Foradil (Formoterol Fumarate)

FORADIL®

Novartis Pharmaceuticals

Formoterol Fumarate

Bronchodilator

Action And Clinical Pharmacology: Formoterol is a potent selective long-acting (12 hours) b2-adrenergic stimulant. It exerts a bronchodilator effect in patients with reversible airways obstruction. The effect is seen within 1 to 3 minutes and is still significant 12 hours after inhalation.

Single dose studies have shown that formoterol is effective in preventing bronchospasm induced by allergen, exercise, cold air, histamine or methacholine challenge. The bronchoprotective effect of formoterol against methacholine provocation has been shown to persist for 12 hours.

In vitro, formoterol inhibits the release of histamine and leukotrienes from passively sensitized human lung. In humans, formoterol was more effective than salbutamol at suppressing late phase airway obstruction and increased airway responsiveness to allergen. The clinical significance of these findings is unclear because the long duration of action of formoterol may produce an apparent effect on late phase reactions due to functional antagonism.

Pharmacokinetics: As for other inhaled drugs, it is likely that 90% of formoterol administered from an inhaler is swallowed and absorbed from the gastrointestinal tract. Formoterol acts locally in the lung; plasma levels therefore do not predict therapeutic effect. Systemic levels of formoterol are low or undetectable after inhalation of recommended doses.

Indications And Clinical Uses: As long-term, twice-daily administration in the maintenance treatment of asthma in patients 12 years of age and older with reversible obstructive airways disease, including patients with symptoms of nocturnal asthma, who are using optimal corticosteroid treatment and experiencing regular or frequent breakthrough symptoms requiring use of a short-acting bronchodilator. Formoterol should not be used in patients whose asthma can be managed by occasional use of short-acting inhaled b2-agonists.

Corticosteroids should not be stopped because formoterol is prescribed.

Formoterol is a long-acting b2-agonist and should not be used as a rescue medication. To relieve acute asthmatic symptoms a short-acting inhaled bronchodilator (e.g., salbutamol) should be used.

Contra-Indications: Patients with cardiac tachyarrhythmias. Formoterol contains lactose (see Supplied) and is contraindicated in patients with an allergy to lactose, milk or in those who have ever had any unusual or allergic reaction to formoterol.

Manufacturers’ Warnings In Clinical States: Important Information: Formoterol should not be initiated in patients with significantly worsening or acutely deteriorating asthma (see Precautions).

Formoterol should not be used to treat acute symptoms. It is crucial to advise patients accordingly and prescribe a short-acting, inhaled bronchodilator for this purpose. Medical attention should be sought if patients find that short-acting relief bronchodilator treatment becomes less effective or that they need more inhalations than usual (see Precautions).

Formoterol is not a substitute for inhaled or oral corticosteroids. Its use is complementary to them. Corticosteroids should not be stopped when formoterol is initiated. Patients must be warned not to stop or reduce corticosteroid therapy without medical advice (see Precautions).

Formoterol and the Management of Asthma: The management of asthma should normally follow a stepwise program, with patient response monitored clinically and by lung function tests. Current asthma management guidelines recommend the following for long-acting b2-agonists: Oral or inhaled corticosteroids should not be stopped. Adequate education should be provided to the patient regarding the use of long-acting b2-agonists and the acute treatment of asthma, with close follow-up to ensure compliance. Long-acting b2-agonists should not be introduced in unstable asthma. Long-acting b2-agonists should never be used as rescue medication.

Increasing use of short-acting inhaled b2-agonists to control symptoms indicates deterioration of asthma control and the need to reassess the patient’s therapy.

Sudden or progressive deterioration in asthma control is potentially life-threatening; the treatment plan must be re-evaluated, and consideration given to increasing corticosteroid therapy. In patients at risk, daily peak flow monitoring with precise instructions for acceptable variation limits should be considered.

Cardiovascular and Other Nonpulmonary Effects: Potentially serious ECG changes (such as increased QTc interval) and hypokalemia may result from b2-agonist therapy. Although clinically not significant, a small increase in QTc interval and/or decrease in serum potassium has been reported at therapeutic doses of formoterol. The effects of single doses of formoterol at 12 to 96 µg were studied in 22 adult asthmatics, all of whom were receiving inhaled corticosteroids and an inhaled short-acting b2-agonist prior to entering the trial. The number of patients whose longest measured QTc in this trial was >440 msec was greater for placebo (3 patients) than it was for formoterol 12 µg (no patient), 24 µg (2 patients), and 48 µg (2 patients). Five patients treated with formoterol 96 µg showed QTc prolongations >440 msec. Six patients had clinically meaningful (K
Beta-adrenergic Blockers: Beta-adrenergic blockers, especially noncardioselective agents, should not be administered to asthmatic patients (see Precautions, Drug Interactions) since these antagonize the action of b2-agonists including formoterol and may produce severe, resistant bronchospasm.

