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Formoterol (Inhalation-Local)


VA CLASSIFICATION
Primary: RE 120

Commonly used brand name(s): Foradil; Oxeze.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Bronchodilator, adrenergic (inhalation)—

Indications

Accepted

Asthma (adjunctive treatment)—Formoterol is indicated to treat asthma concomitantly with short-acting beta 2-agonists, inhaled or systemic corticosteroids and theophylline therapy.{02}

Note: Canadian product information states formoterol is indicated in patients who are using optimal corticosteroid treatment and experiencing regular or frequent breakthrough symptoms requiring regular use of short-acting bronchodilators.{03}


Asthma (treatment)—Formoterol is indicated for long-term maintenance treatment of asthma in adult and children 5 years of age and older with reversible obstructive airway disease, including patients with symptoms of nocturnal asthma, {01}{02}

Note: Canadian product information states formoterol is indicated in treatment of asthma in adults and children ages 6 and older.{03}


Chronic obstructive pulmonary disease [COPD] (treatment)—Formoterol is indicated as long-term, twice-daily administration in the treatment of patients with chronic obstructive pulmonary disease including chronic bronchitis and emphysema. {02}{03}

Exercise-induced bronchospasm [EIB] (prevention) 1— Formoterol is indicated for the acute prevention of exercise-induced bronchospasm when administered on an occasional, as needed basis.{02}

Unaccepted
Not to be used in patients whose asthma can be managed by occasional use of short-acting inhaled β2-agonists.{01}{02}

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    840.9{01}

pKa—
    Phenolic group: 7.9{01}
    Amino group: 9.2{01}

Mechanism of action/Effect:

Formoterol is a long-acting selective stimulator of {02} the beta 2adrenergic receptors in bronchial smooth muscle. This stimulation causes relaxation of smooth muscle fibers and produces bronchodilation.{01}

Bioavailability:

Pulmonary: 21-37%{01}

Total systemic: 46%{01}

Protein binding:

Moderate (61 to 64%) {02}

Serum albumin binding was 31 to 38% over a range of 5 to 500 ng per mL.{02}

Biotransformation:

Hepatic via cytochrome P450 isozymes (CYP2D6, CYP2C19, CYP2C9 and CYP2A6) and non-450 pathways (glucuronidation, O-demethylation and direct conjugation). {02}

Half-life:

Mean terminal: 10 hours. {02}

Onset of action:

1–3 minutes{01}

Time to peak concentration:

5 minutes following a single 120 mcg (10 times the recommended clinical dose){04} inhaled dose.{02}

Peak serum concentration:

92 picograms per mL following inhalation of a single 120 mcg dose.{02}

Duration of action:

12 hours{01}

Elimination:


Following inhalation—
        Primarily eliminated via metabolism{01}
        In asthma patients following a 12 or 24 mcg dose: 10% and 15 to 18% excreted unchanged in the urine, respectively{02}
        In COPD patients following a 12 or 24 mcg dose: 7% and 6 to 9% excreted unchanged in the urine, respectively{02}



Following oral administration—
         In healthy patients following an 80 mcg dose: 59 to 62% excreted in the urine and 32 to 34% excreted in the feces. Renal clearance from the blood was 150 mL per min.{02}



Precautions to Consider

Carcinogenicity

Carcinogenic potential of formoterol has been evaluated in drinking water and dietary studies in both rats and mice. The incidence of ovarian leiomyomas in rats was increased at doses of 15 mg per kg and above in the drinking water study and at 20 mg per kg in the dietary study. The incidence of benign ovarian theca-cell tumors in rats was increased at doses of 0.5 mg per kg and above in the dietary study. The incidence of adrenal subcapsular adenomas and carcinomas was increased in male mice at doses of 69 mg per kg and above in the drinking water study, but not at doses up to 50 mg per kg in the dietary study. The incidence of hepatocarcinomas{04}was increased in the dietary study at doses of 20 and 50 mg per kg in female mice and 50 mg per kg in male mice.{02}Uterine leiomyomas and leiomyosarcomas {02}have been found in mice following oral administration of formoterol. Similarly, mesovarian leiomyomas have been found in rats following inhalation of formoterol.{01}These are expected findings in mice and rats administered beta-stimulating agents.{01}

