formoterol fumarate. There was a linear relationship between urinary formoterol excretion and decreases in serum potassium, increases in plasma glucose, and increases in heart rate.

In a second study, PK/PD relationships between plasma formoterol levels and pulse rate, ECG parameters, and plasma potassium levels were evaluated in 12 healthy volunteers following inhalation of a single 120 mcg dose of formoterol fumarate (10 times the recommended clinical dose). Reductions of plasma potassium concentration were observed in all subjects. Maximum reductions from baseline ranged from 0.55 to 1.52 mmol/L with a median maximum reduction of 1.01 mmol/L. The formoterol plasma concentration was highly correlated with the reduction in plasma potassium concentration. Generally, the maximum effect on plasma potassium was noted 1 to 3 hours after peak formoterol plasma concentrations were achieved. A mean maximum increase of pulse rate of 26 bpm was observed 6 hours post dose. The maximum increase of mean corrected QT interval (QTc) was 25 msec when calculated using Bazett's correction and was 8 msec when calculated using Fridericia's correction. The QTc returned to baseline within 12-24 hours post-dose. Formoterol plasma concentrations were weakly correlated with pulse rate and increase of QTc duration. The effects on plasma potassium, pulse rate, and QTc interval are known pharmacological effects of this class of study drug and were not unexpected at the very high formoterol dose (120 mcg single dose, 10 times the recommended single dose) tested in this study. These effects were well-tolerated by the healthy volunteers.

The electrocardiographic and cardiovascular effects of Foradil AEROLIZER were compared with those of albuterol and placebo in two pivotal 12-week double-blind studies of patients with asthma. A subset of patients underwent continuous electrocardiographic monitoring during three 24-hour periods. No important differences in ventricular or supraventricular ectopy between treatment groups were observed. In these two studies, the total number of patients with asthma exposed to any dose of Foradil AEROLIZER who had continuous electrocardiographic monitoring was about 200.

Continuous electrocardiographic monitoring was performed in an 8-week, randomized, double-blind, and placebo controlled trial in 204 COPD patients treated with Foradil AEROLIZER 12 mcg twice daily or placebo. Holter monitoring was used to evaluate predefined proarrhythmic events. Non-sustained ventricular tachycardia occurred in 2 (2.2%) of Foradil AEROLIZER treated patients compared to none in the placebo group. An increase in ventricular premature beats (VPB) occurred in 3 (3.3 %) of Foradil AEROLIZER treated patients compared to 2 (1.9%) in the placebo group. There were no events of sustained ventricular tachycardia, ventricular flutter or fibrillation, or symptomatic runs of VPB. One patient in the Foradil AEROLIZER group had a serious adverse event of atrial flutter.

The electrocardiographic effects of Foradil AEROLIZER were evaluated versus placebo in a 12-month pivotal double-blind study of patients with COPD. An analysis of ECG intervals was performed for patients who participated at study sites in the United States, including 46 patients treated with Foradil AEROLIZER 12 mcg twice daily, and 50 patients treated with Foradil AEROLIZER 24 mcg twice daily. ECGs were performed predose, and at 5-15 minutes and 2 hours post-dose at study baseline and after 3, 6, and 12 months of treatment. The results showed that there was no clinically meaningful acute or chronic effect on ECG intervals, including QTc, resulting from treatment with Foradil AEROLIZER.

Tachyphylaxis/Tolerance

In a clinical study in 19 adult patients with mild asthma, the bronchoprotective effect of formoterol, as assessed by methacholine challenge, was studied following an initial dose of 24 mcg (twice the recommended dose) and after 2 weeks of 24 mcg twice daily. Tolerance to the bronchoprotective effects of formoterol was observed as evidenced by a diminished bronchoprotective effect on FEV1 after 2 weeks of dosing, with loss of protection at the end of the 12 hour dosing period.

Rebound bronchial hyper-responsiveness after cessation of chronic formoterol therapy has not been observed.

In three large clinical trials in patients with asthma, while efficacy of formoterol versus placebo was maintained, a slightly reduced bronchodilatory response (as measured by 12-hour FEV1 AUC) was observed within the formoterol arms over time, particularly with the 24 mcg twice daily dose (twice the daily recommended dose). A similarly reduced FEV1 AUC over time was also noted in the albuterol treatment arms (180 mcg four times daily by metered-dose inhaler).

     Pharmacokinetics

Information on the pharmacokinetics of formoterol in plasma has been obtained in healthy subjects by oral inhalation of doses higher than the recommended range and in Chronic Obstructive Pulmonary Disease (COPD) patients after oral inhalation of doses at and above the therapeutic dose. Urinary excretion of unchanged formoterol was used as an indirect measure of systemic exposure. Plasma drug disposition data parallel urinary excretion, and the elimination half-lives calculated for urine and plasma are similar.