Paradoxical Bronchospasm: As with other inhaled asthma medication, paradoxical bronchospasm (which can be life-threatening) has been reported following the use of formoterol. If it occurs, treatment with formoterol should be discontinued immediately and alternative therapy instituted.

Labor and Delivery: There are no well-controlled human studies that have investigated the effects of formoterol on preterm labor or labor at term. Because of the potential for b-agonist interference with uterine contractibility, use of b2-agonists, such as formoterol, during labour should be restricted to those patients in whom the benefits clearly outweigh the risks.

Postmarketing Experience: Fatalities, the exact cause of which is unknown, have been reported following excessive use of inhaler preparations containing sympathomimetic amines. In individual patients, any b2-agonist may have a clinically adverse cardiac effect. The incidence of mortality in patients receiving formoterol is consistent with that typically seen in the asthmatic population. In an open-label, uncontrolled study conducted in Europe an overall crude mortality rate of approximately 14/1 000 person years (8 of 1 393 patients followed for 4.8±2.6 months) was reported.

Precautions: Do not introduce formoterol as a treatment for acutely deteriorating asthma. Formoterol is intended for the maintenance treatment of asthma (see Indications) and should not be introduced in acutely deteriorating asthma, which is a potentially life threatening condition. There are no data demonstrating that long-acting b2-agonists provide greater efficacy than or additional efficacy to short-acting, inhaled b2-agonists in patients with worsening asthma. As with other long-acting b2-agonists, serious acute respiratory events, including fatalities, have been reported in patients receiving formoterol, some of which have occurred in patients with severe asthma and/or patients in whom asthma has been acutely deteriorating. Although it is not possible from these reports to determine the causal relationship between long-acting b2-agonists and these adverse events, the use of a long-acting b2-agonist in patients with acutely deteriorating asthma is inappropriate (see Warnings, Postmarketing Experience).

Do not use formoterol to treat acute symptoms. Formoterol should not be used to relieve acute asthma symptoms. When prescribing formoterol, the physician must also provide the patient with a short-acting, inhaled b2-agonist (e.g., salbutamol) for treatment of symptoms that occur acutely, despite regular twice-daily use of formoterol.

When beginning treatment with formoterol, patients who have been taking short-acting, inhaled b2-agonists on a regular basis (e.g., q.i.d.) should be instructed to discontinue the regular use of these drugs and use them only for symptomatic relief if they develop acute asthma symptoms while using formoterol (see Blue Section – Information for the Patient). Although formoterol has a rapid onset of action (1 to 3 minutes), current asthma management guidelines recommend that long-acting inhaled bronchodilators should be used only as twice-daily maintenance bronchodilator therapy.

Watch for increased need for short-acting, inhaled b2-agonists. Asthma may deteriorate acutely over a period of hours or chronically over several days or longer. If the patient’s short-acting inhaled b2-agonist becomes less effective or a patient needs more inhalation than usual, this may be a marker of destabilization of asthma. In this setting, the patient requires reassessment of the treatment regimen. Those patients who require increasing doses or inhalations of short-acting b2-agonists for relief of symptoms should consult a physician for re-evaluation. Increasing the daily dosage of formoterol in this situation is not appropriate. Formoterol should not be used more frequently than twice daily or at higher doses than recommended.

Do not use formoterol as a substitute for oral or inhaled corticosteroids. Patients must be warned not to stop or reduce corticosteroid therapy without medical advice, even if they feel better as a result of formoterol treatment.

Do not exceed recommended dosage. As with other inhaled b2-agonist drugs, formoterol should not be used more often or at higher doses than recommended. Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs (see below).