Mutagenicity

Formoterol was not shown to be mutagenic or clastogenic{02} in any of the following: bacterial and mammalian cell mutagenicity tests, chromosome analyses tests in mammalian cells, unscheduled DNA synthesis repair tests in human fibroblasts or in rat hepatocytes, transformation assay in mammalian fibroblasts and micronucleus tests in mice and in rats. {01}{02}

Pregnancy/Reproduction
Fertility—
Reproduction studies in rats revealed no impairment of fertility{03}{02} at oral doses up to 3 mg per kg (approximately 1000 times the maximum recommended daily inhalation dose in humans on a mg per m basis).{02}

Pregnancy—
There are no adequate and well-controlled studies in pregnant women. {02}Safety and efficacy in pregnant women has not been established.{01}

In animal studies formoterol has been shown to cause stillbirth and neonatal mortality at oral doses of 6 mg per kg (approximately 2000 times the maximum recommended daily inhalation dose in humans on a mg per m 2 basis) and above in rats receiving the drug during the late stage of pregnancy. When formoterol was given to rats throughout organogenesis, oral doses of 0.2 mg per kg and above delayed ossification of the fetus, and doses of 6 mg per kg and above decreased fetal weight. {02}

Formoterol did not cause malformations in rats or rabbits following oral administration.{02}

Note: Canadian product information states the following findings regarding the use of formoterol during pregnancy: Rat studies have found that placental weights increase and maternal weights decrease following inhaled doses of .004—1.2 mg per kg of formoterol. No teratogenic effects were seen at any dosing level.{01}
Studies in rabbits have demonstrated an increase in both maternal and placental weight following oral formoterol doses of .2, 3.5 and 60 mg per kg. A higher percentage of liver cysts, extra ribs and reduced and/or asymmetric/bipartite sternbrae in the fetuses was noted following maternal doses of 60 mg per kg (7000–11000 times the recommended human exposure){01}


FDA Pregnancy Category C {02}


Labor and delivery—

There are no adequate and well controlled studies on the effects of formoterol when used during labor. However, β2-agonists such as formoterol have the potential for interference with uterine contractility and should only be used when the potential benefit to the mother outweighs the potential risk to the fetus.{01}

Breast-feeding

There are no adequate and well-controlled studies in nursing women. {02}It is not known whether formoterol is distributed in human breast milk. However, it is distributed in rat milk after oral administration. Risk-benefit should be carefully considered before administering formoterol to nursing mothers.{01}

Pediatrics

Appropriate studies on the relationship of age to the effect of formoterol have not been performed in children less than 5 {02} years of age. Use in children less than 5 {02} years of age is not recommended due to limited clinical data. {01}

Note: Canadian product information states that use in children less than 6 years of age is not recommended {03}



Geriatrics


Appropriate studies performed to date have not demonstrated geriatrics-specific problems that would limit the usefulness of formoterol in the elderly. However, greater sensitivity of some older individuals cannot be ruled out. {02}

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Adrenergic drugs, additional    ( may potentiate the pharmacologically predictable sympathetic effects of formoterol)

{02}
Alcohol or
Levodopa or
Levothyroxine or
Oxytocin    (may impair cardiac tolerance towards beta2-sympathomimetics )

{01}
» Antidepressants, tricyclic or
» Disopyramide or
» Phenothiazines or
» Procainamide or
» Quinidine     (concomitant treatment may prolong the QTc interval and increase the risk of ventricular arrhythmias)

