Oxeze (Formoterol)

OXEZE® TURBUHALER®

Astra

Formoterol Fumarate Dihydrate

Bronchodilator

Action And Clinical Pharmacology: Pharmacodynamics: Formoterol produces bronchodilation by stimulation of the b2-adrenergic receptors in bronchial smooth muscle, thereby causing relaxation of smooth muscle fibres.

Following inhalation of formoterol, a marked improvement in pulmonary function is observed within 1 to 3 minutes and lasts for a mean duration of 12 hours after a single dose.

Pharmacokinetics: Absorption: Inhaled formoterol is rapidly absorbed. Peak plasma concentration is reached about 15 minutes after inhalation.

In studies the mean lung deposition of formoterol after inhalation via Turbuhaler ranged from 21 to 37% of the metered dose. The total systemic availability for the higher lung deposition was approximately 46% of the metered dose.

Distribution and Metabolism: Plasma protein-binding is approximately 50%.

Formoterol is metabolized via direct glucuronidation and O-demethylation. The enzyme responsible for O-demethylation has not been identified. Total plasma clearance and volume of distribution has not been determined.

Elimination: The major part of the dose of formoterol is eliminated via metabolism. After inhalation 6 to 10% of the metered dose of formoterol is excreted unmetabolized in the urine. About 20% of an i.v. dose is excreted unchanged in the urine. The terminal half-life after inhalation is estimated to be 8 hours.

Indications And Clinical Uses: For long-term, twice daily (morning and evening) 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 regular 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., terbutaline or salbutamol) should be used.

Contra-Indications: Known hypersensitivity to formoterol or inhaled lactose. Like other sympathomimetic amines, formoterol should not be used in patients with tachyarrhythmias.

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

Use of Anti-inflammatory Agents: Patients should be receiving optimal anti-inflammatory therapy with corticosteroids before starting formoterol. 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 advised not to stop or reduce corticosteroid therapy without medical advice (see Precautions).

Treatment of Acute Symptoms: 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 and the Management of Asthma: The management of asthma should normally follow a stepwise programme, 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 significantly worsening or acutely deteriorating 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 be 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 Hypokalemic 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. Particular caution is advised in severe asthma as these effects may be potentiated by hypoxia and concomitant treatment with xanthine derivatives, steroids and diuretics. Hypokalemia will increase the susceptibility of digitalis patients to cardiac arrhythmias (see Precautions). It is recommended that serum potassium levels be monitored in such situations. Therefore, formoterol, like all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, arrhythmias and hypertension.

Other Diseases: Sympathomimetic bronchodilators should be administered cautiously to patients who are unusually responsive to sympathomimetic amines, e.g., in patients with hyperthyroidism not yet under adequate control. Since b2-agonists may increase the blood glucose level, additional blood glucose controls are recommended when asthmatic patients with concomitant diabetes are started on formoterol.

Paradoxical Bronchospasm: As with other inhaled asthma medication, the potential for paradoxical bronchospasm should be kept in mind. If it occurs, treatment with formoterol should be discontinued immediately and alternative therapy instituted.

Postmarketing Experience: The postmarketing experience with Oxeze Turbuhaler is limited. Postmarketing experience with other long-acting b2-agonists (formoterol and salmeterol) have reported serious exacerbations of asthma including some that have been fatal. In most cases, these have occurred in patients with severe asthma and/or in some patients whose asthma has been acutely deteriorating (see Acutely Deteriorating Asthma), but they have occurred in a few patients with less severe asthma as well. It was not possible from these reports to determine whether long-acting b2-agonists contributed to these events or simply failed to relieve the deteriorating asthma.

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 or increased in acutely deteriorating asthma, which is a potentially life-threatening condition. In patients with worsening asthma, there are no data demonstrating that long-acting b2-agonists provide greater efficacy than or additional efficacy to short-acting, inhaled b2-agonists. With other long-acting b2-agonists, serious acute respiratory events, including fatalities, have been reported, 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 introduction or increased use of a long-acting b2-agonist in patients with acutely deteriorating asthma is inappropriate.

Do not use formoterol as a substitute for oral or inhaled corticosteroids. Patients who require therapy with formoterol should also receive optimal anti-inflammatory therapy with corticosteroids. Patients must be advised to continue taking their anti-inflammatory therapy after the introduction of formoterol even when symptoms decrease. Any change in corticosteroid dosage should be made only after clinical evaluation.

Do not use formoterol to treat acute symptoms. Formoterol should only be used in patients requiring long-term regular bronchodilator therapy and not as an alternative to short-acting b2-agonists used on demand or in the event of an acute attack.