Cardiovascular and Other Medical Conditions: Usually no effect on the cardiovascular or CNS is seen after the administration of formoterol at recommended doses, but the cardiovascular and CNS effects seen with all sympathomimetic drugs (e.g., increased heart rate, cardiac contractility, tremor) can occur while using formoterol. Potentially serious ECG changes and hypokalemia were seen at increased doses (96 µg or 4 times the recommended maximum dose) of inhaled formoterol. Therefore, special care and supervision, with particular emphasis on dosage limits, is required in patients receiving formoterol when the following conditions may exist: ischemic heart disease, cardiac arrhythmias, especially third degree AV block, severe cardiac decompensation, idiopathic subvalvular aortic stenosis, hypertrophic obstructive cardiomyopathy, thyrotoxicosis, known or suspected prolongation of the QT-interval (QTc >0.44 seconds).

Use with caution in patients with idiopathic hypertrophic subvalvular aortic stenosis, in whom an increase in the pressure gradient between the left ventricle and the aorta may occur, causing increased strain on the left ventricle.

Immediate Hypersensitivity Reactions: Immediate hypersensitivity reactions may occur after administration of formoterol. Formoterol contains lactose and is contraindicated in patients with allergy to lactose, milk or in those who have ever had any unusual or allergic reaction for formoterol (see Contraindications).

Metabolic Effects: Due to the hyperglycemic effect of b2-stimulants, additional blood glucose controls are recommended in diabetic patients.

Pregnancy: The safety of formoterol during pregnancy has not yet been established (see Warnings, Labor and Delivery).

Lactation: Formoterol was found to be excreted in the milk of lactating rats after oral administration. It is not known whether inhaled formoterol passes into the breast milk in humans. Therefore, mothers nursing their infants should refrain from taking formoterol.

Labor and Delivery: See Warnings.

Geriatrics: No special considerations are required in elderly patients.

Children: Formoterol is not recommended for use in children younger than 12 years of age in the absence of further clinical trial experience in this age group.

Adolescent Patients and Asthma Severity Reassessment: In adolescent patients the severity of asthma may be variable with age and periodic reassessment should be considered to determine if continued maintenance therapy with formoterol is still indicated. Compliance, especially neglect of anti-inflammatory therapy and overuse of short-acting b2-agonists, should be carefully followed in adolescents receiving long-acting b2-agonists.

Drug Interactions: Short-acting b2-agonists: Aerosol bronchodilators of the short-acting adrenergic stimulant type may be used for relief of breakthrough symptoms while using formoterol. However, increasing use of such preparations to control symptoms indicates deterioration of asthma control and the need to reassess the patient’s therapy.

Concomitant administration of other sympathomimetic agents may potentiate the undesirable effects of formoterol.

MAO Inhibitors and Tricyclic Antidepressants: Formoterol should be administered with extreme caution in patients being treated with MAO inhibitors or tricyclic antidepressants because the action of formoterol on the cardiovascular system may be potentiated by these agents.

Corticosteroids, Methylxanthines and Diuretics: Concomitant treatment with xanthine derivatives, steroids, or diuretics may potentiate a possible hypokalemic effect of b2-agonists. Hypokalemia may increase susceptibility to cardiac arrhythmias in patients treated with digitalis.

b-adrenergic Blockers: b-adrenergic blockers may weaken or antagonise the effect of formoterol. Therefore formoterol should not be given together with b-adrenergic blockers (including eye drops) unless there are compelling reasons for their use.

Other Drugs: Drugs such as quinidine, disopyramide, procainamide, phenothiazines, antihistamines, and tricyclic antidepressants may be associated with QT-interval prolongation and an increased risk of ventricular arrhythmia (see Warnings).

The recommended dosage (1 or 2 capsules twice daily, morning and evening) should not be exceeded.

Formoterol is not meant to relieve acute asthma symptoms and extra doses should not be used for that purpose. Acute symptoms should be treated with a short-acting, inhaled b2-agonist such as salbutamol (the physician should provide the patient with such medication and instruct the patient in how it should be used).

The physician should be notified immediately if any of the following situations occur, which may be a sign of seriously worsening asthma: decreased effectiveness of short-acting, inhaled b2-agonists; need for more inhalations than usual of short-acting, inhaled b2-agonists.

Formoterol should not be used as a substitute for oral or inhaled corticosteroids. The dosage of these medications should not be changed and they should not be stopped without consulting the physician, even if the patient feels better after initiating treatment with formoterol.

Patients should be cautioned regarding potential adverse cardiovascular effects, such as palpitations or chest pain.

In patients receiving formoterol, other inhaled medications should be used only as directed by the physician.