{01}
» Beta-receptor blocking agents    (may partly or totally inhibit the effect of beta-stimulants; beta-blockers with less predominant beta2blocking effects should be considered; patients should be monitored for deterioration in pulmonary function; dosage adjustment of either drug may be necessary)

{01}
Diuretics, non potassium-sparing or
Digitalis glycosides or
Methylxanthines or
Steroids {02}    (may potentiate the hypokalemic effect of beta 2 agonists and lead to an increased disposition towards arrhythmias in patients . ECG changes and/or hypokalemia that may result from the administration of non-potassium-sparing diuretics can be acutely worsened by beta-agonists{01})


Halogenated hydrocarbons    (may increase risk of arrhythmias in patients receiving halogenated hydrocarbon anesthesia)

{01}
» Monoamine oxidase inhibitors , including furazolidine and procarbazine    (concomitant treatment may prolong the QTc interval and increase the risk of ventricular arrhythmias; may increase chance of hypertensive reactions )

{01}

Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Blood pressure    (clinically significant changes in systolic and/or diastolic blood pressure have been seen infrequently in controlled clinical studies, but may necessitate the discontinuation of formoterol.{02})


Electrocardiogram    (prolonged QTc interval , flattening of the T wave and ST segment depression {02} reported{01})


Glucose, blood    (concentrations may be increased, possibly due to glycogenolysis; clinically significant changes may be more pronounced following nebulization or with frequent use of higher doses or an overdose{01})


Potassium, serum    (concentrations may be decreased, possibly through intracellular shunting; the decrease is dose-related, is usually transient, and may not require supplementation; effects may be more pronounced following frequent use of higher doses or an overdose {01})


Pulse rate    (clinically significant increases in pulse rate may occur. Although reported as an uncommon occurrence, it may necessitate the discontinuation of formoterol.{02})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problems exist:
Acutely deteriorating asthma    (increased risk of adverse events, contraindicated{01})


» Hypersensitivity to formoterol or
» Inhaled lactose{01}
» Tachyarrhythmias{01}
Risk-benefit should be considered when the following medical problems exist
» Cardiovascular disorders, especially:
» Cardiac arrhythmias,
» Coronary insufficiency and
» Hypertension
» Convulsive disorders
» Thyrotoxicosis
» Unusual responsiveness to sympathomimetic amines     ( changes in systolic and/or diastolic blood pressure, pulse rate and electrocardiograms have been reported in controlled clinical studies {02})


» Cardiac decompensation, severe or
Hypertrophic obstructive cardiomyopathy or
Ischemic heart disease     (may require special care and supervision, with particular emphasis on dosage limits)

{01}
Hyperthyroidism, uncontrolled    (unusually responsive to sympathomimetic amines; signs and symptoms of excessive beta-adrenergic stimulation are more likely to occur{01})


Idiopathic hypertrophic subvalvular aortic stenosis     (may lead to an increase in the pressure gradient between the left ventricle and the aorta)


» Diabetes    (additional blood glucose monitoring is recommended)

{01}

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Pulmonary function monitoring    (objective measures of lung function are essential for diagnosis and for guiding therapeutic decision-making in the treatment of asthma; measurement of forced expiratory air flow, using a spirometer or a peak expiratory flowmeter, is recommended at periodic intervals {01})




Side/Adverse Effects

Note: Adverse reactions to formoterol are similar in nature to other selective beta2-adrenoreceptor agonists; for example, angina, hypertension or hypotension, tachycardia, arrhythmias, nervousness, headache, tremor, dry mouth, palpitation, muscle cramps, nausea, dizziness, fatigue, malaise, hypokalemia, hyperglycemia, metabolic acidosis and insomnia. {02}

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Infection, viral {02}(chills; cough or hoarseness; fever; cold, flu-like symptoms)
    
upper respiratory infection {02}(cough; fever; sneezing or sore throat)