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., terbutaline or salbutamol) for treatment of symptoms that occur acutely, despite regular twice-daily use of formoterol.

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. Bronchodilators of the short-acting, adrenergic stimulant type may be used for relief of breakthrough symptoms while using formoterol. Asthma may deteriorate acutely over a period of hours or slowly over several days or longer. Should symptoms persist, or treatment with short-acting, inhaled b2-agonist become less effective or a patient needs more inhalations than usual, this indicates a worsening of the underlying condition and warrants reassessment of the treatment regimen and consideration given to increasing corticosteroid therapy. Increasing the daily dosage of formoterol in this situation is not appropriate. Patients requiring increasing doses or inhalations of short-acting b2-agonists for relief of symptoms should be advised to consult a physician for re-evaluation.

Do not exceed recommended dosage. Formoterol should not be used more frequently than twice daily 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 central nervous system is seen after the administration of formoterol at recommended doses, but the cardiovascular and central nervous system effects seen with all sympathomimetic drugs (e.g., increased heart rate, cardiac contractility, tremor) can occur while using formoterol. 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, severe hypertension, hypertrophic obstructive cardiomyopathy, thyrotoxicosis or severe heart failure.

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.

Caution should be observed when treating patients with known or suspected prolongation of the QTc-interval. Formoterol itself may induce prolongation of the QTc-interval.

Immediate Hypersensitivity Reactions: Immediate hypersensitivity reactions may occur after administration of formoterol. Oxeze Turbuhaler contains lactose (600 g/metered dose) and is contraindicated in patients with hypersensitivity to inhaled lactose or formoterol. The amount of lactose in Oxeze Turbuhaler does not normally cause problems in lactose intolerant people (see Contraindications).

Metabolic Effects: Due to the reversible hyperglycemic effect of b2-agonists, additional blood glucose monitoring is recommended initially in diabetic patients.

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

Lactation: Formoterol was found to be excreted in the milk of lactating rats after oral administration. Since there is no experience in the use of formoterol in nursing mothers, its use in such circumstances should only be considered if the expected benefit to the mother is greater than the risk to the infant.

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 labor should be restricted to those patients in whom the benefits clearly outweigh the risks.

Geriatrics: No adjustment of dose should be required in the elderly, or in patients with renal or hepatic impairment, at the recommended normal doses (see Cardiovascular and Other Medical Conditions and Warnings).

Children: Formoterol is not currently recommended for use in children younger than 12 years of age due to limited clinical data 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: b-Receptor Blocking Agents: b-receptor blocking agents, especially nonselective ones, may partly or totally inhibit the effect of b-stimulants.

Should a patient treated with formoterol also require concomitant treatment with a b-blocker, it is recommended that a b-blocker (e.g., metoprolol) with less predominant b2-blocking effects be considered. If concomitant treatment is necessary, patients should be monitored carefully for possible deterioration in pulmonary function and the need to adjust the dosage of either drug.

Xanthine Derivatives, Steroids and Diuretics: Concomitant treatment with xanthine derivatives, steroids or diuretics may potentiate a possible hypokalemic effect of b2-agonists. Hypokalemia may increase the disposition towards arrhythmias in patients who are treated with digitalis glycosides.

Other Drugs: Concomitant treatment with quinidine, disopyramide, procainamide, phenothiazines, antihistamines (terfenadine), MAO inhibitors and tricyclic antidepressants can prolong the QTc-interval and increase the risk of ventricular arrhythmias.

L-dopa, L-thyroxine, oxytocin and alcohol can impair cardiac tolerance towards b2-sympathomimetics.

Concomitant treatment with MAO inhibitors including agents with similar properties such as furazolidone and procarbazine may precipitate hypertensive reactions.

There is elevated risk of arrhythmias in patients receiving concomitant anesthesia with halogenated hydrocarbons.

Information to be Provided to the Patient: See Blue Section – Information for the Patient. It is important that patients understand how to use formoterol for oral inhalation and how it should be used in relation to other asthma medications they are taking. Patients should be given the following information:

The recommended dosage, as follows: Adults: The usual dose is 6 or 12 g, twice daily, at 12-hour intervals. Some adults may need 24 g, twice daily. The maximum daily dosage for adults, 48 g, should not be exceeded. Adolescent Children (12 to 16 years): The usual dose is 6 g, twice daily, at 12-hour intervals. Some children may need 12 g, twice daily. The maximum daily dosage for adolescent children, 24 g, 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 terbutaline or 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-agonist; need for more inhalations than usual of short-acting, inhaled b2-agonist.