Parents/guardians of adolescent children who have been prescribed formoterol should be alerted to the general concern regarding asthma therapy compliance, especially neglect of anti-inflammatory therapy and overuse of short-acting b2-agonists.

Adverse Reactions: The adverse reactions observed with formoterol in controlled, comparative and noncomparative clinical studies were dose-dependent and corresponded to those known to occur with other b2-adrenergic agonists.
The clinical trial program conducted with formoterol has involved over 6 000 patients.

Based on its worldwide use involving over 6 million of patient-treatment-months since first introduction onto the market in 1990, the adverse events profile of formoterol is in keeping with those observed in controlled clinical trials.

Isolated cases of the following adverse events have been reported through spontaneous reporting from those countries where the product is already marketed: hypersensitivity reactions such as severe hypotension, urticaria, angiodema, pruritus, exanthema. Peripheral edema, taste perversion, nausea.

Symptoms And Treatment Of Overdose: Symptoms: An overdosage of formoterol is likely to lead to effects that are typical of b2-adrenergic stimulants: nausea, vomiting, headache, tremor, somnolence, palpitations, tachycardia, ventricular arrhythmias, metabolic acidosis, hypokalemia, hyperglycemia.

Treatment: Supportive and symptomatic treatment is indicated. Serious cases should be hospitalized.

Use of cardioselective b-adrenergic blockers may be considered, but only subject to extreme caution since the use of b-adrenergic blocker medication may provoke bronchospasm.

Dosage And Administration: Formoterol should not be initiated in patients with significantly worsening or acutely deteriorating asthma, which may be a life-threatening condition (see Precautions).

Formoterol is not a replacement for inhaled or oral corticosteroid therapy; its use is complementary to it. Patients must be warned not to stop or reduce anti-inflammatory therapy without medical advice, even if they feel better on formoterol.

Formoterol should not be used to treat acute symptoms. It is crucial to inform patients of this and prescribe a short-acting, inhaled b2-agonist for this purpose. The need for additional symptomatic bronchodilator therapy is usually reduced with formoterol. Medical attention should be sought if patients find that short-acting relief bronchodilator treatment becomes less effective or if they need more inhalations than usual.

Bronchodilators should not be the only or main treatment in patients with moderate to severe asthma. Patients with severe asthma require regular medical assessment since death may occur. These patients will require high-dose inhaled or oral corticosteroid therapy. Sudden worsening of symptoms may require increased corticosteroids dosage which should be administered under medical supervision (see Precautions).

Long-term Maintenance Therapy: Adults: 1 capsule (12 µg) is inhaled using the Aerolizer inhaler twice daily, in the morning and evening. In severe cases, adults may require 2 capsules (2´12 µg) twice daily, in the morning and evening. In adults, the maximum recommended daily dose of formoterol is 48 µg.

Adolescent Children (12 to 16 years): 1 capsule (12 µg) is inhaled using the Aerolizer inhaler twice daily, in the morning and evening. A daily dose of 24 µg should not be exceeded. In adolescent patients the severity of asthma may be variable with age and periodic reassessment should be considered to determine if continued maintenance therapy with formoterol is still indicated (see Precautions).

If a previously effective dosage fails to provide the usual relief, medical advice should be sought immediately; this is a sign of seriously worsening asthma that requires reassessment of therapy. Formoterol should not be used more than twice daily with a 12-hour interval between doses.

Special Instructions: Only use formoterol capsules with the Aerolizer inhaler that is provided with each prescription refill. Do not use another type of inhaler with the capsules. Do not use other capsules in the Aerolizer inhaler.

Always use the new Aerolizer inhaler that is supplied with each prescription refill. To ensure proper administration of the drug, the physician or other health professional should show the patient how to operate the Aerolizer inhaler. Remove the capsules from the blister pack only immediately before use.

The emitted dose from 1 capsule when inhaled by the Aerolizer inhaler is 9.6 µg.

Availability And Storage: Each clear, hard gelatin capsule of white free flowing powder for inhalation only, contains: formoterol fumarate 12 µg. Use capsules only with the supplied Aerolizer inhalation device. Nonmedicinal ingredients: lactose. Cartons of 60 along with 1 Aerolizer inhalation device. Protect from heat (i.e., store between 15 to 25°C) and humidity.

FORADIL® Novartis Pharmaceuticals Formoterol Fumarate Bronchodilator

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