Incidence less frequent
    
Bronchitis {02}(cough producing mucus; difficulty breathing; shortness of breath; tightness in chest; wheezing)
    
chest infection {02}
    
chest pain {02}(chest pain or discomfort)
    
dyspnea {02}( shortness of breath; difficult or labored breathing; tightness in chest; wheezing)
    
fever {02}
    
pharyngitis {02}(body aches or pain; congestion; cough; dryness or soreness of throat; fever; hoarseness; runny nose; tender, swollen glands in neck; trouble in swallowing; voice changes)
    
sinusitis {02}(pain or tenderness around eyes and cheekbones; fever; stuffy or runny nose; headache; cough; shortness of breath or troubled breathing; tightness of chest or wheezing)
    
tonsillitis {02}( congestion; fever; sore throat; swollen glands)
    
trauma {02}

Incidence rare
    
Bronchospasm{01} (cough; ; difficulty breathing; noisy breathing ; shortness of breath ; tightness in chest; wheezing)
    
hypokalemia{01} (convulsions ; decreased urine ; dry mouth; irregular heartbeat ; increased thirst ; or loss of appetite )
    
tachycardia{01} (fainting ; fast pounding, or irregular heartbeat or pulse; palpitations or pounding in the ears)



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Headache{01}
{01}
Incidence less frequent
    
Agitation{01}
    
anxiety {02}
    
back pain {02}
    
cramps{01}
    
dizziness {02}
    
dry mouth {02}
    
dysphonia {02}(hoarseness; sore throat; voice changes)
    
exanthema{01} (skin rash)
    
insomnia {02}( sleeplessness; trouble sleeping; unable to sleep)
    
pruritis{01} ( itching skin )
    
rash {02}
    
restlessness{01}
    
sleep disturbances{01}
    
sputum, increased {02}(increased mucous in throat and lungs)
    
tremor {02}(trembling or shaking of hands or feet; shakiness in legs, arms, hands, feet)
    
urticaria{01} (hives or welts ; itching ; redness of skin ; skin rash)





Overdose
For more information on the management of overdose or unintentional ingestion, contact a poison control center (see Poison Control Center Listing).

Clinical effects of overdose

Note: The expected signs and symptoms with overdosage of formoterol are those of excessive beta-adrenergic stimulation and/or any of the signs and symptoms listed under side and adverse effects.{02}

The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
    
Angina {02}( arm, back or jaw pain; chest pain or discomfort; chest tightness or heaviness; fast or irregular heartbeat; shortness of breath; sweating; nausea)
    
arrhythmias {02}( dizziness; fainting; fast, slow, or irregular heartbeat)
    
cardiac arrest {02}(stopping of heart; no blood pressure or pulse; unconsciousness)
    
dizziness {02}
    
dry mouth {02}
    
fatigue {02}
    
headache
    
hyperglycemia{01} (blurred vision; increased hunger or thirst; increased urination)
    
hypertension {02}(blurred vision; dizziness, severe or continuing; nervousness; headache; pounding in the ears; slow or fast heartbeat)
    
hypokalemia {02}(convulsions; decreased urine; dry mouth; irregular heartbeat; increased thirst; loss of appetite; mood changes; muscle pain or cramps; nausea or vomiting; numbness or tingling in hands, feet, or lips; shortness of breath; unusual tiredness or weakness)
    
hypotension{01} (dizziness or light-headedness)
    
insomnia {02}(trouble sleeping; unable to sleep)
    
malaise {02}( general feeling of discomfort or illness; unusual tiredness or weakness)
    
metabolic acidosis{01} (shortness of breath ; troubled breathing){01}
    
muscle cramps {02}
    
muscle tremor
    
nausea {02}
    
nervousness {02}
    
palpitation {02}
    
seizures {02}(convulsions; muscle spasm or jerking of all extremities; sudden loss of consciousness)
    
tachycardia{01} (fainting ; fast pounding, or irregular heartbeat or pulse; palpitations)


Treatment of overdose
There is no clinical experience on the management of overdose{01}

Treatment should be symptomatic and supportive{01}

The judicious use of a cardioselective beta-receptor blocker may be considered, bearing in mind that such medication can produce bronchospasm. {02}

Cardiac monitoring is recommended. {02}

There is insufficient evidence to determine if dialysis is beneficial is beneficial for overdosage of formoterol. {02}



Supportive care:
Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.



Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Formoterol (Inhalation-Local).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Hypersensitivity to formoterol or inhaled lactose



Carcinogenicity—
Carcinogenic potential of formoterol has been evaluated in drinking water and dietary studies in both rats and mice. The incidence of ovarian leiomyomas in rats was increased at doses of 15 mg per kg and above in the drinking water study and at 20 mg per kg in the dietary study. The incidence of benign ovarian theca-cell tumors in rats was increased at doses of 0.5 mg per kg and above in the dietary study. The incidence of adrenal subcapsular adenomas and carcinomas was increased in male mice at doses of 69 mg per kg and above in the drinking water study, but not at doses up to 50 mg per kg in the dietary study. The incidence of hepatocarcinomas{04}{05} was increased in the dietary study at doses of 20 and 50 mg per kg in female mice and 50 mg per kg in male mice.{02}Uterine leiomyomas have been found in mice following oral administration of formoterol. Similarly, mesovarian leiomyomas have been found in rats following inhalation of formoterol




Use in children——Not indicated for children less than 5 years of age

Note: Canadian product information states that formoterol is not indicated for children less than 6 years of age




Critical/Emergency care
Not using for treatment of acute symptoms
Other medications, especially antidepressants (tricyclic), beta-receptor blocking agents, disopyramide, furazolidine, monoamine oxidase inhibitors, phenothiazines, procainamide, procarbazine, quinidine, and terfenadine
Other medical problems, especially arrhythmias, cardiac decompensation (severe),cardiovascular disorders, coronary insufficiency, convulsive disorders, diabetes, hypertension (severe), tachyarrhythmias , thyrotoxicosis and unusual responsiveness to sympathomimetic amines.

Proper use of this medication
» Importance of not using to relieve an acute asthma attack

» Having a rapid-acting inhaled beta-adrenergic bronchodilator available for symptomatic relief of acute asthma attacks

» Reading patient instructions carefully before using

» Importance of not using more medication than prescribed; not using more than two times a day or less than 12 hours apart

Knowing correct administration technique for using inhaler

» Proper dosing
Missed dose: Taking as soon as possible; not taking if almost time for next scheduled dose; not doubling doses; using rapid-acting inhaled bronchodilator if symptoms occur before next dose is due

Proper storage

Precautions while using this medication
» Regular visits to physician at least every 6 to 12 months to check progress

» Checking with physician immediately if difficulty in breathing persists after use of this medication or if condition becomes worse

» For patients also using anti-inflammatory medication, checking with physician before stopping or reducing anti-inflammatory therapy


Side/adverse effects
Signs of potential side effects, especially viral infection, upper respiratory infection, bronchitis, chest infection, chest pain, dyspnea, fever, pharyngitis, sinusitis, tonsillitis, bronchospasms, hypokalemia, tachycardia or trauma.


General Dosing Information
Corticosteroid therapy should not be stopped or reduced {02}when formoterol therapy is initiated{01}.