Absorption

Following inhalation of a single 120 mcg dose of formoterol fumarate by 12 healthy subjects, formoterol was rapidly absorbed into plasma, reaching a maximum drug concentration of 92 pg/mL within 5 minutes of dosing. In COPD patients treated for 12 weeks with formoterol fumarate 12 or 24 mcg twice daily, the mean plasma concentrations of formoterol obtained at 10 min, 2 h, and 6 h post inhalation ranged between 4.0 and 8.8 pg/mL and 8.0 and 17.3 pg/mL, respectively.

Following inhalation of 12 to 96 mcg of formoterol fumarate by 10 healthy males, urinary excretion of both (R,R)- and (S,S)-enantiomers of formoterol increased proportionally to the dose. Thus, absorption of formoterol following inhalation appeared linear over the dose range studied.

In a study in patients with asthma, when formoterol 12 or 24 mcg twice daily was given by oral inhalation for 4 weeks or 12 weeks, the accumulation index, based on the urinary excretion of unchanged formoterol ranged from 1.63 to 2.08 in comparison with the first dose. For COPD patients, when formoterol 12 or 24 mcg twice daily was given by oral inhalation for 12 weeks, the accumulation index, based on the urinary excretion of unchanged formoterol was 1.19 - 1.38. This suggests some accumulation of formoterol in plasma with multiple dosing. The excreted amounts of formoterol at steady-state were close to those predicted based on single-dose kinetics. As with many drug products for oral inhalation, it is likely that the majority of the inhaled formoterol fumarate delivered is swallowed and then absorbed from the gastrointestinal tract.

Distribution

The binding of formoterol to human plasma proteins in vitro was 61%-64% at concentrations from 0.1 to 100 ng/mL. Binding to human serum albumin in vitro was 31%-38% over a range of 5 to 500 ng/mL. The concentrations of formoterol used to assess the plasma protein binding were higher than those achieved in plasma following inhalation of a single 120 mcg dose.

Metabolism

Formoterol is metabolized primarily by direct glucuronidation at either the phenolic or aliphatic hydroxyl group and O-demethylation followed by glucuronide conjugation at either phenolic hydroxyl groups. Minor pathways involve sulfate conjugation of formoterol and deformylation followed by sulfate conjugation. The most prominent pathway involves direct conjugation at the phenolic hydroxyl group. The second major pathway involves O-demethylation followed by conjugation at the phenolic 2'-hydroxyl group. Four cytochrome P450 isozymes (CYP2D6, CYP2C19, CYP2C9, and CYP2A6) are involved in the O-demethylation of formoterol. Formoterol did not inhibit CYP450 enzymes at therapeutically relevant concentrations. Some patients may be deficient in CYP2D6 or 2C19 or both. Whether a deficiency in one or both of these isozymes results in elevated systemic exposure to formoterol or systemic adverse effects has not been adequately explored.

Excretion

Following oral administration of 80 mcg of radiolabeled formoterol fumarate to 2 healthy subjects, 59%-62% of the radioactivity was eliminated in the urine and 32%-34% in the feces over a period of 104 hours. Renal clearance of formoterol from blood in these subjects was about 150 mL/min. Following inhalation of a 12 mcg or 24 mcg dose by 16 patients with asthma, about 10% and 15%-18% of the total dose was excreted in the urine as unchanged formoterol and direct conjugates of formoterol, respectively. Following inhalation of 12 mcg or 24 mcg dose by 18 patients with COPD the corresponding values were 7% and 6-9% of the dose, respectively.

Based on plasma concentrations measured following inhalation of a single 120 mcg dose by 12 healthy subjects, the mean terminal elimination half-life was determined to be 10 hours. From urinary excretion rates measured in these subjects, the mean terminal elimination half-lives for the (R,R)- and (S,S)-enantiomers were determined to be 13.9 and 12.3 hours, respectively. The (R,R)- and (S,S)-enantiomers represented about 40% and 60% of unchanged drug excreted in the urine, respectively, following single inhaled doses between 12 and 120 mcg in healthy volunteers and single and repeated doses of 12 and 24 mcg in patients with asthma. Thus, the relative proportion of the two enantiomers remained constant over the dose range studied and there was no evidence of relative accumulation of one enantiomer over the other after repeated dosing.

Special Populations

Gender: After correction for body weight, formoterol pharmacokinetics did not differ significantly between males and females.

Geriatric and Pediatric: The pharmacokinetics of formoterol have not been studied in the elderly population, and limited data are available in pediatric patients.