Formoterol for oral inhalation should not be used as a substitute for oral or inhaled corticosteroids. Patients must be advised to continue taking their corticosteroid therapy after the introduction of formoterol even when symptoms decrease.

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

In patients receiving formoterol for oral inhalation, 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: Pharmacologically predictable side-effects of b2-agonist therapy, such as tremor and palpitations, may occur but tend to be transient and reduced with regular therapy. As with other inhalation therapy, paradoxical bronchospasm may occur in very rare cases. The following adverse reactions can be classified as common (i.e., frequency ³1% and
The clinical program conducted with formoterol, has involved more than 1 800 patients. The incidence of adverse events, irrespective of causality towards the drug, from 4 controlled trials (duration 1, 3, 3 and 6 months respectively) with formoterol

Symptoms And Treatment Of Overdose: Symptoms and Treatment: There is no clinical experience on the management of overdose. An overdose would likely lead to effects that are typical of b2-adrenergic agonists: tremor, headache, palpitations and tachycardia. Hypotension, metabolic acidosis, hypokalemia and hyperglycemia may also occur. Supportive and symptomatic treatment may be indicated.

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

Formoterol should only be used in patients requiring long-term regular bronchodilator therapy in addition to optimal corticosteroid therapy and not as an alternative to short-acting b-agonists used on demand or in the event of an acute attack.

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.

Fomoterol should not be used more frequently than twice daily with a 12-hour Interval between doses or at higher doses than recommended. 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 inhalations than usual, this may be a marker of destabilization of asthma. In this setting, the patient requires immediate reassessment of the treatment regimen. Increasing the daily dosage of formoterol in this situation is not appropriate (see Precautions).

Bronchodilators should not be the only or the main treatment in patients with moderate to severe or unstable asthma. Patients with severe asthma may require regular medical assessment. 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.

Since there may be serious adverse effects associated with excessive dosing, the dosage or frequency of administration should not be increased.

As a twice daily regular treatment, formoterol provides 24-hour bronchodilation and can replace regular use of a fast-acting, short-duration, inhaled bronchodilator (e.g., salbutamol or terbutaline), when used concurrently with corticosteroid therapy.

Dosage should be individualized and patient response should be monitored by the prescribing physician on an ongoing basis.

Long-term, Twice Daily Maintenance Therapy: The dose of formoterol should be individualized to the patient’s needs and should be the lowest possible dose that keeps the patient symptom-free or fulfills the therapeutic objective.

Adults: The normal dose is 6 or 12 g twice daily, at 12-hour intervals. Some patients may need 24 g twice daily. In adults, the maximum recommended daily dose is 48 g.

Adolescent Children (12 to 16 years): The normal dose is 6 g twice daily, at 12-hour intervals. Some patients may need 12 g twice daily. In adolescent children, the maximum recommended daily dose is 24 g.

In adolescent patients, the severity of asthma may be variable with age and periodic reassessment should be considered to identify the lowest dose required to maintain control and to determine if continued maintenance therapy with formoterol is still indicated (see Precautions).

Oxeze Turbuhaler is available in 2 strengths, 6 or 12 g/inhalation. Use of the higher strength is recommended for patients requiring 12 g or more, twice daily. Formoterol is not currently recommended for children younger than 12 years of age due to the limited clinical data in this age group.

It is important to instruct patients to avoid exhaling into the device and to always replace the cover after using Oxeze Turbuhaler.

Note: The medication from Oxeze Turbuhaler is delivered to the lungs as the patient inhales and, therefore, it is important to instruct the patient to breathe in forcefully and deeply through the mouthpiece. The patient may not taste or feel any medication when using Oxeze Turbuhaler due to the small amount of drug dispensed.

Availability And Storage: 6 g/metered dose: Each inhalation of a white to off-white or slightly yellow nonhygroscopic crystalline powder contains: formoterol fumarate dihydrate 6 g. Nonmedicinal ingredients: lactose monohydrate 600 g/metered dose (this amount does not normally cause problems in lactose-intolerant people). Turbuhalers of 60 doses with a light greenish-blue turning grip.

12 g/metered dose: Each inhalation of a white to off-white or slightly yellow nonhygroscopic crystalline powder contains: formoterol fumarate dihydrate 12 g. Nonmedicinal ingredients: lactose monohydrate 600 g/metered dose (this amount does not normally cause problems in lactose-intolerant people). Turbuhalers of 60 doses with a dark greenish-blue turning grip.

Oxeze Turbuhaler cannot be refilled and should be discarded when empty. Store at room temperature between 15 and 30°C with the cover tightened, away from moisture.

OXEZE® TURBUHALER® Astra Formoterol Fumarate Dihydrate Bronchodilator

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