Formoterol should not be used to treat acute symptoms{01} or in patients with significantly worsening symptoms.{02}

Need for increased use to treat symptoms indicates deterioration of asthma control and the need to reassess the patients therapy.{01} 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.{02}

A satisfactory clinical response to formoterol does not eliminate the need for continued treatment with an anti-inflammatory agent. {02}

When beginning treatment with formoterol, patients who have been taking inhaled, short-acting beta2-agonists on a regular basis should be instructed to discontinue the regular use of these drugs and use them only for symptomatic relief of acute asthma symptoms.{02}

With use in exercise induced bronchospasm, formoterol should be taken 15 minutes prior to exercise and not be re-dosed for 12 hours. {02}

The inhaler should never be washed and the patient should always use the new inhaler that comes with each refill. {02}

Formoterol should never be used with a spacer. {02}

Patients should handle capsules with dry hands. In rare instances the gelatin capsule might break into small pieces, but should be caught by the screen built into the inhaler. Tiny pieces of gelatin might however reach the mouth or throat. The capsule is less likely to shatter when pierced once. {02}

Patients should be instructed to never exhale into the device.{02}

The inhaler should only be used for formoterol capsules and not be used with any other medication. {02}


Inhalation Dosage Forms

FORMOTEROL FUMARATE DIHYDRATE POWDER FOR INHALATION

Usual Adult and Adolescent Dose
Asthma, chronic (treatment)
Oral inhalation, 12 mcg every 12 hours{01}{02}

Note: Canadian product information states that some patients may need up to 24 mcg every 12 hours. {01}


Chronic Obstructive Pulmonary Disease [COPD] (treatment)
Oral inhalation, 12 mcg every 12 hours. {02}

Note: Canadian product information states that 12 or 24 mcg should be taken every 12 hours. {03}


Exercise-induced bronchospasm [EIB] (prevention)1
12 mcg at least 15 minutes before exercise administered on an occasional as needed basis.{02}

Note: Additional doses should not be used for 12 hours after administration; regular, twice-daily dosing has not been studied in preventing EIB; patients who are receiving formoterol twice daily for maintenance treatment of their asthma should not use additional doses for prevention of EIB and may require a short-acting bronchodilator. {02}



Usual adult prescribing limits
Up to 24 mcg daily.{01}

Note: Canadian product information states that up to 24 mcg twice daily can be prescribed. {03}


Usual Pediatric Dose
Asthma, chronic treatment
Children 5 years of age and older: See Usual adult and adolescent dose{02}

Note: Canadian product information states that in children 6 years of age and older: See Usual adult and adolescent dose{01}



Usual pediatric prescribing limits
Up to 24 mcg daily{01}{02}.

Note: Canadian product information states that up to 24 mcg twice daily can be prescribed. {03}


Usual Geriatric Dose
See Usual adult dose.

Usual geriatric prescribing limits
See Usual adult prescribing limits.

Strength(s) usually available
U.S.—


12 mcg per capsule for inhalation (Rx) [Foradil ( lactose)]{02}

Canada—


6 mcg per metered dose (Rx) [Oxeze ( lactose)]{01}


12 mcg per metered dose (Rx) [Oxeze (lactose )]{01}


12 mcg per capsule for inhalation (Rx) [Foradil ( lactose)]{03}

Packaging and storage:
Prior to dispensing— store in a refrigerator, 2° to 8°C (36° to 46°F) {02}

After dispensing to patient— store at 20° to 25°C (68° to 77°F) {02}

Protect from heat and moisture.{01}{02}

Note: Capsules should always be stored in the blister and only removed from the blister immediately before use. {02}


Note: Canadian product information states to store between 15 and 25 °C {03}




Developed: 03/05/2001
Revised: 04/03/2002



References
  1. Product Information: Oxeze Turbohaler ®, formoterol. Astra Zeneca, Mississauga, Ontario (PI revised 08/2000) reviewed 01/2001.
  1. Product Information: Foradil® Aerolizer™, formoterol. Novartis, East Hanover, NJ (PI revised 09/2001) reviewed 12/2001.
  1. Product Information: Foradil® Aerolizer™, formoterol. Novartis, Dorval, Quebec, Canada (PI revised 01/04/2001) reviewed 12/2001.
  1. Expert Committee comment, 3/2002.
  1. Expert Committee comment, 3/2002.
  1. Expert Committee comment, 3/2002.
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