In a study of children with asthma who were 5 to 12 years of age, when formoterol fumarate 12 or 24 mcg was given twice daily by oral inhalation for 12 weeks, the accumulation index ranged from 1.18 to 1.84 based on urinary excretion of unchanged formoterol. Hence, the accumulation in children did not exceed that in adults, where the accumulation index ranged from 1.63 to 2.08 (see above). Approximately 6% and 6.5% to 9% of the dose was recovered in the urine of the children as unchanged and conjugated formoterol, respectively.

Hepatic/Renal Impairment

The pharmacokinetics of formoterol have not been studied in subjects with hepatic or renal impairment.

Animal reproduction studies in rats and rabbits revealed evidence of teratogenicity as well as other developmental toxic effects. Oral doses equal to or greater than 80 times the maximum recommended human adult dose (MRHD) caused delayed ossification of the fetus and doses equal to or greater than 2400 times the MRHD for adults caused decreased fetal weight. This drug has been shown to cause stillbirth and neonatal mortality at oral doses equal to or greater than 2400 times the MRHD for adults in rats receiving the drug during the late stage of pregnancy; these effects, however, were not produced at a dose equal to 80 times the MRHD. Umbilical hernia was observed in rat fetuses at oral doses equal to or greater than 1200 times the MRHD for adults. Brachygnathia, a skeletal malformation, was observed for rat fetuses at an oral dose equal to 6100 times the MRHD for adults. Subcapsular cysts on the liver were observed for rabbit fetuses at an oral dose equal to 49000 times the MRHD for adults. No teratogenic effects were observed at oral doses up to 3000 times the MRHD for adults. There are no controlled data in human pregnancy. AU TGA pregnancy category B3: Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals have shown evidence of an increased occurrence of fetal damage, the significance of which is considered uncertain in humans. US FDA pregnancy category C: Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

This drug should be used during pregnancy only if the benefit outweighs the risk to the fetus. AU TGA pregnancy category: B3 US FDA pregnancy category: C Comment: -Beta-agonists, including this drug, may potentially interfere with uterine contractility due to a relaxant effect on uterine smooth muscle.

Caution is recommended. Benefit should outweigh risk. Excreted into human milk: Unknown Excreted into animal milk: Yes Comments: -Women should contact their physician if they are nursing while taking the inhalation solution. -The effects in the nursing infant are unknown.

This drug and its metabolites was excreted in the breast milk of lactating rats given oral doses of 50 mcg/kg, and growth and survival of the pups were decreased when lactating rats were given oral doses greater than 1 mg/kg/day. A study in rats showed increased postnatal mortality at maternal oral doses of 0.2 mg/kg/day or greater, and retardation of pup growth at 15 mg/kg/day.

Summary of Use during Lactation

Although no published data exist on the use of formoterol by inhaler during lactation, data from the related drug, terbutaline, indicate that very little is expected to be excreted into breastmilk.[1] The authors of several reviews and an expert panel agree that use of inhaled bronchodilators is acceptable during breastfeeding because of the low bioavailability and maternal serum levels after use.[2][3][4][5][6]

Drug Levels

Maternal Levels. Relevant published information was not found as of the revision date.

Infant Levels. Relevant published information was not found as of the revision date.

Effects in Breastfed Infants

Relevant published information was not found as of the revision date.

Effects on Lactation and Breastmilk

Relevant published information was not found as of the revision date.

Alternate Drugs to Consider

Salmeterol

References

1. Lindberg C, Boreus LO, de Chateau P et al. Transfer of terbutaline into breast milk. Eur J Resp Dis. 1984;65(Suppl 134):87-91. PMID: 6586490

2. McDonald CF, Burdon JGW. Asthma in pregnancy and lactation. A position paper for the Thoracic Society of Australia and New Zealand. Med J Aust. 1996;165:485-8. PMID: 8937369

3. Ellsworth A. Pharmacotherapy of asthma while breastfeeding. J Hum Lact. 1994;10:39-41. PMID: 7619245

4. Nelson-Piercy C. Asthma in pregnancy. Thorax. 2001;56:325-8. PMID: 11254828

5. Taddio A, Ito S. Drugs and breast-feeding. In: Koren G, ed. Maternal-fetal toxicology. A clinician's guide. 3rd ed. New York: Marcel Dekker, 2001:177-32.

6. National Heart, Lung, and Blood Institute, National Asthma Education and Prevention Program Asthma and Pregnancy Working Group. NAEPP expert panel report. Managing asthma during pregnancy: recommendations for pharmacologic treatment-2004 update. 2004;1-57. http://www.nhlbi.nih.gov/health/prof/lung/asthma/astpreg.htm

LactMed Record Number

121

Last Revision Date

20170411

Disclaimer

Information presented in this database is not meant as a substitute for professional judgment. You should consult your healthcare provider for breastfeeding advice related to your particular situation. The U.S. government does not warrant or assume any liability or responsibility for the accuracy or completeness of the information on this Site.